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The dysregulation of the splicing process has emerged as a novel hallmark of metabolic and tumor pathologies. In breast cancer (BCa), which represents the most diagnosed cancer type among women worldwide, the generation and/or dysregulation of several oncogenic splicing variants have been described. This is the case of the splicing variants of HER2, ER, BRCA1, or the recently identified by our group, In1-ghrelin and SST5TMD4, which exhibit oncogenic roles, increasing the malignancy, poor prognosis, and resistance to treatment of BCa. This altered expression of oncogenic splicing variants has been closely linked with the dysregulation of the elements belonging to the macromolecular machinery that controls the splicing process (spliceosome components and the associated splicing factors). In this review, we compile the current knowledge demonstrating the altered expression of splicing variants and spliceosomal components in BCa, showing the existence of a growing body of evidence supporting the close implication of the alteration in the splicing process in mammary tumorigenesis.

Rhabdomyosarcoma is a highly aggressive malignant cancer that arises from skeletal muscle progenitor cells and is the third most common solid tumour in children. Despite significant advances, rhabdomyosarcoma still presents a therapeutic challenge, and while targeted therapy has shown promise, there are limited options because the molecular drivers of rhabdomyosarcoma are poorly understood. We previously reported that the T-box transcription factor 3 (TBX3), which has been identified as a druggable target in many cancers, is overexpressed in rhabdomyosarcoma patient samples and cell lines. To identify new molecular therapeutic targets to treat rhabdomyosarcoma, this study investigates the potential oncogenic role(s) for TBX3 and the factors responsible for upregulating it in this cancer. To this end, rhabdomyosarcoma cell culture models in which TBX3 was either stably knocked down or overexpressed were established and the impact on key hallmarks of cancer were examined using growth curves, soft agar and scratch motility assays, as well as tumour-forming ability in nude mice. Our data show that TBX3 promotes substrate-dependent and -independent proliferation, migration and tumour formation. We further reveal that TBX3 is upregulated by c-Myc transcriptionally and AKT1 post-translationally. This study identifies c-Myc/AKT1/TBX3 as an important axis that could be targeted for the treatment of rhabdomyosarcoma.

MicroRNAs (miRNAs) comprise short non-coding RNAs that function in regulating the expression of tumor suppressors or oncogenes and modulate oncogenic signaling pathways in cancer. miRNAs expression alters significantly in several tumor tissues and cancer cell lines. For example, miR-106b functions as an oncogene and increases in multiple cancers. The miR-106b directly targets genes involved in tumorigenesis, proliferation, invasion, migration, and metastases. This review has focused on the miR-106b function and its downstream target in different cancers and provide perspective into how miR-106 regulates cancer cell proliferation, migration, invasion, and metastases by regulating the tumor suppressor genes. Since miRNAs-based therapies are currently being developed to enhance cancer therapy outcomes, miR-106b could be an attractive and prospective candidate in different cancer types for detection, diagnosis, and prognosis assessment in the tumor.

Background One-third of cancers activate endogenous synthesis of serine/glycine, and can become addicted to this pathway to sustain proliferation and survival. Mechanisms driving this metabolic rewiring remain largely unknown. Methods NKX2–1 overexpressing and NKX2–1 knockdown/knockout T-cell leukaemia and lung cancer cell line models were established to study metabolic rewiring using ChIP-qPCR, immunoblotting, mass spectrometry, and proliferation and invasion assays. Findings and therapeutic relevance were validated in mouse models and confirmed in patient datasets. Results Exploring T-cell leukaemia, lung cancer and neuroendocrine prostate cancer patient datasets highlighted the transcription factor NKX2–1 as putative driver of serine/glycine metabolism. We demonstrate that transcription factor NKX2–1 binds and transcriptionally upregulates serine/glycine synthesis enzyme genes, enabling NKX2–1 expressing cells to proliferate and invade in serine/glycine-depleted conditions. NKX2–1 driven serine/glycine synthesis generates nucleotides and redox molecules, and is associated with an altered cellular lipidome and methylome. Accordingly, NKX2–1 tumour-bearing mice display enhanced tumour aggressiveness associated with systemic metabolic rewiring. Therapeutically, NKX2–1-expressing cancer cells are more sensitive to serine/glycine conversion inhibition by repurposed anti-depressant sertraline, and to etoposide chemotherapy. Conclusion Collectively, we identify NKX2–1 as a novel transcriptional regulator of serine/glycine synthesis addiction across cancers, revealing a therapeutic vulnerability of NKX2–1-driven cancers.

