104 results on '"Peiqing Sun"'
Search Results
2. Supplementary Figures from Recruitment of KMT2C/MLL3 to DNA Damage Sites Mediates DNA Damage Responses and Regulates PARP Inhibitor Sensitivity in Cancer
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Peiqing Sun, Wei Zhang, Rong Xiang, Boris C. Pasche, W.J. Petty, Xiaoming Tan, Dongmei Cheng, Guanwen Wang, Juan Wang, Shan Huang, Stacey S. O'Neill, Yanan Chen, Dan Wu, Justin M. Ashby, Liang Liu, and Antao Chang
- Abstract
Supplementary Figures
- Published
- 2023
3. Supplementary Methods from Recruitment of KMT2C/MLL3 to DNA Damage Sites Mediates DNA Damage Responses and Regulates PARP Inhibitor Sensitivity in Cancer
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Peiqing Sun, Wei Zhang, Rong Xiang, Boris C. Pasche, W.J. Petty, Xiaoming Tan, Dongmei Cheng, Guanwen Wang, Juan Wang, Shan Huang, Stacey S. O'Neill, Yanan Chen, Dan Wu, Justin M. Ashby, Liang Liu, and Antao Chang
- Abstract
Supplementary Methods
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- 2023
4. Supplementary Tables from Recruitment of KMT2C/MLL3 to DNA Damage Sites Mediates DNA Damage Responses and Regulates PARP Inhibitor Sensitivity in Cancer
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Peiqing Sun, Wei Zhang, Rong Xiang, Boris C. Pasche, W.J. Petty, Xiaoming Tan, Dongmei Cheng, Guanwen Wang, Juan Wang, Shan Huang, Stacey S. O'Neill, Yanan Chen, Dan Wu, Justin M. Ashby, Liang Liu, and Antao Chang
- Abstract
Supplementary Tables
- Published
- 2023
5. Data from The miR-17-92 Cluster of MicroRNAs Confers Tumorigenicity by Inhibiting Oncogene-Induced Senescence
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Peiqing Sun, Jiahuai Han, Wen-Yuan Hu, Changchun Xiao, Young Jun Kang, Rong Liao, Changchuan Xie, Michelle Chen, Maoyi Lai, and Lixin Hong
- Abstract
In mammalian cells, activation of oncogenes usually triggers innate tumor-suppressing defense mechanisms, including apoptosis and senescence, which are compromised by additional mutations before cancers are developed. The miR-17-92 gene cluster, a polycistron encoding six microRNAs (miRNA), is frequently overexpressed in human cancers and has been shown to promote several aspects of oncogenic transformation, including evasion of apoptosis. In the current study, we show a new role of miR-17-92 in inhibiting oncogenic ras-induced senescence. Further dissection of the miRNA components in this cluster reveals that the miR-17/20a seed family accounts for this antisenescence activity. miR-17 and miR-20a are both necessary and sufficient for conferring resistance to ras-induced senescence by directly targeting p21WAF1, a key effector of senescence. By contrast, these components are not essential for the ability of miR-17-92 to evade Myc-induced apoptosis. Moreover, disruption of senescence by miR-17-92 or its miR-17/20a components leads to enhanced oncogenic transformation by activated ras in primary human cells. Taken together with previous reports that miR-17-92 inhibits apoptosis by suppressing Pten via the miR-19 components, our results indicate that this miRNA cluster promotes tumorigenesis by antagonizing both tumor-suppressing mechanisms, apoptosis, and senescence, through the activities of different miRNA components encoded in this cluster. Cancer Res; 70(21); 8547–57. ©2010 AACR.
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- 2023
6. Supplementary Figures 1-6 from The miR-17-92 Cluster of MicroRNAs Confers Tumorigenicity by Inhibiting Oncogene-Induced Senescence
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Peiqing Sun, Jiahuai Han, Wen-Yuan Hu, Changchun Xiao, Young Jun Kang, Rong Liao, Changchuan Xie, Michelle Chen, Maoyi Lai, and Lixin Hong
- Abstract
Supplementary Figures 1-6 from The miR-17-92 Cluster of MicroRNAs Confers Tumorigenicity by Inhibiting Oncogene-Induced Senescence
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- 2023
7. Peptide‐mediated Aqueous Synthesis of NIR‐II Emitting Ag 2 S Quantum Dots for Rapid Photocatalytic Bacteria Disinfection
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Peiqing Sun, Kunlun Li, Xiao Liu, Jing Wang, Xusheng Qiu, Wei Wei, and Jing Zhao
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General Chemistry ,General Medicine ,Catalysis - Published
- 2023
8. An unexpected all-metal aromatic tetranuclear silver cluster in human copper chaperone Atox1
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Xiuxiu Wang, Zong-Chang Han, Wei Wei, Hanshi Hu, Pengfei Li, Peiqing Sun, Xiangzhi Liu, Zhijia Lv, Feng Wang, Yi Cao, Zijian Guo, Jun Li, and Jing Zhao
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General Chemistry - Abstract
Metal clusters, such as iron-sulfur clusters, play key roles in sustaining life and are intimately involved in the functions of metalloproteins. Herein we report the formation and crystal structure of a planar square tetranuclear silver cluster when silver ions were mixed with human copper chaperone Atox1. Quantum chemical studies reveal that two Ag 5s
- Published
- 2022
9. A pan-cancer interrogation of intronic polyadenylation and its association with cancer characteristics
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Liang Liu, Peiqing Sun, and Wei Zhang
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mRNA cleavage and polyadenylation is an integral 2-step process in the generation of protein-encoding mRNA or noncoding transcripts. More than 60% of human genes have multiple polyadenylation sites either in the 3’ untranslated region (3’UTR-APA) or in the intronic/exonic region, resulting in expression of isoforms with alternative polyadenylation (APA) under different physiologic conditions. The 3’UTR-APAs have been extensively studied, but the biology of intronic polyadenylations (IPA) remain largely unexplored. Here we characterized the IPA profiles of 9,679 patient samples across 32 cancer types from the Cancer Genome Atlas (TCGA) cohort. Overall, we identified 22,260 detectable IPA sites; 9,014 (40.5%) occurred in all 32 cancer types and 11,676 (52.5%) occurred in 2 to 31 cancer types. By comparing tumors and their paired normal tissues, we identified 180 to 4,645 dysregulated IPAs in 132 to 2,249 genes in each of 690 patient tumors from 22 cancer types that showed consistent patterns within individual cancer types. Furthermore, across all cancer types, IPA isoforms and their gene regulation showed consistent pan-cancer patterns, and cancer types with similar histologic features were clustered at higher levels of hierarchy. We selected 2,741 genes that were consistently regulated by IPAs across cancer types, including 1,834 pan-cancer tumor-enriched and 907 tumor-depleted IPA genes. Pan-cancer tumor-enriched IPA genes were amply represented in the functional pathways such as cilium assembly and DNA damage repair. Expression of IPA isoforms in DNA damage repair genes was associated with tumor mutation burdens. Expression of IPA isoforms of tumor-enriched IPA genes was also associated with patient characteristics (e.g., sex, race, cancer stages, and subtypes) in cancer-specific and feature-specific manners. Importantly, IPA isoform expression for some genes could be a more accurate prognostic marker than gene expression (summary of all possible isoforms). In summary, our study reveals the roles and the clinical relevance of tumor-associated IPAs in cancer.
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- 2022
10. A broadband and polarization-independent metasurface perfect absorber for hot-electron photoconversion
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Qinyu Qian, Peiqing Sun, Cheng Zhang, Tingting Liu, Haitao Chen, Fan Li, Liwen Cheng, Liang Zhao, Xiaofeng Li, and Chinhua Wang
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General Materials Science - Abstract
We report an ultra-broadband metasurface perfect absorber from the UV to NIR region based on TiN nanostructures. A polarization-independent experimental average absorption of 0.900 (0.921 in simulation) at the wavelength band from 300 nm to 1500 nm is realized with only an 82 nm-thick TiN layer with TiO
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- 2022
11. Recruitment of KMT2C/MLL3 to DNA Damage Sites Mediates DNA Damage Responses and Regulates PARP Inhibitor Sensitivity in Cancer
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Dan Wu, Dongmei Cheng, Shan Huang, Peiqing Sun, Juan Wang, Rong Xiang, Boris Pasche, Wei Zhang, Antao Chang, Guanwen Wang, Liang Liu, Stacey S O'Neill, Yanan Chen, Xiaoming Tan, William J. Petty, and Justin M. Ashby
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Methyltransferase ,DNA repair ,DNA damage ,Mice, Nude ,Apoptosis ,Poly(ADP-ribose) Polymerase Inhibitors ,medicine.disease_cause ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Homologous Recombination ,Cell Proliferation ,Mutation ,biology ,Promoter ,Prognosis ,Xenograft Model Antitumor Assays ,Chromatin ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Survival Rate ,030104 developmental biology ,Histone ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Argonaute Proteins ,PARP inhibitor ,biology.protein ,Cancer research ,Female ,DNA Damage - Abstract
When recruited to promoters, histone 3 lysine 4 (H3K4) methyltransferases KMT2 (KMT2A-D) activate transcription by opening chromatin through H3K4 methylation. Here, we report that KMT2 mutations occur frequently in non–small cell lung cancer (NSCLC) and are associated with high mutation loads and poor survival. KMT2C regulated DNA damage responses (DDR) through direct recruitment to DNA damage sites by Ago2 and small noncoding DNA damage response RNA, where it mediates H3K4 methylation, chromatin relaxation, secondary recruitment of DDR factors, and amplification of DDR signals along chromatin. Furthermore, by disrupting homologous recombination (HR)–mediated DNA repair, KMT2C/D mutations sensitized NSCLC to Poly(ADP-ribose) polymerase inhibitors (PARPi), whose efficacy is unclear in NSCLC due to low BRCA1/2 mutation rates. These results demonstrate a novel, transcription-independent role of KMT2C in DDR and identify high-frequency KMT2C/D mutations as much-needed biomarkers for PARPi therapies in NSCLC and other cancers with infrequent BRCA1/2 mutations. Significance: This study uncovers a critical role for KMT2C in DDR via direct recruitment to DNA damage sites, identifying high-frequency KMT2C/D mutations as biomarkers for response to PARP inhibition in cancer.
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- 2021
12. Protein expression alteration in hippocampus upon genetic repression of <scp>AMPKα</scp> isoforms
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Dan Wu, Tao Ma, Xueyan Zhou, Xin Wang, Peiqing Sun, Jingyun Lee, Wenzhong Yang, and Cristina M. Furdui
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Proteomics ,Gene isoform ,Chemistry ,Cognitive Neuroscience ,Protein subunit ,05 social sciences ,AMPK ,Mice, Transgenic ,Translation (biology) ,AMP-Activated Protein Kinases ,Hippocampus ,Article ,050105 experimental psychology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Heterotrimeric G protein ,Animals ,Protein Isoforms ,0501 psychology and cognitive sciences ,Signal transduction ,Protein kinase A ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The AMP-activated protein kinase (AMPK) is a molecular sensor to help maintain cellular energy homeostasis. AMPK is a heterotrimeric complex and its enzymatic catalytic subunit includes two isoforms: α1 and α2. Dysregulation of AMPK signaling is linked to neuronal diseases characterized with cognitive impairments. Emerging evidence also suggest isoform-specific roles of AMPK in the brain. AMPK regulates protein synthesis, which is critical for memory formation and neuronal plasticity. However, the consequence of altering AMPK activity on the translation of specific proteins in the brain is unknown. Here, we use unbiased mass spectrometry-based proteomics approach to analyze protein profile alterations in hippocampus and prefrontal cortex of transgenic mice in which the genes for the two AMPKα isoforms are conditionally deleted. The study revealed identities of proteins whose expression is sensitive to suppression of AMPKα1 and/or α2 isoform. These data may serve as a basis for future in-depth study. Elucidation of the functional relevance of the alteration of specific proteins could provide insights into identification of novel therapeutic targets for neuronal disorders characterized with AMPK signaling dysregulation and impaired cellular energy metabolism.
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- 2021
13. A novel isoform of ATOH8 promotes the metastasis of breast cancer by regulating RhoC
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Guanwen Wang, Shan Huang, Rong Xiang, Yanhua Liu, Wen Shi, Mengyao Xu, Yanan Chen, Miao Li, Qiong Wang, Shuang Yang, Peiqing Sun, Chongbiao Huang, Antao Chang, and Xiaoli Dong
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Gene isoform ,RhoC ,Cancer metastasis ,Breast Neoplasms ,Kaplan-Meier Estimate ,AcademicSubjects/SCI01180 ,Metastasis ,Mice ,Breast cancer ,breast cancer ,Breast cancer cell line ,Cell Line, Tumor ,Genetics ,Basic Helix-Loop-Helix Transcription Factors ,Medicine ,Gene silencing ,metastasis ,Animals ,Humans ,Protein Isoforms ,Neoplasm Invasiveness ,Breast ,Molecular Biology ,biology ,business.industry ,Cell Biology ,General Medicine ,Articles ,ATOH8 ,Middle Aged ,medicine.disease ,Prognosis ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,rhoC GTP-Binding Protein ,Cancer research ,biology.protein ,Female ,Breast cancer cells ,business - Abstract
Metastases are the main cause of cancer-related mortality in breast cancer. Although significant progress has been made in the field of tumor metastasis, the exact molecular mechanisms involved in tumor metastasis are still unclear. Here, we report that ATOH8-V1, a novel isoform of ATOH8, is highly expressed in breast cancer and is a negative prognostic indicator of survival for patients. Forced expression of ATOH8-V1 dramatically enhances, while silencing of ATOH8-V1 decreases the metastasis of breast cancer cell lines. Moreover, ATOH8-V1 directly binds to the RhoC promoter and stimulates the expression of RhoC, which in turn enhances the metastasis of breast cancer. Altogether, our data demonstrate that ATOH8-V1 is a novel pro-metastatic factor that enhances cancer metastasis, suggesting that ATOH8-V1 is a potential therapeutic target for treatment of metastatic cancers.
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- 2020
14. Jagged1-Notch1-deployed tumor perivascular niche promotes breast cancer stem cell phenotype through Zeb1
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Wenhao Wang, Zhaoyang Wang, Quansheng Zhang, Huimin Wei, Jianjun Li, Wei Sun, Wen Shi, Yang Ou, Zhen Zhang, Shuang Yang, Huimin Jiang, Hang Wang, Qiong Wang, Chen Zhou, and Peiqing Sun
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0301 basic medicine ,JAG1 ,Science ,General Physics and Astronomy ,Breast Neoplasms ,Tumor initiation ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Paracrine signalling ,Mice ,0302 clinical medicine ,Breast cancer ,Downregulation and upregulation ,Cancer stem cell ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Receptor, Notch1 ,skin and connective tissue diseases ,lcsh:Science ,Mice, Knockout ,Tumor microenvironment ,Mice, Inbred BALB C ,Multidisciplinary ,Cancer stem cells ,Zinc Finger E-box-Binding Homeobox 1 ,General Chemistry ,medicine.disease ,Vascular endothelial growth factor A ,030104 developmental biology ,Phenotype ,030220 oncology & carcinogenesis ,Cancer research ,Neoplastic Stem Cells ,Female ,lcsh:Q ,Jagged-1 Protein - Abstract
Zinc finger E-box binding homeobox 1 (Zeb1) has been demonstrated to participate in the acquisition of the properties of cancer stem cells (CSCs). However, it is largely unknown how signals from the tumor microenvironment (TME) contribute to aberrant Zeb1 expression. Here, we show that Zeb1 depletion suppresses stemness, colonization and the phenotypic plasticity of breast cancer. Moreover, we demonstrate that, with direct cell-cell contact, TME-derived endothelial cells provide the Notch ligand Jagged1 (Jag1) to neighboring breast CSCs, leading to Notch1-dependent upregulation of Zeb1. In turn, ectopic Zeb1 in tumor cells increases VEGFA production and reciprocally induces endothelial Jag1 in a paracrine manner. Depletion of Zeb1 disrupts this positive feedback loop in the tumor perivascular niche, which eventually lessens tumor initiation and progression in vivo and in vitro. In this work, we highlight that targeting the angiocrine Jag1-Notch1-Zeb1-VEGFA loop decreases breast cancer aggressiveness and thus enhances the efficacy of antiangiogenic therapy., The transcription factor Zeb1 is known to promote tumorigenesis and stemness in breast cancer. Here the authors show that tumor endothelial Jagged1 induces activation of Notch1 signaling and increases Zeb1 expression in neighboring breast cancer stem cells, promoting tumor aggressiveness.
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- 2020
15. TGFBR1*6A as a modifier of breast cancer risk and progression: advances and future prospects
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Kojo Agyemang, Allan M. Johansen, Grayson W. Barker, Michael J. Pennison, Kimberly Sheffield, Hugo Jimenez, Carl Blackman, Sambad Sharma, Patrick A. Fordjour, Ravi Singh, Katherine L. Cook, Hui-Kuan Lin, Wei Zhang, Hui-Wen Lo, Kounosuke Watabe, Peiqing Sun, Carl D. Langefeld, and Boris Pasche
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Oncology ,Pharmacology (medical) ,Radiology, Nuclear Medicine and imaging - Abstract
There is growing evidence that germline mutations in certain genes influence cancer susceptibility, tumor evolution, as well as clinical outcomes. Identification of a disease-causing genetic variant enables testing and diagnosis of at-risk individuals. For breast cancer, several genes such as BRCA1, BRCA2, PALB2, ATM, and CHEK2 act as high- to moderate-penetrance cancer susceptibility genes. Genotyping of these genes informs genetic risk assessment and counseling, as well as treatment and management decisions in the case of high-penetrance genes. TGFBR1*6A (rs11466445) is a common variant of the TGF-β receptor type I (TGFBR1) that has a global minor allelic frequency (MAF) of 0.051 according to the 1000 Genomes Project Consortium. It is emerging as a high frequency, low penetrance tumor susceptibility allele associated with increased cancer risk among several cancer types. The TGFBR1*6A allele has been associated with increased breast cancer risk in women, OR 1.15 (95% CI 1.01–1.31). Functionally, TGFBR1*6A promotes breast cancer cell proliferation, migration, and invasion through the regulation of the ERK pathway and Rho-GTP activation. This review discusses current findings on the genetic, functional, and mechanistic associations between TGFBR1*6A and breast cancer risk and proposes future directions as it relates to genetic association studies and mechanisms of action for tumor growth, metastasis, and immune suppression.
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- 2022
16. A Novel CDK4/6 and PARP Dual Inhibitor ZC-22 Effectively Suppresses Tumor Growth and Improves the Response to Cisplatin Treatment in Breast and Ovarian Cancer
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Chenchen Tian, Yufan Wei, Jianjun Li, Zhi Huang, Qiong Wang, Yingxue Lin, Xingping Lv, Yanan Chen, Yan Fan, Peiqing Sun, Rong Xiang, Antao Chang, and Shuang Yang
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Ovarian Neoplasms ,endocrine system ,endocrine system diseases ,Organic Chemistry ,breast cancer ,ovarian cancer ,ZC-22 ,PARP inhibitor ,CDK4/6 inhibitor ,Cyclin-Dependent Kinase 4 ,Antineoplastic Agents ,General Medicine ,Cyclin-Dependent Kinase 6 ,Carcinoma, Ovarian Epithelial ,Poly(ADP-ribose) Polymerase Inhibitors ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,Humans ,Female ,Physical and Theoretical Chemistry ,Cisplatin ,Neoplasm Recurrence, Local ,Molecular Biology ,Spectroscopy - Abstract
In recent years, three PARP inhibitors and three CDK4/6 inhibitors have been approved by the FDA for the treatment of recurrent ovarian cancer and advanced ER-positive breast cancer, respectively. However, the clinical benefits of the PARPi or CDK4/6i monotherapy are not as satisfied as expected and benefit only a fraction of patients. Current studies have shown therapeutic synergy for combinations of PARPi and CDK4/6i in breast and ovarian cancers with homologous recombination (HR) proficiency, which represents a new synthetic lethal strategy for treatment of these cancers regardless HR status. Thus, any compounds or strategies that can combine PARP and CDK4/6 inhibition will likely have great potential in improving clinic outcomes and in benefiting more patients. In this study, we developed a novel compound, ZC-22, that effectively inhibited both PARP and CDK4/6. This dual-targeting compound significantly inhibited breast and ovarian cancer cells by inducing cell cycle arrest and severe DNA damage both in vitro and in vivo. Interestingly, the efficacy of ZC-22 is even higher than the combination of PARPi Olaparib and CDK4/6i Abemaciclib in most breast and ovarian cancer cells, suggesting that it may be an effective alternative for the PARPi and CDK4/6i combination therapy. Moreover, ZC-22 sensitized breast and ovarian cancer cells to cisplatin treatment, a widely used chemotherapeutic agent. Altogether, our study has demonstrated the potency of a novel CDK4/6 and PARP dual inhibitor, which can potentially be developed into a monotherapy or combinatorial therapy with cisplatin for breast and ovarian cancer patients with HR proficiency.
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- 2022
17. Her2 promotes early dissemination of breast cancer by suppressing the p38 pathway through Skp2-mediated proteasomal degradation of Tpl2
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Guanwen Wang, Juan Wang, Antao Chang, Dongmei Cheng, Shan Huang, Dan Wu, Sherona Sirkisoon, Shuang Yang, Hui-Kuan Lin, Hui-Wen Lo, Rong Xiang, and Peiqing Sun
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Cancer Research ,Proteasome Endopeptidase Complex ,MAP Kinase Signaling System ,Receptor, ErbB-2 ,Primary Cell Culture ,Datasets as Topic ,Breast Neoplasms ,Mice, Transgenic ,p38 ,p38 Mitogen-Activated Protein Kinases ,Disease-Free Survival ,Article ,early dissemination ,Mice ,Mammary Glands, Animal ,Her2 ,Tpl2 ,breast cancer ,Cell Movement ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Genetics ,Animals ,Humans ,Breast ,Neoplasm Metastasis ,skin and connective tissue diseases ,Molecular Biology ,S-Phase Kinase-Associated Proteins ,Mammary Neoplasms, Experimental ,Epithelial Cells ,MAP Kinase Kinase Kinases ,Gene Expression Regulation, Neoplastic ,Proteolysis ,Female ,Skp2 - Abstract
While mechanisms for metastasis were extensively studied in cancer cells from patients with detectable tumors, pathways underlying metastatic dissemination from early lesions before primary tumors appear are poorly understood. Her2 promotes breast cancer early dissemination by suppressing p38, but how Her2 downregulates p38 is unclear. Here, we demonstrate that in early lesion breast cancer models, Her2 inhibits p38 by inducing Skp2 through Akt-mediated phosphorylation, which promotes ubiquitination and proteasomal degradation of Tpl2, a p38 MAP3K. The early disseminating cells are Her2+Skp2highTpl2lowp-p38lowE-cadherinlow in the MMTV-Her2 breast cancer model. In human breast carcinoma, high Skp2 and low Tpl2 expression are associated with the Her2+ status; Tpl2 expression positively correlates with that of activated p38; Skp2 expression negatively correlates with that of Tpl2 and activated p38. Moreover, the Her2-Akt-Skp2-Tpl2-p38 axis plays a key role in the disseminating phenotypes in early lesion breast cancer cells; inhibition of Tpl2 enhances early dissemination in vivo. These findings identify the Her2-Akt-Skp2-Tpl2-p38 cascade as a novel mechanism mediating breast cancer early dissemination and a potential target for novel therapies targeting early metastatic dissemination.