OBJECTIVES: The recent accelerated FDA approval of sotorasib, a highly selective KRAS G12C inhibitor, offers new opportunities for the treatment of KRAS p.(G12C)-mutated non-squamous non-small cell lung cancer (NSCLC). The objective of the current study was to the determine the prevalence of KRAS mutations in stage IV non-squamous NSCLC in The Netherlands to reveal the potential impact of upcoming KRAS targeted therapy.MATERIALS AND METHODS: All patients diagnosed with stage IV non-squamous NSCLC in 2013, 2015 and 2017 in the Netherlands were selected by linking the nation-wide Netherlands Cancer Registry (NCR) and the Dutch Pathology Registry (PALGA). Demographic and pathological variables were retrieved from the pathology reports including sex, age, KRAS mutation status, molecular test method used, and the mutation status of other genes.RESULTS: Prevalence for any KRAS mutations in codon 12/13/61/146 was 39.1%. KRAS p.(G12C) was detected in 15.5% of all non-squamous NSCLC cases representing 39.6% of all KRAS-mutant cases. National testing rate for KRAS mutations increased from 70% in 2013 to 82% in 2017. Testing techniques changed significantly over time with next generation sequencing as the main used method in 2017 (71.6%) but did not affect prevalence of KRAS mutations over time. When KRAS was tested as part of a larger panel, the KRAS p.(G12C) mutation was frequently reported with a concurrent mutation in TP53 (47.7%) or STK11 (10.3%).CONCLUSION: The high prevalence for KRAS p.(G12C) offers a promising new specific treatment option for 15% of all stage IV non-squamous NSCLC patients.

Ovarian cancer comprises the most lethal gynecologic malignancy and is accompanied by the high potential for the incidence of metastasis, recurrence and chemotherapy resistance, often associated with a formation of ascitic fluid. The differentially expressed ascites-derived microRNAs may be linked to ovarian carcinogenesis. The article focuses on a number of miRNAs that share a common expression pattern as determined by independent studies using ascites samples and with regard to their functions and outcomes in experimental and clinical investigations. Let-7b and miR-143 have featured as tumor suppressors in ovarian cancer, which is in line with data on other types of cancer. Although two miRNAs, i.e. miR-26a-5p and miR-145-5p, act principally as tumor suppressor miRNAs, they occasionally exhibit oncogenic roles. The performance of miR-95-3p, upregulated in ascites, is open to debate given the current lack of supportive data on ovarian cancer; however, data on other cancers indicates its probable oncogenic role. Different findings have been reported for miR-182-5p and miR-200c-3p; in addition to their presumed oncogenic roles, contrasting findings have indicated their ambivalent functions. Further research is required for the identification and evaluation of the potential of specific miRNAs in the diagnosis, prediction, treatment and outcomes of ovarian cancer patients.