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- 2020
18. WIP1 promotes cancer stem cell properties by inhibiting p38 MAPK in NSCLC
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Shuang Yang, Kaiyuan Deng, Peiqing Sun, Liang Liu, Zhen Zhang, Rong Xiang, Jianjun Li, Xin Wang, Xiaoming Tan, and Yang Ou
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0301 basic medicine ,Cancer Research ,MAP Kinase Signaling System ,Population ,lcsh:Medicine ,Apoptosis ,p38 Mitogen-Activated Protein Kinases ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Hsp27 ,In vivo ,Cancer stem cell ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Phosphorylation ,education ,Transcription factor ,lcsh:QH301-705.5 ,education.field_of_study ,biology ,Chemistry ,Cancer stem cells ,lcsh:R ,Cancer ,medicine.disease ,respiratory tract diseases ,Gene Expression Regulation, Neoplastic ,Protein Phosphatase 2C ,030104 developmental biology ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Cancer research ,Neoplastic Stem Cells ,Heterografts ,Signal transduction ,Lung cancer ,Signal Transduction - Abstract
Cancer stem cells (CSCs) are a small population of stem cell-like cancer cells that can initiate tumors in vivo, and are the major source of cancer initiation, relapse, and drug resistance. We previously reported that the p38 MAPK, through its downstream effectors MK2 and HSP27, suppressed CSC properties by downregulating the expression of transcription factors that mediate stemness in non-small-cell lung cancer (NSCLC) cells, and that despite unaltered total expression of total p38 proteins, the levels of activated p38 were reduced in NSCLC tissues. However, the mechanism underlying the reduced levels of activated p38 in NSCLC is unknown. In this study, we identified WIP1, a p38 phosphatase frequently overexpressed in cancer, as a suppressor of p38 in a pathway that regulates CSC properties in NSCLC. Increased WIP1 expression correlated with reduced levels of activated p38, and with increased levels of a CSC marker in NSCLC tissues. Further investigation revealed that WIP1 promoted stemness-related protein expression and CSC properties by inhibiting p38 activity in NSCLC cells. WIP1 inhibitors are currently under development as anticancer drugs based on their ability to reactivate p53. We found that a WIP1 inhibitor suppressed stemness-related protein expression and CSC properties by activating p38 in NSCLC cells in vitro and in vivo. These studies have identified the WIP1–p38–MK2–HSP27 cascade as a novel signaling pathway that, when altered, promotes CSC properties in NSCLC development, and have defined novel mechanisms underlying the oncogenic activity of WIP1 and the anticancer efficacy of WIP1 inhibitors.
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- 2020
19. Novel CDKs inhibitors for the treatment of solid tumour by simultaneously regulating the cell cycle and transcription control
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Yi Shi, Yakun Ma, Yao Li, Yan Fan, Tianqi Wang, Cheng Wang, Peiqing Sun, Shengyong Yang, Kaiyuan Deng, Xin Wang, Zhi Huang, and Rong Xiang
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Transcription, Genetic ,Short Communication ,Cell ,Antineoplastic Agents ,RM1-950 ,01 natural sciences ,Mice ,Structure-Activity Relationship ,cdk4 ,Cyclin-dependent kinase ,Transcription (biology) ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,medicine ,Animals ,Humans ,cdk9 ,cancer ,Transcription control ,Protein Kinase Inhibitors ,Pharmacology ,Solid tumour ,Mice, Inbred BALB C ,biology ,010405 organic chemistry ,Kinase ,Chemistry ,Cell Cycle ,General Medicine ,Cell cycle ,Xenograft Model Antitumor Assays ,Cyclin-Dependent Kinases ,0104 chemical sciences ,Cell biology ,inhibitor ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,biology.protein ,Female ,Cyclin-dependent kinase 9 ,Therapeutics. Pharmacology ,Drug Screening Assays, Antitumor - Abstract
A novel series of cyclin-dependent kinases (CDKs) inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription, were synthesised. A systematic study of enzymatic and cellular assays led to the identification of compound X22 with a nanomolar potency against CDK4 and CDK9 and potent antiproliferative activities against a panel of tumour cell lines. X22 could induce cell cycle arrest and cell apoptosis in cancer cell lines. X22 dose-dependently inhibits signalling pathways downstream of CDKs in cancer cells. In vivo antitumor activity assays, oral administration of X22 led to significant tumour regression in mouse model without obvious toxicity. Superior anti-cancer efficacy in vitro and in vivo of X22 demonstrated combined depletion of cell cycle and transcriptional CDK all contributed to antitumor activity. Taken together, concomitant inhibition of cell cycle and transcriptional CDK activities provided valuable guide for further structural optimisation.
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- 2020
20. Seryl tRNA synthetase cooperates with POT1 to regulate telomere length and cellular senescence
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Li Yingxi, Rongcun Yang, Longlong Wang, Ze Liu, Jie Yan, Peiqing Sun, Xu Chen, Mei Cao, Yi Shi, Xiyang Li, Yuke Jiang, and Rong Xiang
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0301 basic medicine ,Senescence ,Cancer Research ,Telomerase ,lcsh:Medicine ,Biology ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cancer genomics ,Genetics ,Protein biosynthesis ,lcsh:QH301-705.5 ,chemistry.chemical_classification ,Aminoacyl tRNA synthetase ,lcsh:R ,Shelterin ,Cell biology ,Telomere ,030104 developmental biology ,Enzyme ,chemistry ,lcsh:Biology (General) ,Cytoplasm ,030220 oncology & carcinogenesis - Abstract
Deregulated telomere length is a causative factor in many physiological and pathological processes, including aging and cancer. Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length. However, it remains largely unknown whether and how aging-related stresses, such as deregulated protein homeostasis, impact telomere length. Here, we explored the possible roles of aminoacyl tRNA synthetases (AARSs), key enzymes catalyzing the first reactions in protein synthesis, in regulating telomere length and aging. We selected seryl tRNA synthetase (SerRS) since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis. In this study, we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells. In the nucleus, SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1. We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres, resulting in progressive telomere shortening. Our data suggested a possible molecular link between protein synthesis and telomere length control, the deregulation of which may be associated with aging and cancer.
- Published
- 2019
21. MZF1 mediates oncogene-induced senescence by promoting the transcription of p16
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Dan, Wu, Hua, Tan, Weijun, Su, Dongmei, Cheng, Guanwen, Wang, Juan, Wang, Ding A, Ma, George M, Dong, and Peiqing, Sun
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Mice, Knockout ,Mice ,Kruppel-Like Transcription Factors ,Animals ,Humans ,Oncogenes ,Cells, Cultured ,Cyclin-Dependent Kinase Inhibitor p16 ,Transcription Factors - Abstract
Oncogene induced senescence is a tumor suppressing defense mechanism, in which the cell cycle-dependent protein kinase (CDK) inhibitor p16
- Published
- 2021
22. TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers
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Angelina T. Regua, Grace L. Wong, Austin Arrigo, Sara Abu Jalboush, Jiayuh Lin, Alexandra Thomas, Jimmy Ruiz, Roy E. Strowd, Sara G. Manore, Daniel Doheny, Yang Yu, Noah R. Aguayo, Dongqin Zhu, Calvin J. Wagner, Guangxu Jin, Peiqing Sun, Michael D. Chan, and Hui-Wen Lo
- Subjects
0301 basic medicine ,cancer stem cells ,Cancer Research ,animal structures ,SOX2 ,MYC ,Tropomyosin receptor kinase A ,Biology ,Article ,STAT3 ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,breast cancer ,Cancer stem cell ,hemic and lymphatic diseases ,medicine ,skin and connective tissue diseases ,RC254-282 ,Kinase ,TrkA ,food and beverages ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,030104 developmental biology ,Oncology ,nervous system ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Signal transduction ,Stem cell - Abstract
JAK2–STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers, however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining–confocal microscopy and immunoprecipitation–Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA–STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA–STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes, SOX2 and MYC. The co-activation of both pathways promotes breast cancer stem cells. Finally, we found that TNBC and HER2-enriched breast cancer with JAK2–STAT3 and TrkA co-activation are positively associated with poor overall metastasis-free and organ-specific metastasis-free survival. Collectively, our study uncovered that TrkA is a novel activating kinase of STAT3, and their co-activation enhances gene transcription and promotes breast cancer stem cells in TNBC and HER2-enriched breast cancer.
- Published
- 2021
23. Ca2+ and CACNA1H mediate targeted suppression of breast cancer brain metastasis by AM RF EMF
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Kerui Wu, Yin Liu, Peiqing Sun, Alexandra Thomas, Sambad Sharma, Christopher T. Whitlow, Hugo Jimenez, Linda J. Metheny-Barlow, Carl Blackman, Michael D. Chan, Hui-Wen Lo, Kounosuke Watabe, Ralph B. D'Agostino, Volker Kirchner, Shih-Ying Wu, Dan Zhao, Alexandre Barbault, Dongqin Zhu, Fei Xing, J.D. Bourland, Abhishek Tyagi, and Boris Pasche
- Subjects
0301 basic medicine ,business.industry ,medicine.medical_treatment ,Cancer ,General Medicine ,medicine.disease ,Metastatic breast cancer ,General Biochemistry, Genetics and Molecular Biology ,3. Good health ,Radiation therapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,Cancer stem cell ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Medicine ,business ,Triple-negative breast cancer ,Brain metastasis - Abstract
Background Brain metastases are a major cause of death in patients with metastatic breast cancer. While surgical resection and radiation therapy are effective treatment modalities, the majority of patients will succumb from disease progression. We have developed a novel therapy for brain metastases that delivers athermal radiofrequency electromagnetic fields that are amplitude-modulated at breast cancer specific frequencies (BCF). Methods 27.12 MHz amplitude-modulated BCF were administered to a patient with a breast cancer brain metastasis by placing a spoon-shaped antenna on the anterior part of the tongue for three one-hour treatments every day. In preclinical models, a BCF dose, equivalent to that delivered to the patient's brain, was administered to animals implanted with either brain metastasis patient derived xenografts (PDXs) or brain-tropic cell lines. We also examined the efficacy of combining radiation therapy with BCF treatment. Additionally, the mechanistic underpinnings associated with cancer inhibition was identified using an agnostic approach. Findings Animal studies demonstrated a significant decrease in growth and metastases of brain-tropic cell lines. Moreover, BCF treatment of PDXs established from patients with brain metastases showed strong suppression of their growth ability. Importantly, BCF treatment led to significant and durable regression of brain metastasis of a patient with triple negative breast cancer. The tumour inhibitory effect was mediated by Ca2+ influx in cancer cells through CACNA1H T-type voltage-gated calcium channels, which, acting as the cellular antenna for BCF, activated CAMKII/p38 MAPK signalling and inhibited cancer stem cells through suppression of β-catenin/HMGA2 signalling. Furthermore, BCF treatment downregulated exosomal miR-1246 level, which in turn decreased angiogenesis in brain environment. Therefore, targeted growth inhibition of breast cancer metastases was achieved through CACNA1H. Interpretation We demonstrate that BCF, as a single agent or in combination with radiation, is a novel treatment approach to the treatment of brain metastases. This paradigm shifting modality warrants further clinical trials for this unmet medical need.
- Published
- 2019
24. Ca2+ and CACNA1H mediate targeted suppression of breast cancer brain metastasis by AM RF EMFResearch in context
- Author
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Sambad Sharma, Shih-Ying Wu, Hugo Jimenez, Fei Xing, Dongqin Zhu, Yin Liu, Kerui Wu, Abhishek Tyagi, Dan Zhao, Hui-Wen Lo, Linda Metheny-Barlow, Peiqing Sun, John D. Bourland, Michael D. Chan, Alexandra Thomas, Alexandre Barbault, Ralph B. D'Agostino, Christopher T. Whitlow, Volker Kirchner, Carl Blackman, Boris Pasche, and Kounosuke Watabe
- Subjects
lcsh:R5-920 ,lcsh:R ,lcsh:Medicine ,lcsh:Medicine (General) - Abstract
Background: Brain metastases are a major cause of death in patients with metastatic breast cancer. While surgical resection and radiation therapy are effective treatment modalities, the majority of patients will succumb from disease progression. We have developed a novel therapy for brain metastases that delivers athermal radiofrequency electromagnetic fields that are amplitude-modulated at breast cancer specific frequencies (BCF). Methods: 27.12 MHz amplitude-modulated BCF were administered to a patient with a breast cancer brain metastasis by placing a spoon-shaped antenna on the anterior part of the tongue for three one-hour treatments every day. In preclinical models, a BCF dose, equivalent to that delivered to the patient's brain, was administered to animals implanted with either brain metastasis patient derived xenografts (PDXs) or brain-tropic cell lines. We also examined the efficacy of combining radiation therapy with BCF treatment. Additionally, the mechanistic underpinnings associated with cancer inhibition was identified using an agnostic approach. Findings: Animal studies demonstrated a significant decrease in growth and metastases of brain-tropic cell lines. Moreover, BCF treatment of PDXs established from patients with brain metastases showed strong suppression of their growth ability. Importantly, BCF treatment led to significant and durable regression of brain metastasis of a patient with triple negative breast cancer. The tumour inhibitory effect was mediated by Ca2+ influx in cancer cells through CACNA1H T-type voltage-gated calcium channels, which, acting as the cellular antenna for BCF, activated CAMKII/p38 MAPK signalling and inhibited cancer stem cells through suppression of β-catenin/HMGA2 signalling. Furthermore, BCF treatment downregulated exosomal miR-1246 level, which in turn decreased angiogenesis in brain environment. Therefore, targeted growth inhibition of breast cancer metastases was achieved through CACNA1H. Interpretation: We demonstrate that BCF, as a single agent or in combination with radiation, is a novel treatment approach to the treatment of brain metastases. This paradigm shifting modality warrants further clinical trials for this unmet medical need. Keywords: Breast Cancer, Brain metastasis, Electromagnetic field, Radiofrequency, Calcium, Novel therapeutics, Cav3.2 T-type channel, Exosomes, Radiation, miRNA, Angiogenesis
- Published
- 2019
25. Pan-cancer analysis on microRNA-associated gene activation
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Xiaohua Qian, Xiaobo Zhou, Peiqing Sun, Zhigang Zhang, Shan Huang, and Hua Tan
- Subjects
Transcriptional Activation ,0301 basic medicine ,Research paper ,Biology ,medicine.disease_cause ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Super-enhancer ,Genes, Reporter ,Neoplasms ,microRNA ,Gene expression ,medicine ,Humans ,RNA, Messenger ,Gene ,Genetics ,Regulation of gene expression ,Three prime untranslated region ,Gene Expression Profiling ,Computational Biology ,General Medicine ,Argonaute ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Enhancer Elements, Genetic ,030104 developmental biology ,030220 oncology & carcinogenesis ,RNA Interference ,Carcinogenesis - Abstract
Background While microRNAs (miRNAs) were widely considered to repress target genes at mRNA and/or protein levels, emerging evidence from in vitro experiments has shown that miRNAs can also activate gene expression in particular contexts. However, this counterintuitive observation has rarely been reported or interpreted in in vivo conditions. Methods We systematically explored the positive correlation between miRNA and gene expressions and its potential implications in tumorigenesis, based on 8375 patient samples across 31 major human cancers from The Cancer Genome Atlas (TCGA). Findings We found that positive miRNA-gene correlations are surprisingly prevalent and consistent across cancer types, and show distinct patterns than negative correlations. The top-ranked positive correlations are significantly involved in the immune cell differentiation and cell membrane signaling related processes, and display strong power in stratifying patients in terms of survival rate. Although intragenic miRNAs generally tend to co-express with their host genes, a substantial portion of miRNAs shows no obvious correlation with their host gene plausibly due to non-conservation. A miRNA can upregulate a gene by inhibiting its upstream suppressor, or shares transcription factors with that gene, both leading to positive correlation. The miRNA/gene sites associated with the top-ranked positive correlations are more likely to form super-enhancers compared to randomly chosen pairs. Wet-lab experiments revealed that positive correlations partially remain in in vitro condition. Interpretation Our study brings new insights into the critical role of miRNA in gene regulation and the complex mechanisms underlying miRNA functions, and reveals both biological and clinical significance of miRNA-associated gene activation.
- Published
- 2019
26. Pan-cancer analysis on microRNA-associated gene activationResearch in context
- Author
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Hua Tan, Shan Huang, Zhigang Zhang, Xiaohua Qian, Peiqing Sun, and Xiaobo Zhou
- Subjects
lcsh:R5-920 ,lcsh:R ,lcsh:Medicine ,lcsh:Medicine (General) - Abstract
Background: While microRNAs (miRNAs) were widely considered to repress target genes at mRNA and/or protein levels, emerging evidence from in vitro experiments has shown that miRNAs can also activate gene expression in particular contexts. However, this counterintuitive observation has rarely been reported or interpreted in in vivo conditions. Methods: We systematically explored the positive correlation between miRNA and gene expressions and its potential implications in tumorigenesis, based on 8375 patient samples across 31 major human cancers from The Cancer Genome Atlas (TCGA). Findings: We found that positive miRNA-gene correlations are surprisingly prevalent and consistent across cancer types, and show distinct patterns than negative correlations. The top-ranked positive correlations are significantly involved in the immune cell differentiation and cell membrane signaling related processes, and display strong power in stratifying patients in terms of survival rate. Although intragenic miRNAs generally tend to co-express with their host genes, a substantial portion of miRNAs shows no obvious correlation with their host gene plausibly due to non-conservation. A miRNA can upregulate a gene by inhibiting its upstream suppressor, or shares transcription factors with that gene, both leading to positive correlation. The miRNA/gene sites associated with the top-ranked positive correlations are more likely to form super-enhancers compared to randomly chosen pairs. Wet-lab experiments revealed that positive correlations partially remain in in vitro condition. Interpretation: Our study brings new insights into the critical role of miRNA in gene regulation and the complex mechanisms underlying miRNA functions, and reveals both biological and clinical significance of miRNA-associated gene activation. Keywords: Pan-cancer miRNA, miRNA activation, Intragenic miRNA, Super-enhancer
- Published
- 2019
27. Dissecting intratumoral myeloid cell plasticity by single cell RNA‐seq
- Author
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Leonard Wudel, Kounosuke Watabe, Gregory A. Hawkins, Liang Liu, Lance D. Miller, Guangxu Jin, Umit Topaloglu, Peiqing Sun, Ashok K. Pullikuth, Stacey S O'Neill, Boris Pasche, Edward A. Levine, Yong Lu, Elizabeth Forbes, Ping Chieh Chou, Qianqian Song, Wei Zhang, Lou Craddock, Martha A. Alexander-Miller, and Gregory L. Kucera
- Subjects
0301 basic medicine ,Cancer Research ,Myeloid ,Cell Plasticity ,Cell ,Biology ,lcsh:RC254-282 ,single‐cell RNA sequencing (scRNA‐seq) ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,Tumor Microenvironment ,medicine ,Humans ,intercellular interaction ,non‐small cell lung cancer (NSCLC) ,Myeloid Cells ,Radiology, Nuclear Medicine and imaging ,RNA-Seq ,Transcription factor ,Original Research ,Cancer Biology ,monocyte‐to‐M2 differentiation ,Tumor microenvironment ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Phenotype ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,trajectory analysis ,Tumor necrosis factor alpha ,Reprogramming ,Signal Transduction - Abstract
Tumor‐infiltrating myeloid cells are the most abundant leukocyte population within tumors. Molecular cues from the tumor microenvironment promote the differentiation of immature myeloid cells toward an immunosuppressive phenotype. However, the in situ dynamics of the transcriptional reprogramming underlying this process are poorly understood. Therefore, we applied single cell RNA‐seq (scRNA‐seq) to computationally investigate the cellular composition and transcriptional dynamics of tumor and adjacent normal tissues from 4 early‐stage non‐small cell lung cancer (NSCLC) patients. Our scRNA‐seq analyses identified 11 485 cells that varied in identity and gene expression traits between normal and tumor tissues. Among these, myeloid cell populations exhibited the most diverse changes between tumor and normal tissues, consistent with tumor‐mediated reprogramming. Through trajectory analysis, we identified a differentiation path from CD14+ monocytes to M2 macrophages (monocyte‐to‐M2). This differentiation path was reproducible across patients, accompanied by increased expression of genes (eg, MRC1/CD206, MSR1/CD204, PPARG, TREM2) with significantly enriched functions (Oxidative phosphorylation and P53 pathway) and decreased expression of genes (eg, CXCL2, IL1B) with significantly enriched functions (TNF‐α signaling via NF‐κB and inflammatory response). Our analysis further identified a co‐regulatory network implicating upstream transcription factors (JUN, NFKBIA) in monocyte‐to‐M2 differentiation, and activated ligand‐receptor interactions (eg, SFTPA1‐TLR2, ICAM1‐ITGAM) suggesting intratumoral mechanisms whereby epithelial cells stimulate monocyte‐to‐M2 differentiation. Overall, our study identified the prevalent monocyte‐to‐M2 differentiation in NSCLC, accompanied by an intricate transcriptional reprogramming mediated by specific transcriptional activators and intercellular crosstalk involving ligand‐receptor interactions.
- Published
- 2019
28. Exosomal MiR-1290 Promotes Angiogenesis of Hepatocellular Carcinoma via Targeting SMEK1
- Author
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Huimin Jiang, Hang Wang, Shaorong Zhao, Lianjie Niu, Zhen Zhang, Qiong Wang, Rong Xiang, Shuang Yang, Quansheng Zhang, Jianjun Li, Peiqing Sun, Antao Chang, and Guanwen Wang
- Subjects
0301 basic medicine ,Article Subject ,Angiogenesis ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Microvesicles ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,microRNA ,medicine ,Cancer research ,Phosphorylation ,business ,Exosomal secretion ,Function (biology) ,RC254-282 ,Blood vessel ,Research Article - Abstract
Hepatocellular carcinoma (HCC), the most common primary liver cancer, relies on the formation of new blood vessel for growth and frequent intrahepatic and extrahepatic metastasis. Therefore, it is important to explore the underlying molecular mechanisms of tumor angiogenesis of HCC. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, the potential roles of tumor-derived exosomal microRNAs in regulating tumor angiogenesis remain to be elucidated. In this study, our miRNome sequencing demonstrated that miR-1290 was overexpressed in HCC patient serum-derived exosomes, and we found that delivery of miR-1290 into human endothelial cells enhanced their angiogenic ability. Our results further revealed that SMEK1 is a direct target of miR-1290 in endothelial cells. MiR-1290 exerted its proangiogenic function, at least in part, by alleviating the inhibition of VEGFR2 phosphorylation done by SMEK1. Collectively, our findings provide evidence that miR-1290 is overexpressed in HCC and promotes tumor angiogenesis via exosomal secretion, implicating its potential role as a therapeutic target for HCC.
- Published
- 2021
29. Exosomal miR-1290 promotes angiogenesis in hepatocellular carcinoma via targeting SMEK1
- Author
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Qiong Wang, Guanwen Wang, Lianjie Niu, Shaorong Zhao, Jianjun Li, Zhen Zhang, Huimin Jiang, Quansheng Zhang, Hang Wang, Peiqing Sun, Rong Xiang, Antao Chang, and Shuang Yang
- Abstract
Background: Hepatocellular carcinoma (HCC), the most common primary liver cancer, rely on the formation of new blood vessel for growth and frequent intrahepatic and extrahepatic metastasis. Therefore, it is important to explore the underlying molecular mechanisms of tumor angiogenesis of HCC. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, the potential roles of tumor-derived exosomal microRNAs in regulating tumor angiogenesis remain to be elucidated. Methods: MiRNome sequencing was performed to uncover the miRNAs that are dysregulated in HCC patient serum-derived exosomes. Expression levels of miR-1290 in tissues and cells were determined by quantitative real-time PCR. The effect of mir-1290 on proliferation was evaluated by CCK-8 assay. The angiogenic ability of cells were determined by transwell, wound-healing, tube formation and matrigel plug assays. SMMC-7721 xenograft tumor model was established in NOD-SCID nude mice using miR-1290 and NC antagomirs to determin the angiogenic effect of mir-1290 in vivo. Target protein expression was determined by western blotting. Dual luciferase reporter assay was performed to confirm the action of miR-1290 on downstream target genes including SMEK1. Results are reported as means ± S.D. and differences were tested for significance using 2-sided Student’s t-test.Results: In this study, our miRNome sequencing demonstrated that miR-1290 was overexpressed in HCC patient serum-derived exosomes, and we found that delivery of miR-1290 into human endothelial cells enhanced their angiogenic ability. Our results further revealed that SMEK1 is a direct target of miR-1290 in endothelial cells. MiR-1290 exerted its pro-angiogenic function, at least in part, by alleviating the inhibition of VEGFR2 phosphorylation done by SMEK1. Conclusions: Collectively, our findings provide evidence that miR-1290 is overexpressed in HCC and promotes tumor angiogenesis via exosomal secretion, implicating its potential role as a therapeutic target for HCC.