Glioma is the most common type of tumor in the central nervous system, accounting for around 80% of all malignant brain tumors. Previous studies showed a significant association between nuclear morphology and the malignant progress of gliomas. By virtue of integrated proteomics and genomics analyses as well as experimental validations, we identify three nuclear lamin genes (LMNA, LMNB1, and LMNB2) that are significantly upregulated in glioma tissues compared with normal brain tissues. We show that elevated expressions of LMNB1, LMNB2, and LMNA in glioma cells are highly associated with the rapid progression of the disease and the knockdown of LMNB1, LMNB2, and LMNA dramatically suppresses glioma progression in both in vitro and in vivo mouse models. Moreover, the repression of glioma cell growth by lamin knockdown is mediated by the pRb-mediated G1-S inhibition. On the contrary, overexpression of lamins in normal human astrocytes dramatically induced nuclear morphological aberrations and accelerated cell growth. Together, our multi-omics-based analysis has revealed a previously unrecognized role of lamin genes in gliomagenesis, providing a strong support for the key link between aberrant tumor nuclear shape and the survival of glioma patients. Based on these findings, lamins are proposed to be potential oncogene targets for therapeutic treatments of brain tumors.

The Kirsten ras oncogene KRAS is a member of the small GTPase superfamily participating in the RAS/MAPK pathway. A single amino acid substitution in KRAS gene has been shown to activate the encoded protein resulting in cell transformation. This oncogene is involved in the malignant transformation in several tissues. Notably, numerous non-coding RNAs have been found to interact with KRAS protein. Such interaction results in a wide array of human disorders, particularly cancers. Orilnc1, KIMAT1, SLCO4A1-AS1, LINC01420, KRAS1P, YWHAE, PART1, MALAT1, PCAT-1, lncRNA-NUTF2P3-001 and TP53TG1 are long non-coding RNAs (lncRNAs) whose interactions with KRAS have been verified in the context of cancer. miR-143, miR-96, miR-134 and miR-126 have also been shown to interact with KRAS in different tissues. Finally, circITGA7, circ_GLG1, circFNTA and circ-MEMO1 are examples of circular RNAs (circRNAs) that interact with KRAS. In this review, we describe the interaction between KRAS and lncRNAs, miRNAs and circRNAs, particularly in the context of cancer.

Sirtuin-3 (SIRT3) has been described as a colorectal cancer oncogene and to be regulated by glycyrrhizic acid (GA). However, few studies have explored the interaction between GA and SIRT3. Therefore, in the present study, we showed that GA could significantly decrease SIRT3 protein levels in SW620 and HT29 cells in a dose-dependent manner. Then, we overexpressed SIRT3 by lentivirus infection on SW620 and HT29 cells. We found that, in vitro, GA treatment significantly decreased cell viability, cell clone number, and invasion and migration number, besides significantly increasing apoptosis. Also, GA treatment significantly decreased the Bax/Bcl2 protein ratio and the expression of Cyclin D1, CDK2, CDK4, MMP-9, N-cadherin, and vimentin in SW620 and HT29 cells. Meanwhile, the SIRT3 overexpression could significantly reverse these changes. Moreover, the GA treatment could significantly decrease the weight of xenograft tumor tissues and its SIRT3 protein levels in vivo, while SIRT3 overexpression reversed these effects. Overall, GA inhibited the proliferation, invasion, and migration of colorectal cancer cells, and induced their apoptosis by SIRT3 inhibition.

Esophageal squamous cell carcinoma (ESCC) is the most significant subtype of esophageal cancer featured with high occurrence. Long noncoding RNAs (lncRNAs) have been proved to modulate the biological properties of cancer cells, including cell proliferation, invasion, migration, and apoptosis. LncRNA protein tyrosine phosphatase receptor type G-antisense RNA 1 (PTPRG-AS1) has been reported to play as an oncogene in diverse cancers. However, the detailed function PTPRG-AS1 may exert in ESCC is unclear.PTPRG-AS1 expression in ESCC cells was investigated via quantitative reverse transcription real-time polymerase chain reaction (RT-qPCR). The effects of PTPRG-AS1 on ESCC cell proliferation, migration, glycolysis, and stemness were verified through functional assays. Mechanism assays including RIP assay, RNA pull down assay, and luciferase reporter assays were performed to verify the molecular mechanism of PTPRG-AS1.PTPRG-AS1 silencing hindered the proliferation, migration, glycolysis and stemness of ESCC cells. PTPRG-AS1 regulated pyruvate dehydrogenase kinase 1 (PDK1) expression via sponging miR-599. The PTPRG-AS1/miR-599/PDK1 axis was further verified to aggravate the progression of ESCC cells.PTPRG-AS1 sponged miR-599 to up-regulate PDK1 expression, thereby promoting the proliferation and migration as well as glycolysis and stemness properties of ESCC cells.