- Published
- 2020
30. miRactDB characterizes miRNA–gene relation switch between normal and cancer tissues across pan-cancer
- Author
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Xiaobo Zhou, Hua Tan, Peiqing Sun, and Pora Kim
- Subjects
Carcinogenesis ,Genomics ,MiRNA binding ,Computational biology ,Biology ,medicine.disease_cause ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,microRNA ,medicine ,Coding region ,Humans ,Epigenetics ,Promoter Regions, Genetic ,Molecular Biology ,Gene ,030304 developmental biology ,0303 health sciences ,Binding Sites ,Cancer ,medicine.disease ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030220 oncology & carcinogenesis ,Problem Solving Protocol ,Information Systems - Abstract
It has been increasingly accepted that microRNA (miRNA) can both activate and suppress gene expression, directly or indirectly, under particular circumstances. Yet, a systematic study on the switch in their interaction pattern between activation and suppression and between normal and cancer conditions based on multi-omics evidences is not available. We built miRactDB, a database for miRNA–gene interaction, at https://ccsm.uth.edu/miRactDB, to provide a versatile resource and platform for annotation and interpretation of miRNA–gene relations. We conducted a comprehensive investigation on miRNA–gene interactions and their biological implications across tissue types in both tumour and normal conditions, based on TCGA, CCLE and GTEx databases. We particularly explored the genetic and epigenetic mechanisms potentially contributing to the positive correlation, including identification of miRNA binding sites in the gene coding sequence (CDS) and promoter regions of partner genes. Integrative analysis based on this resource revealed that top-ranked genes derived from TCGA tumour and adjacent normal samples share an overwhelming part of biological processes, which are quite different than those from CCLE and GTEx. The most active miRNAs predicted to target CDS and promoter regions are largely overlapped. These findings corroborate that adjacent normal tissues might have undergone significant molecular transformations towards oncogenesis before phenotypic and histological change; and there probably exists a small yet critical set of miRNAs that profoundly influence various cancer hallmark processes. miRactDB provides a unique resource for the cancer and genomics communities to screen, prioritize and rationalize their candidates of miRNA–gene interactions, in both normal and cancer scenarios.
- Published
- 2020
31. Her2 promotes early dissemination of breast cancer by suppressing the p38-MK2-Hsp27 pathway that is targetable by Wip1 inhibition
- Author
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Dongmei Cheng, Dan Wu, Xiaoming Tan, Shan Huang, Peiqing Sun, Qiong Wang, Rong Xiang, Shaorong Zhao, Antao Chang, Juan Wang, Guanwen Wang, Shuang Yang, and Andy T Liu
- Subjects
0301 basic medicine ,Cancer Research ,Pyridines ,Receptor, ErbB-2 ,Wip1 ,Aminopyridines ,Metastasis ,Mitogen-Activated Protein Kinase 14 ,Mice ,0302 clinical medicine ,Neoplasm Metastasis ,Phosphorylation ,Hsp27 ,skin and connective tissue diseases ,Heat-Shock Proteins ,Imidazoles ,Intracellular Signaling Peptides and Proteins ,Dipeptides ,Protein Phosphatase 2C ,030220 oncology & carcinogenesis ,Female ,Proto-oncogene tyrosine-protein kinase Src ,MAP Kinase Signaling System ,p38 mitogen-activated protein kinases ,Antineoplastic Agents ,Breast Neoplasms ,Biology ,Protein Serine-Threonine Kinases ,Heterocyclic Compounds, 4 or More Rings ,Article ,MK2 ,early dissemination ,03 medical and health sciences ,Breast cancer ,Cell Line, Tumor ,Genetics ,Carcinoma ,medicine ,Animals ,Humans ,Molecular Biology ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Her2+ breast cancer ,Cancer cell ,Cancer research ,biology.protein ,Molecular Chaperones - Abstract
Cancer can metastasize from early lesions without detectable tumors. Despite extensive studies on metastasis in cancer cells from patients with detectable primary tumors, mechanisms for early metastatic dissemination are poorly understood. Her2 promotes breast cancer early dissemination by inhibiting p38, but the downstream pathway in this process was unknown. Using early lesion breast cancer models, we demonstrate that the effect of p38 suppression by Her2 on early dissemination is mediated by MK2 and heat shock protein 27 (Hsp27). The early disseminating cells in the MMTV-Her2 breast cancer model are Her2highp-p38lowp-MK2lowp-Hsp27low, which also exist in human breast carcinoma tissues. Suppression of p38 and MK2 by Her2 reduces MK2-mediated Hsp27 phosphorylation, and unphosphorylated Hsp27 binds to β-catenin and enhances its phosphorylation by Src, leading to β-catenin activation and disseminating phenotypes in early lesion breast cancer cells. Pharmacological inhibition of MK2 promotes, while inhibition of a p38 phosphatase Wip1 suppresses, early dissemination in vivo. These findings identify Her2-mediated suppression of the p38-MK2-Hsp27 pathway as a novel mechanism for cancer early dissemination, and provide a basis for new therapies targeting early metastatic dissemination in Her2+ breast cancer.
- Published
- 2020
32. MGAT3-mediated glycosylation of tetraspanin CD82 at asparagine 157 suppresses ovarian cancer metastasis by inhibiting the integrin signaling pathway
- Author
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Peiqing Sun, Xiaoyue Tan, Thomas Braun, Poonam Kumari, Jun Li, Alessandro Ianni, Luhan Li, Rong Xiang, Jiawen Xu, Shijing Yue, and Shuo Liu
- Subjects
0301 basic medicine ,Integrins ,Glycosylation ,Tetraspanins ,Integrin ,Medicine (miscellaneous) ,Exosomes ,Kangai-1 Protein ,N-Acetylglucosaminyltransferases ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Tetraspanin ,Ovarian cancer ,Cell Line, Tumor ,CD82 ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Cell adhesion ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Integrin Signaling Pathway ,Ovarian Neoplasms ,biology ,Cell Membrane ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,carbohydrates (lipids) ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,lipids (amino acids, peptides, and proteins) ,Female ,Asparagine ,Signal Transduction ,Research Paper - Abstract
Background: Tetraspanins constitute a family of transmembrane spanning proteins that function mainly by organizing the plasma membrane into micro-domains. CD82, a member of tetraspanins, is a potent inhibitor of cancer metastasis in numerous malignancies. CD82 is a highly glycosylated protein, however, it is still unknown whether and how this post-translational modification affects CD82 function and cancer metastasis. Methods: The glycosylation of CD82 profiles are checked in the paired human ovarian primary and metastatic cancer tissues. The functional studies on the various glycosylation sites of CD82 are performed in vitro and in vivo. Results: We demonstrate that CD82 glycosylation at Asn157 is necessary for CD82-mediated inhibition of ovarian cancer cells migration and metastasis in vitro and in vivo. Mechanistically, we discover that CD82 glycosylation is pivotal to disrupt integrin α5β1-mediated cellular adhesion to the abundant extracellular matrix protein fibronectin. Thereby the glycosylated CD82 inhibits the integrin signaling pathway responsible for the induction of the cytoskeleton rearrangements required for cellular migration. Furthermore, we reveal that the glycosyltransferase MGAT3 is responsible for CD82 glycosylation in ovarian cancer cells. Metastatic ovarian cancers express reduced levels of MGAT3 which in turn may result in impaired CD82 glycosylation. Conclusions: Our work implicates a pathway for ovarian cancers metastasis regulation via MGAT3 mediated glycosylation of tetraspanin CD82 at asparagine 157.
- Published
- 2020
33. CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism
- Author
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Zhaoyang Wang, Qiong Wang, Guang Yang, Quansheng Zhang, Yang Ou, Jianjun Li, Shuang Yang, Hang Wang, Peiqing Sun, Kaiyuan Deng, Wenhao Wang, Zhen Zhang, and Wei Sun
- Subjects
0301 basic medicine ,Adult ,Cancer Research ,Epithelial-Mesenchymal Transition ,lcsh:Medicine ,Article ,Disease-Free Survival ,Deubiquitinating enzyme ,Metastasis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Breast cancer ,Neoplasms ,Genetics ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,lcsh:QH301-705.5 ,Transcription factor ,biology ,lcsh:R ,Ubiquitination ,Cancer ,Cyclin-Dependent Kinase 4 ,Zinc Finger E-box-Binding Homeobox 1 ,Cyclin-Dependent Kinase 6 ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Homeobox ,Phosphorylation ,Heterografts ,Epigenetics ,Female ,Ubiquitin-Specific Proteases ,CDK4/6 Inhibition - Abstract
Tumor metastasis is the most common cause of cancer-related deaths, yet it remains poorly understood. The transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) is involved in the epithelial-to-mesenchymal transition (EMT) and plays a pivotal role in tumor metastasis. However, the underlying mechanisms of the posttranslational modification of ZEB1 remain largely unknown. Herein, we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in vivo. Mechanistically, we determined that the deubiquitinase USP51 is a bona fide target of CDK4/6. The phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ZEB1. Moreover, we found a strong positive correlation between the expression of p-RB (an indicator of CDK4/6 activity), p-USP51 and ZEB1 in metastatic human breast cancer samples. Notably, the high expression of p-RB, p-USP51, and ZEB1 was significantly correlated with a poor clinical outcome. Taken together, our results provide evidence that the CDK4/6-USP51-ZEB1 axis plays a key role in breast cancer metastasis and could be a viable therapeutic target for the treatment of advanced human cancers.
- Published
- 2019
34. miR-30 Disrupts Senescence and Promotes Cancer by Targeting both p16INK4A and DNA Damage Pathways
- Author
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Jiahuai Han, Xin Xu, Peiqing Sun, Weijun Su, Lixin Hong, Yingxi Xu, Shan Huang, Rong Xiang, Changchun Xiao, Wen-Yuan Hu, Wei Zhang, Denise Herpai, Lan Truong, Xiaohua Wu, Lisheng Li, and Waldemar Debinski
- Subjects
0301 basic medicine ,Senescence ,p53 ,Cancer Research ,DNA damage ,Mice, Transgenic ,Chromatin remodeling ,Article ,03 medical and health sciences ,Mice ,Cell Line, Tumor ,microRNA ,Genetics ,Animals ,Humans ,Molecular Biology ,Cellular Senescence ,Cyclin-Dependent Kinase Inhibitor p16 ,Regulation of gene expression ,biology ,oncogene-induced senescence ,Cell biology ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Histone ,p16INK4A ,Cell Transformation, Neoplastic ,biology.protein ,Signal transduction ,DNA damage responses ,Genetic screen ,DNA Damage - Abstract
miR-30 is a microRNA frequently overexpressed in human cancers. However, the biological consequence of miR-30 overexpression in cancer has been unclear. In a genetic screen, miR-30 was found to abrogate oncogenic-induced senescence, a key tumor-suppressing mechanism that involves DNA damage responses, activation of p53 and induction of p16INK4A. In cells and mouse models, miR-30 disrupts senescence and promotes cancer by suppressing 2 targets, CHD7 and TNRC6A. We show that while CHD7 is a transcriptional coactivator essential for induction of p16INK4A in senescent cells, TNRC6A, a miRNA machinery component, is required for expression and functionality of DNA damage response RNAs (DDRNAs) that mediate DNA damage responses and p53 activation by orchestrating histone modifications, chromatin remodeling and recruitment of DNA damage factors at damaged sites. Thus, miR-30 inhibits both p16INK4A and p53, 2 key senescence effectors, leading to efficient senescence disruption. These findings have identified novel signaling pathways mediating oncogene-induced senescence and tumor-suppression, and revealed the molecular and cellular mechanisms underlying the oncogenic activity of miR-30. Thus, the miR-30/CHD7/TNRC6A pathway is potentially a novel diagnostic biomarker and therapeutic target for cancer.
- Published
- 2018
35. ZEB1 confers chemotherapeutic resistance to breast cancer by activating ATM
- Author
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Xiang Zhang, Shuang Yang, Peiqing Sun, Rong Xiang, Zhen Zhang, Quansheng Zhang, Qing Zhang, and Guosheng Ren
- Subjects
0301 basic medicine ,Cancer Research ,Immunology ,Mice, Nude ,Breast Neoplasms ,Ataxia Telangiectasia Mutated Proteins ,Pharmacology ,Article ,Metastasis ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Cyclin D1 ,Breast cancer ,Nude mouse ,Cell Line, Tumor ,medicine ,Animals ,Humans ,lcsh:QH573-671 ,Epirubicin ,Mice, Inbred BALB C ,Antibiotics, Antineoplastic ,biology ,Kinase ,business.industry ,lcsh:Cytology ,DNA Breaks ,Zinc Finger E-box-Binding Homeobox 1 ,Cancer ,Cell Biology ,medicine.disease ,biology.organism_classification ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Cancer research ,Heterografts ,Female ,Ectopic expression ,business ,medicine.drug - Abstract
Although zinc finger E-box binding homeobox 1 (ZEB1) has been identified as a key factor in the regulation of breast cancer differentiation and metastasis, its potential role in modulating tumor chemoresistance has not been fully understood. Here, through the study of specimens from a large cohort of human breast cancer subjects, we showed that patients with tumors that expressed high levels of ZEB1 responded poorly to chemotherapy. Moreover, ZEB1 expression was positively correlated with expression of B-cell lymphoma-extra large (Bcl-xL) and cyclin D1, which are key components of tumor chemoresistant mechanisms. At the molecular level, ectopic expression of ZEB1 impaired the responsiveness of breast cancer cells to genotoxic drug treatment, such as epirubicin (EPI). During this process, ZEB1 transcriptionally activated the expression of ataxia-telangiectasia mutated (ATM) kinase by forming a ZEB1/p300/PCAF complex on its promoter, leading to increased homologous recombination (HR)-mediated DNA damage repair and the clearance of DNA breaks. Using a nude mouse xenograft model, we further confirmed that ectopic expression of ZEB1 decreased breast cancer responsiveness to EPI treatment in vivo. Collectively, our findings suggest that ZEB1 is a crucial determinant of chemotherapeutic resistance in breast cancer.
- Published
- 2018
36. Inflammatory Human Umbilical Cord-Derived Mesenchymal Stem Cells Promote Stem Cell-Like Characteristics of Cancer Cells in an IL-1β-Dependent Manner
- Author
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Xiaohe Luo, Rong Xiang, Na Li, Yanan Chen, Ningning He, Yanhua Liu, Zongjin Li, Chen Liu, Shan Huang, Peiqing Sun, Weijun Su, and Xue Mi
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0301 basic medicine ,Tumor microenvironment ,Article Subject ,General Immunology and Microbiology ,medicine.medical_treatment ,lcsh:R ,Mesenchymal stem cell ,lcsh:Medicine ,General Medicine ,Biology ,Stem cell marker ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,03 medical and health sciences ,030104 developmental biology ,Cytokine ,Side population ,Cancer cell ,medicine ,Cancer research ,Stem cell - Abstract
To ensure the safety of clinical applications of MSCs, thorough understanding of their impacts on tumor initiation and progression is essential. Here, to further explore the complex dialog between MSCs and tumor cells, umbilical cord-derived mesenchymal stem cells (UC-MSCs) were employed to be cocultured with either breast or ovarian cancer cells. Though having no obvious influence on proliferation or apoptosis, UC-MSCs exerted intense stem cell-like properties promoting effects on both cancer models. Cocultured cancer cells showed enriched side population, enhanced sphere formation ability, and upregulated pluripotency-associated stem cell markers. Human cytokine array and real-time PCR revealed a panel of MSC-derived prostemness cytokines CCL2, CXCL1, IL-8, and IL-6 which were induced upon coculturing. We further revealed IL-1β, a well-characterized proinflammatory cytokine, to be the inducer of these prostemness cytokines, which was generated from inflammatory UC-MSCs in an autocrine manner. Additionally, with introduction of IL-1RA (an IL-1 receptor antagonist) into the coculturing system, the stem cell-like characteristics promoting effects of inflammatory UC-MSCs were partially blocked. Taken together, these findings suggest that transduced inflammatory MSCs work as a major source of IL-1β in tumor microenvironment and initiate the formation of prostemness niche via regulating their secretome in an IL-1β-dependent manner.
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- 2018
37. Abstract 1979: JAK2/STAT3 and TrkA pathways are frequently co-activated in triple-negative and HER2-enriched breast cancers and the co-activation correlates with an increased potential of metastasis
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Karen Baylon, Roy E. Strowd, Noah R. Aguayo, Sara G. Manore, Austin Arrigo, Jiayuh Lin, Calvin J. Wagner, Sara Abu Jalboush, Grace L. Wong, Daniel L. Doheny, Angelina T. Regua, Linda J. Metheny-Barlow, Jimmy Ruiz, Dongqin Zhu, Yang Yu, Alexandra Thomas, Peiqing Sun, Michael D. Chan, Hui-Wen Lo, and Guangxu Jin
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Cancer Research ,Oncology ,Chemistry ,Jak2 stat3 ,Cancer research ,medicine ,Tropomyosin receptor kinase A ,skin and connective tissue diseases ,medicine.disease ,Co activation ,Triple negative ,Metastasis - Abstract
Breast cancer is the leading cause of cancer-related deaths in American women. Despite the current standard-of-care, which implements tumor resection, radiotherapy, and chemotherapy, triple-negative and HER2-positive breast cancer patients often relapse and present with recurrent disease, for which there is no cure. Thus, there is an urgent need to identify new molecular targets to improve patient response to anti-cancer therapies. The JAK2-STAT3 and TrkA receptor tyrosine kinase signaling pathways have been separately implicated in metastatic breast cancers, but information about their crosstalk remains limited. Activated Janus kinase 2 (JAK2) receptor tyrosine kinase phosphorylates signal transducer and activator of transcription 3 (STAT3) transcription factor, inducing STAT3 nuclear translocation and transcriptional activity. Abnormal activation of STAT3-mediated transcription has been identified as a pro-tumorigenic event in breast cancers and promotes progression through induction of breast cancer stem cells, invasion, and angiogenesis. Tropomyosin receptor kinase A (TrkA) frequently forms oncogenic fusion proteins and its overexpression has been shown to drive malignant transformation of breast cancer cells. JAK2 inhibitors, while approved for treatment of myeloproliferative neoplasms, are currently in clinical trials for triple-negative breast cancers. Currently, there are two FDA-approved TrkA inhibitors for treatment of NTRK1 fusion-positive solid tumors, one of which is considered a tumor-agnostic inhibitor. However, whether these two important pathways are co-activated in breast cancers and whether the co-activation is associated with overall progression of breast cancer have not been investigated. Herein, we report that STAT3 and TrkA are more co-activated in triple-negative and HER2-enriched breast cancers, compared to luminal subtypes, as determined by immunohistochemical staining of 33 invasive breast carcinomas and datamining data of over 1,500 breast cancer patients. We also observed that high co-activation of both JAK2-STAT3 and TrkA pathways significantly shortens overall metastasis-free survival of both triple-negative and HER2-enriched breast cancer patients when compared to patients with low co-activation. Similarly, we also find that JAK2-STAT3 and TrkA co-activation also significantly shortens brain, lung, and bone metastasis-free survival in both of these breast cancer subtypes, suggesting a critical role for JAK2-STAT3 and TrkA in distant metastasis of aggressive breast cancers. Taken together, our findings indicate a novel signaling crosstalk between JAK2-STAT3 and TrkA pathways in triple-negative and HER2-enriched breast cancers, and the use of their co-activation as a prognostic indicator for metastatic breast cancers of both subtypes. Citation Format: Angelina T. Regua, Noah R. Aguayo, Sara Abu Jalboush, Daniel L. Doheny, Sara G. Manore, Dongqin Zhu, Grace L. Wong, Austin Arrigo, Calvin J. Wagner, Yang Yu, Karen Baylon, Alexandra Thomas, Michael D. Chan, Jimmy Ruiz, Guangxu Jin, Roy E. Strowd, Peiqing Sun, Linda J. Metheny-Barlow, Jiayuh Lin, Hui-Wen Lo. JAK2/STAT3 and TrkA pathways are frequently co-activated in triple-negative and HER2-enriched breast cancers and the co-activation correlates with an increased potential of metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1979.
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- 2021
38. ZEB1 confers stem cell-like properties in breast cancer by targeting neurogenin-3
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Rong Xiang, Shuang Yang, Chen Zhou, Hang Wang, Quansheng Zhang, Zhen Zhang, Peiqing Sun, Huimin Jiang, and Guomin Zhang
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0301 basic medicine ,tumor initiation ,endocrine system ,Tumor initiation ,digestive system ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,breast cancer ,Cancer stem cell ,Medicine ,Gene silencing ,ZEB1 ,neurogenin-3 ,Tumor microenvironment ,business.industry ,medicine.disease ,030104 developmental biology ,Oncology ,stemness properties ,030220 oncology & carcinogenesis ,Cancer cell ,Immunology ,Cancer research ,Ectopic expression ,Stem cell ,business ,Research Paper - Abstract
// Chen Zhou 1, * , Huimin Jiang 1, * , Zhen Zhang 1 , Guomin Zhang 1 , Hang Wang 1 , Quansheng Zhang 2 , Peiqing Sun 3 , Rong Xiang 1 and Shuang Yang 1 1 Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical School of Nankai University, Tianjin 300071, China 2 Tianjin Key Laboratory of Organ Transplantation, Tianjin First Center Hospital, Tianjin 300192, China 3 Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA * These authors have contributed equally to this work Correspondence to: Shuang Yang, email: yangshuang@nankai.edu.cn Keywords: breast cancer, neurogenin-3, stemness properties, tumor initiation, ZEB1 Received: December 29, 2016 Accepted: March 20, 2017 Published: April 13, 2017 ABSTRACT Cancer stem cells (CSCs) are a subpopulation of cancer cells believed to be implicated in cancer initiation, progression, and recurrence. Here, we report that ectopic expression of zinc finger E-box binding homeobox 1 protein (ZEB1) results in the acquisition of CSC properties by breast cancer cells, leading to tumor initiation and progression in vitro and in vivo . The neurogenin 3 gene ( Ngn3 ) is a bona fide target of ZEB1, and its repression is a key factor contributing to ZEB1-induced cancer cell stemness. ZEB1 suppressed Ngn3 transcription by forming a ZEB1/DNA methyltransferase (DNMT)3B/histone deacetylase 1 (HDAC1) complex on the Ngn3 promoter, leading to promoter hypermethylation and gene silencing. The rescue of Ngn3 expression attenuated ZEB1-induced cancer stemness and symmetric CSC division. Immunohistological analysis of human breast cancer specimens revealed a strong inverse relationship between ZEB1 and NGN3 protein expression. Thus, our findings suggest ZEB1-mediated silencing of Ngn3 is required for breast tumor initiation and maintenance. Targeted therapies against the ZEB1/Ngn3 axis may be highly valuable for the prevention and treatment of breast cancer.
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- 2017
39. Inactivation of p38 MAPK contributes to stem cell-like properties of non-small cell lung cancer
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Peiqing Sun, Weijun Su, Chen Zhou, Guanwen Wang, Juan Wang, Shaorong Zhao, Shuangtao Zhao, Shan Huang, Rong Xiang, Yan Fang, Pengling Jiang, Peng Wang, and Antao Chang
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Male ,0301 basic medicine ,Homeobox protein NANOG ,Proteasome Endopeptidase Complex ,Lung Neoplasms ,stemness markers ,p38 ,p38 Mitogen-Activated Protein Kinases ,MK2 ,Kruppel-Like Factor 4 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,SOX2 ,Cancer stem cell ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Phosphorylation ,Hsp27 ,Lung cancer ,Protein Stability ,business.industry ,SOXB1 Transcription Factors ,Cancer ,medicine.disease ,3. Good health ,Enzyme Activation ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,Cell Transformation, Neoplastic ,030104 developmental biology ,Oncology ,KLF4 ,030220 oncology & carcinogenesis ,Proteolysis ,Immunology ,Cancer cell ,Neoplastic Stem Cells ,Cancer research ,Heterografts ,lung cancer stem cells ,Stem cell ,business ,Biomarkers ,Research Paper - Abstract
// Yan Fang 1 , Juan Wang 1 , Guanwen Wang 1 , Chen Zhou 1 , Peng Wang 1 , Shuangtao Zhao 1 , Shaorong Zhao 1 , Shan Huang 2 , Weijun Su 1, 2 , Pengling Jiang 3 , Antao Chang 1, 2 , Rong Xiang 1 , Peiqing Sun 1, 2 1 Department of Immunology, School of Medicine, Nankai University, Tianjin, China 2 Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University Medical Center, Winston-Salem, North Carolina, USA 3 Key Laboratory of Cancer and Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China Correspondence to: Peiqing Sun, email: psun@wakehealth.edu Rong Xiang, email: rxiang@nankai.edu.cn Keywords: p38, Hsp27, MK2, stemness markers, lung cancer stem cells Received: November 15, 2016 Accepted: February 15, 2017 Published: March 01, 2017 ABSTRACT Cancer stem cells (CSCs) are recognized as the major source for cancer initiation and recurrence. Yet, the mechanism by which the cancer stem cell properties are acquired and maintained in a cancer cell population is not well understood. In the current study, we observed that the level of active p38 MAPK is downregulated, while the level of the stemness marker SOX2 is upregulated in lung cancer tissues as compared to normal tissues. We further demonstrated that inactivation of p38 is a potential mechanism contributing to acquisition and maintenance of cancer stem cell properties in non-small cell lung cancer (NSCLC) cells. p38, in particular the p38γ and p38δ isoforms, suppresses the cancer stem cell properties and tumor initiating ability of NSCLC cells by promoting the ubiquitylation and degradation of stemness proteins such as SOX2, Oct4, Nanog, Klf4 and c-Myc, through MK2-mediated phosphorylation of Hsp27 that is an essential component of the proteasomal degradation machinery. In contrast, inactivation of p38 in lung cancer cells leads to upregulation of the stemness proteins, thus promoting the cancer stem cell properties of these cells. These findings have demonstrated a novel mechanism by which cancer stem cell properties are acquired and maintained in a cancer cell population, and have revealed a new function of the p38 pathway in suppressing cancer development. These studies have also identified a new pathway that can potentially serve as a target for cancer therapies aimed at eliminating CSCs.
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- 2017
40. Liposomal Nanoparticles Carrying anti-IL6R Antibody to the Tumour Microenvironment Inhibit Metastasis in Two Molecular Subtypes of Breast Cancer Mouse Models
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Wenjuan Gao, Rong Xiang, Yunping Luo, Na Li, Peiqing Sun, Chunlei Guo, Yanan Chen, Shengyong Yang, Wenzhi Shen, Antao Chang, and Yujie Ye
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Pathology ,medicine.medical_specialty ,Lung Neoplasms ,anti-IL6R antibody ,Medicine (miscellaneous) ,Breast Neoplasms ,metastatic niche ,02 engineering and technology ,Antibodies ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,SOX2 ,Tumor Microenvironment ,medicine ,metastasis ,Animals ,Neoplasm Metastasis ,Lung ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Mice, Inbred BALB C ,Tumor microenvironment ,biology ,Chemistry ,CD44 ,Cancer ,liposomal nanoparticles ,021001 nanoscience & nanotechnology ,medicine.disease ,Receptors, Interleukin-6 ,Disease Models, Animal ,Hyaluronan Receptors ,Treatment Outcome ,030220 oncology & carcinogenesis ,Liposomes ,Cancer cell ,Cancer research ,biology.protein ,Nanoparticles ,Stem cell ,tumour microenvironment ,0210 nano-technology ,Research Paper - Abstract
Tumour microenvironment (TME) contributes significantly towards potentiating the stemness and metastasis properties of cancer cells. IL6-Stat3 is one of the important cell signaling pathways in mediating the communication between tumour and immune cells. Here, we have systematically developed a novel anti-CD44 antibody-mediated liposomal nanoparticle delivery system loaded with anti-IL6R antibody, which could specifically target the TME of CD44+ breast cancer cells in different mouse models for triple negative and luminal breast cancer. This nanoparticle had an enhanced and specific tumour targeting efficacy with dramatic anti-tumour metastasis effects in syngeneic BALB/c mice bearing 4T1 cells as was in the syngeneic MMTV-PyMT mice. It inhibited IL6R-Stat3 signaling and moderated the TME, characterized by the reduced expression of genes encoding Stat3, Sox2, VEGFA, MMP-9 and CD206 in the breast tissues. Furthermore, this nanoparticle reduced the subgroups of Sox2+ and CD206+ cells in the lung metastatic foci, demonstrating its inhibitory effect on the lung metastatic niche for breast cancer stem cells. Taken together, the CD44 targeted liposomal nanoparticles encapsulating anti-IL6R antibody achieved a significant effect to inhibit the metastasis of breast cancer in different molecular subtypes of breast cancer mouse models. Our results shed light on the application of nanoparticle mediated cancer immune-therapy through targeting TME.
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- 2017
41. miR-885-5p suppresses hepatocellular carcinoma metastasis and inhibits Wnt/β-catenin signaling pathway
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Chunyan Zhang, Peiqing Sun, Rong Xiang, Yunping Luo, Zhuhong Zhang, Hua Yan, Wenjun Mou, Jian Yang, Wenzhi Shen, Jinhua Luo, Jing Yin, and Yaping Tian
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0301 basic medicine ,Carcinoma, Hepatocellular ,Cirrhosis ,Wnt β catenin signaling ,Down-Regulation ,migration ,Wnt/β-catenin HCC ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,microRNA ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,miR-885-5p ,neoplasms ,Wnt Signaling Pathway ,Cell Proliferation ,Neoplasm Staging ,Traditional medicine ,business.industry ,Liver Neoplasms ,Wnt signaling pathway ,Prognosis ,invasion ,medicine.disease ,digestive system diseases ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cancer research ,Heterografts ,Signal transduction ,business ,Research Paper - Abstract
// Zhuhong Zhang 1, 3, 6 , Jing Yin 1 , Jian Yang 1 , Wenzhi Shen 1 , Chunyan Zhang 1, 2 , Wenjun Mou 1, 2 , Jinhua Luo 1, 2 , Hua Yan 3 , Peiqing Sun 4 , Yunping Luo 5 , Yaping Tian 2 , Rong Xiang 1 1 Department of Immunology, School of Medicine, Nankai University, Tianjin, 300071, China 2 Department of Clinical Biochemistry, Chinese PLA General Hospital, Beijing, 100853, China 3 Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, 300052, China 4 The Scripps Research Institute, La Jolla, CA, 92037, USA 5 Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100005, China 6 Current address: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079, USA Correspondence to: Rong Xiang, email: rxing@nankai.edu.cn Yaping Tian, email: tianyp@301hospital.com.cn , tianyp61@gmail.com Keywords: miR-885-5p, Wnt/β-catenin HCC, migration, invasion Received: June 14, 2016 Accepted: September 25, 2016 Published: October 12, 2016 ABSTRACT MicroRNAs (miRNAs) inhibit or improve the malignant progression of hepatocellular carcinoma (HCC). We previously reported that compared to health controls, patients with liver cirrhosis present the highest levels of circulating miR-885-5p, followed by those with chronic hepatitis B and those with HCC. However, the molecular involvement of miR-885-5p in HCC metastasis is presently unclear. Here, we demonstrated that the expression of miR-885-5p negatively correlated with the invasive and metastatic capabilities of human HCC tissue samples and cell lines. We found that miR-885-5p expression levels correlated with the survival of patients with HCC. Overexpression of miR-885-5p decreased metastasis of HCC cells in vitro and in vivo . Inhibition of miR-885-5p improved proliferation of non-metastatic HCC cells. Furthermore, we disclosed that miR-885-5p targeted gene encoding β-catenin CTNNB1 , leading to decreased activity of the Wnt/β-catenin signaling pathway. The present study indicates that miR-885-5p suppresses the metastasis of HCC and inhibits Wnt/β-catenin signaling pathway by its CTNNB1 target, which suggests that miR-885-5p to be a promising negative regulator of HCC progression and as a novel therapeutic agent to treat HCC.
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- 2016
42. Exosomal miR-1290 promotes angiogenesis in hepatocellular carcinoma via targeting SMEK1
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Qiong Wang, Guanwen Wang, Lianjie Niu, Shaorong Zhao, Jianjun Li, Zhen Zhang, Huimin Jiang, Quansheng Zhang, Hang Wang, Peiqing Sun, Shuang Yang, and Rong Xiang
- Abstract
Abstract Background: Hepatocellular carcinoma (HCC), the most common primary liver cancer, rely on the formation of new blood vessel for growth and frequent intrahepatic and extrahepatic metastasis. Therefore, it is important to explore the underlying molecular mechanisms of tumor angiogenesis of HCC. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, the potential roles of tumor-derived exosomal microRNAs in regulating tumor angiogenesis remain to be elucidated. Methods: MiRNome sequencing was performed to uncover the miRNAs that are dysregulated in HCC patient serum-derived exosomes. Expression levels of miR-1290 in tissues and cells were determined by quantitative real-time PCR. The effect of mir-1290 on proliferation was evaluated by CCK-8 assay. The angiogenic ability of cells were determined by transwell, wound-healing, tube formation and matrigel plug assays. SMMC-7721 xenograft tumor model was established in NOD-SCID nude mice using miR-1290 and NC antagomirs to determin the angiogenic effect of mir-1290 in vivo. Target protein expression was determined by western blotting. Dual luciferase reporter assay was performed to confirm the action of miR-1290 on downstream target genes including SMEK1. Results are reported as means ± S.D. and differences were tested for significance using 2-sided Student’s t-test. Results: In this study, our miRNome sequencing demonstrated that miR-1290 was overexpressed in HCC patient serum-derived exosomes, and we found that delivery of miR-1290 into human endothelial cells enhanced their angiogenic ability. Our results further revealed that SMEK1 is a direct target of miR-1290 in endothelial cells. MiR-1290 exerted its pro-angiogenic function, at least in part, by inhibiting the VEGFR2 signaling pathway in a SMEK1-dependent manner. Conclusions: Collectively, our findings provide evidence that miR-1290 is overexpressed in HCC and promotes tumor angiogenesis via exosomal secretion, implicating its potential role as a therapeutic target for HCC.
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- 2019
43. TGIF2 promotes the progression of lung adenocarcinoma by bridging EGFR/RAS/ERK signaling to cancer cell stemness
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Yanan Chen, Jun Li, Yunping Luo, Peiqing Sun, Wenzhi Shen, Shuangtao Zhao, Wenjuan Gao, Yi Liu, Renle Du, Yi Shi, Chong Chen, Wei Zhou, Rong Xiang, and Yanhua Liu
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0301 basic medicine ,Cancer Research ,lcsh:Medicine ,Cell fate determination ,Biology ,Article ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Cancer stem cell ,Genetics ,medicine ,Gene silencing ,Lung cancer ,lcsh:QH301-705.5 ,Cancer stem cells ,lcsh:R ,Oncogenes ,medicine.disease ,030104 developmental biology ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Adenocarcinoma ,Signal transduction - Abstract
TGF-β-induced factor homeobox 2 (TGIF2) is a transcription regulator that plays essential roles in the regulation of development and cell fate decisions. Aberrant expression of TGIF family proteins has been observed in several cancers, including ovarian, esophageal, and colorectal cancers. Here, we report that TGIF2 mediates the EGFR–RAS–ERK signaling pathway to enhance the stemness of lung adenocarcinoma (LUAD) cells and, therefore, promote the progression and metastasis of LUAD. We found that high TGIF2 expression was closely correlated with tumor growth, lymph node metastasis, and survival of patients with LUAD. Mice bearing TGIF2-silenced H1299 xenografts developed smaller tumors and fewer lung metastases. Importantly, silencing TGIF2 decreased the cancer stem cell (CSC)-like properties in A549 and H1299 cells. Furthermore, we identified that TGIF2 binding to the OCT4 promoter promotes its expression. In both LUAD cells and in vivo LUAD mouse models, we revealed that EGFR–RAS–ERK signaling phosphorylated TGIF2 and increased its stability, which was important for TGIF2-promoted LUAD stemness since phosphorylation-deficient TGIF2 mutants lost these functions. Thus, our study revealed that an important factor, TGIF2, bridges EGFR signaling to the CSC characteristics of LUAD cells, which can be utilized as an effective target for LUAD therapy.
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- 2019
44. Exosomal miR-451a Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Targeting LPIN1
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Shaorong Zhao, Guomin Zhang, Qiong Wang, Hang Wang, Peiqing Sun, Quansheng Zhang, Shuang Yang, Jianjun Li, Chao Wu, and Rong Xiang
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0301 basic medicine ,Carcinoma, Hepatocellular ,Physiology ,Angiogenesis ,Carcinogenesis ,Phosphatidate Phosphatase ,Apoptosis ,Biology ,medicine.disease_cause ,Exosomes ,lcsh:Physiology ,lcsh:Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Movement ,Cell Line, Tumor ,microRNA ,medicine ,Human Umbilical Vein Endothelial Cells ,Humans ,lcsh:QD415-436 ,Genes, Tumor Suppressor ,Tube formation ,lcsh:QP1-981 ,Liver Neoplasms ,Cell cycle ,digestive system diseases ,Microvesicles ,Endothelial stem cell ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Disease Progression - Abstract
Background/aims Emerging evidence suggests that exosomal microRNAs (miRNAs) mediate hepatoma progression through the post-translational regulation of their targets. However, characteristically-expressed miRNAs and their functions in the tumor and tumor-associated angiogenesis remain poorly understood. Methods miRNA sequencing (HiSeq 2500 SE50) was performed to identify miRNA species that are involved in the hepatocellular carcinoma (HCC) pathogenesis. We identified miR-451a downregulation according to its expression and TCGA analysis. miR-451a was found to be mainly involved in cell viability, apoptosis, cell cycle and migration both in HCC and endothelial cell lines. LPIN1 was predicted to be a target of this miRNA based on TargetScan, GSEA analysis, and the Uniprot database. We performed real time PCR and dual luciferase assays to confirm these results. Results We identified that miR-451a is significantly downregulated in serum-derived exosomes from HCC patients, as compared to expression in those from normal individuals. We further confirmed that overexpression of miR-451a functions in HCC and endothelia cells in vitro and in vivo. Exosomal miR-451a, as a tumor suppressor, was found to induce apoptosis both in HCC cell lines and human umbilical vein endothelial cells (HUVECs). In addition, miR-451a suppressed HUVEC migration, tube formation, and vascular permeability. Importantly, we demonstrated that LPIN1 is a critical target of miR-451a, and promotes apoptosis in both HCC and endothelial cells. Conclusion Our study provides the novel finding that exosomal miR-451a targets LPIN1 to inhibit hepatocellular tumorigenesis by regulating tumor cell apoptosis and angiogenesis. These results have clinical implications regarding the deregulation of miRNAs in HCC.
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- 2019
45. Ca
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Sambad, Sharma, Shih-Ying, Wu, Hugo, Jimenez, Fei, Xing, Dongqin, Zhu, Yin, Liu, Kerui, Wu, Abhishek, Tyagi, Dan, Zhao, Hui-Wen, Lo, Linda, Metheny-Barlow, Peiqing, Sun, John D, Bourland, Michael D, Chan, Alexandra, Thomas, Alexandre, Barbault, Ralph B, D'Agostino, Christopher T, Whitlow, Volker, Kirchner, Carl, Blackman, Boris, Pasche, and Kounosuke, Watabe
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Research paper ,Brain Neoplasms ,MAP Kinase Signaling System ,Gene Expression Profiling ,Magnetic Field Therapy ,HMGA2 Protein ,Breast Neoplasms ,Immunohistochemistry ,Models, Biological ,Calcium Channels, T-Type ,Disease Models, Animal ,Mice ,Electromagnetic Fields ,Cell Line, Tumor ,Neoplastic Stem Cells ,Animals ,Humans ,Calcium ,Female ,Cell Proliferation - Abstract
BACKGROUND: Brain metastases are a major cause of death in patients with metastatic breast cancer. While surgical resection and radiation therapy are effective treatment modalities, the majority of patients will succumb from disease progression. We have developed a novel therapy for brain metastases that delivers athermal radiofrequency electromagnetic fields that are amplitude-modulated at breast cancer specific frequencies (BCF). METHODS: 27.12 MHz amplitude-modulated BCF were administered to a patient with a breast cancer brain metastasis by placing a spoon-shaped antenna on the anterior part of the tongue for three one-hour treatments every day. In preclinical models, a BCF dose, equivalent to that delivered to the patient's brain, was administered to animals implanted with either brain metastasis patient derived xenografts (PDXs) or brain-tropic cell lines. We also examined the efficacy of combining radiation therapy with BCF treatment. Additionally, the mechanistic underpinnings associated with cancer inhibition was identified using an agnostic approach. FINDINGS: Animal studies demonstrated a significant decrease in growth and metastases of brain-tropic cell lines. Moreover, BCF treatment of PDXs established from patients with brain metastases showed strong suppression of their growth ability. Importantly, BCF treatment led to significant and durable regression of brain metastasis of a patient with triple negative breast cancer. The tumour inhibitory effect was mediated by Ca(2+) influx in cancer cells through CACNA1H T-type voltage-gated calcium channels, which, acting as the cellular antenna for BCF, activated CAMKII/p38 MAPK signalling and inhibited cancer stem cells through suppression of β-catenin/HMGA2 signalling. Furthermore, BCF treatment downregulated exosomal miR-1246 level, which in turn decreased angiogenesis in brain environment. Therefore, targeted growth inhibition of breast cancer metastases was achieved through CACNA1H. INTERPRETATION: We demonstrate that BCF, as a single agent or in combination with radiation, is a novel treatment approach to the treatment of brain metastases. This paradigm shifting modality warrants further clinical trials for this unmet medical need.
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- 2019
46. Integration of a Gold-Specific Whole
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Li, Yan, Peiqing, Sun, Yun, Xu, Shanbo, Zhang, Wei, Wei, and Jing, Zhao
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Salmonella typhimurium ,whole-cell bacterial biosensor ,Escherichia coli Proteins ,Communication ,red fluorescence protein ,Biosensing Techniques ,BioBrick ,Regulon ,Recombinant Proteins ,Luminescent Proteins ,Spectrometry, Fluorescence ,Genes, Reporter ,Limit of Detection ,Metals, Heavy ,gold detection ,Escherichia coli ,Humans ,Adsorption ,Gold ,Carrier Proteins ,Environmental Pollution ,Genetic Engineering ,Promoter Regions, Genetic ,Water Pollutants, Chemical ,gold adsorption - Abstract
Detection and recovery of heavy metals from environmental sources is a major task in environmental protection and governance. Based on previous research into cell-based visual detection and biological adsorption, we have developed a novel system combining these two functions by the BioBrick technique. The gold-specific sensory gol regulon was assembled on the gold-chaperone GolB (Gold-specific binding protein), which is responsible for selectively absorbing gold ions, and this led to an integration system with increased probe tolerance for gold. After being incorporated into E. coli, this system featured high-selective detection and recycling of gold ions among multi-metal ions from the environment. It serves as an efficient method for biological detection and recovery of various heavy metals. We have developed modular methods for cell-based detection and adsorption of heavy metals, and these offer a quick and convenient tool for development in this area.
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- 2018
47. Pan-cancer analysis on microRNA-mediated gene activation
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Xiaobo Zhou, Xiaohua Qian, Shan Huang, Zhigang Zhang, Hua Tan, and Peiqing Sun
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Genetics ,Regulation of gene expression ,0303 health sciences ,Biology ,medicine.disease_cause ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,030220 oncology & carcinogenesis ,microRNA ,Gene expression ,medicine ,Epigenetics ,Carcinogenesis ,Gene ,Transcription factor ,030304 developmental biology - Abstract
While microRNAs (miRNAs) were widely considered to repress target genes at mRNA and/or protein levels, emerging evidence from in vitro experiments has shown that miRNAs can also activate gene expression in particular contexts. However, this counterintuitive observation has rarely been reported or interpreted in in vivo conditions. We systematically explored the positive correlation between miRNA and gene expressions and its potential implications in tumorigenesis, based on 8375 patient samples across 31 major human cancers from The Cancer Genome Atlas (TCGA). Results indicated that positive miRNA-gene correlations are surprisingly prevalent and consistent across cancer types, and show distinct patterns than negative correlations. The top-ranked positive correlations are significantly involved in the immune cell differentiation and cell membrane signaling related processes, and display strong power in stratifying patients in terms of survival rate, demonstrating their promising clinical relevance. Although intragenic miRNAs generally tend to co-express with their host genes, a substantial portion of miRNAs shows no obvious correlation with their host gene due to non-conservation. A miRNA can upregulate a gene by inhibiting its upstream suppressor, or shares transcription factors with that gene, both leading to positive correlation. The miRNA/gene sites associated with the top-ranked positive correlations are more likely to form super-enhancers compared to randomly chosen pairs, suggesting a potential epigenetics mechanism underlying the upregulation. Wet-lab experiments revealed that positive correlations partially remain in the in vitro condition. Our study provides the field with new perspectives on the critical role of miRNA in gene regulation and novel insights regarding the complex mechanisms underlying miRNA functions, and reveals the clinical significance of the potential positive regulation of gene expression by miRNA.
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- 2018
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48. Correction to: Her2 promotes early dissemination of breast cancer by suppressing the p38 pathway through Skp2-mediated proteasomal degradation of Tpl2
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Juan Wang, Shan Huang, Peiqing Sun, Antao Chang, Hui Kuan Lin, Rong Xiang, Sherona Sirkisoon, Hui-Wen Lo, Dan Wu, Shuang Yang, Guanwen Wang, and Dongmei Cheng
- Subjects
0301 basic medicine ,Regulation of gene expression ,Cancer Research ,Cancer ,Biology ,medicine.disease ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,030220 oncology & carcinogenesis ,Cancer cell ,Genetics ,Cancer research ,medicine ,SKP2 ,Carcinoma ,Experimental pathology ,skin and connective tissue diseases ,Molecular Biology - Abstract
While mechanisms for metastasis were extensively studied in cancer cells from patients with detectable tumors, pathways underlying metastatic dissemination from early lesions before primary tumors appear are poorly understood. Her2 promotes breast cancer early dissemination by suppressing p38, but how Her2 downregulates p38 is unclear. Here, we demonstrate that in early lesion breast cancer models, Her2 inhibits p38 by inducing Skp2 through Akt-mediated phosphorylation, which promotes ubiquitination and proteasomal degradation of Tpl2, a p38 MAP3K. The early disseminating cells are Her2+Skp2highTpl2lowp-p38lowE-cadherinlow in the MMTV-Her2 breast cancer model. In human breast carcinoma, high Skp2 and low Tpl2 expression are associated with the Her2+ status; Tpl2 expression positively correlates with that of activated p38; Skp2 expression negatively correlates with that of Tpl2 and activated p38. Moreover, the Her2-Akt-Skp2-Tpl2-p38 axis plays a key role in the disseminating phenotypes in early lesion breast cancer cells; inhibition of Tpl2 enhances early dissemination in vivo. These findings identify the Her2-Akt-Skp2-Tpl2-p38 cascade as a novel mechanism mediating breast cancer early dissemination and a potential target for novel therapies targeting early metastatic dissemination.
- Published
- 2021
49. Correction to: CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism
- Author
-
Qiong Wang, Wenhao Wang, Hang Wang, Peiqing Sun, Shuang Yang, Kaiyuan Deng, Yang Ou, Zhen Zhang, Wei Sun, Quansheng Zhang, Jianjun Li, Zhaoyang Wang, and Guang Yang
- Subjects
Cancer Research ,Chemistry ,Mechanism (biology) ,lcsh:R ,Cancer metastasis ,lcsh:Medicine ,Breast cancer ,lcsh:Biology (General) ,Genetics ,Cancer research ,Epigenetics ,CDK4/6 Inhibition ,Author Correction ,lcsh:QH301-705.5 ,Deubiquitination - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
50. Novel cyclin-dependent kinase 9 (CDK9) inhibitor with suppression of cancer stemness activity against non-small-cell lung cancer
- Author
-
Rong Xiang, Shengyong Yang, Xin Wang, Yan Fan, Yao Li, Jianyu Zheng, Yakun Ma, Zhi Huang, Manqian Zhou, Peiqing Sun, Chenhua Yu, Cheng Wang, and Tianqi Wang
- Subjects
Lung Neoplasms ,Antineoplastic Agents ,Apoptosis ,01 natural sciences ,Structure-Activity Relationship ,03 medical and health sciences ,Isothiocyanates ,Cyclin-dependent kinase ,Cancer stem cell ,Carcinoma, Non-Small-Cell Lung ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,Lung cancer ,Protein Kinase Inhibitors ,Cell Proliferation ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Kinase ,Chemistry ,Cell growth ,Organic Chemistry ,General Medicine ,medicine.disease ,Cyclin-Dependent Kinase 9 ,0104 chemical sciences ,Sulfoxides ,biology.protein ,Cancer research ,Cyclin-dependent kinase 9 ,Drug Screening Assays, Antitumor ,Signal transduction - Abstract
A series of novel, highly potent, selective CDK9 inhibitors with cancer stem cells (CSCs) inhibition activity were designed and synthesized for non-small-cell lung cancer (NSCLC) therapy. Structure-activity relationship analysis based on enzymatic and cellular activities led to the discovery of a promising inhibitor 21e. 21e potently inhibited CDK9 with IC50 value of 11 nM and suppressed the stemness properties of NSCLC effectively. It could decrease the stemness phenotypes of NSCLC cells, including tumor sphere formation, side-population and stemness markers abundance. 21e displayed good selectivity over the CDK family kinases and kinase profiling assay against 381 kinases. In addition, 21e inhibited cell proliferation, colony-formation, and cell cycle progression and induced apoptosis in NSCLC. In H1299 xenograft mouse model, a once-daily dose of compound 21e at 20 mg/kg significantly suppressed the tumor growth without obvious toxicity. Studies of mechanisms of action indicated that 21e efficiently inhibited CDK9 signaling pathway and stemness both in vitro and in vivo. Collectively, 21e as a novel CDK9 inhibitor with CSCs inhibition properties could be a promising agent for the treatment of NSCLC.
- Published
- 2019
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