FBXO31, a member of F-box protein family, has been shown to play an important role in preventing tumorigenesis by preserving genomic stability during cell proliferations as well as upon genotoxic stresses. Inactivation of FBXO31 due to loss of heterozygosity is associated with various cancers, including ovarian cancer, one of the deadliest forms of gynecological cancers. However, the role and regulation of FBXO31 in ovarian cancer remained elusive. Here, using biochemical and molecular biology techniques, we show that c-Myc suppresses the mRNA levels of FBXO31 in ovarian cancer cell lines and mouse model. Chromatin immunoprecipitation experiment showed that c-Myc is recruited to the promoter region of FBXO31 and prevents FBXO31 mRNA synthesis. In contrast, FBXO31 maintains the c-Myc expression at an optimum through proteasome pathway. FBXO31 interacts with and facilitates the polyubiquitination of c-Myc through the SCF complex and thereby inhibits ovarian cancer growth both in vitro and in vivo. Moreover, FBXO31-mediated proteasomal degradation of c-Myc is unique. Unlike other negative regulators, FBXO31 recognizes c-Myc in phosphorylation independent manner to direct its degradation. Further, expression levels analysis revealed that c-Myc and FBXO31 share a converse correlation of expression in ovarian cancer cell lines and patient samples. We observed an increase in the expression levels of c-Myc with a concomitant decrease in the levels of FBXO31 in higher grades of ovarian cancer patient samples. In conclusion, our study demonstrated that oncogene c-Myc impairs the tumor-suppressive functions of FBXO31 to promote ovarian cancer progression, and therefore c-Myc-FBXO31 axis can be explored to develop better cancer therapy. This article is protected by copyright. All rights reserved.

Cancer occurs when cells begin to grow abnormally and abruptly in the body. Cancer is one of the dangerous diseases due to which many people die in the world. Many kinds of cancers occur in the human body in which ovarian cancer is also one of the most fatal cancers found among women. It causes many deaths in women. Ovarian cancer generally occurs because of hereditary. Both types of molecules can be used in medicines; i.e., synthesized by man in the laboratories and naturally occurring molecules. Phytochemicals are the naturally occurring molecules found in plants. Phytochemicals are of great importance nowadays because our research is more focusing on plant-based molecules which can be helpful in the treatment of any kind of disease and have fewer side effects. In this review article, we examined how various phytochemicals are utilized as inhibitors in the therapy of ovarian malignancy. Phytochemicals including flavonoids, terpenes, and organo-Sulphur compounds have antioxidant, anti-inflammatory, antitumor, antiviral, apoptosis induction, anti-proliferation, and cell cycle arrest induction properties that help in the inhibition of CAOV3, OVCAR3, OVCAR5, TOV112D, and A2780 ovarian cancer cells. Also helps in suppressing the expression of c-Myc (cellular-Myc: An oncogene on chromosome 8q24 of cellular), VEGF (Vascular endothelial growth factor), and NF-κB (Nuclear factor-kappa B) in ovarian cancer cell lines.

Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. Dysregulation of circular RNAs (circRNAs) appears to be a critical factor in CRC progression. However, mechanistic studies delineating the role of circRNAs in CRC remain limited. In this study, qRT-PCR and western blot assays were used to measure the expression of genes and proteins. Migration, invasion, proliferation, and apoptosis were examined by wound-healing, transwell, CCK-8, colony formation, and flow cytometry assays, respectively. Molecular interactions were validated by a dual-luciferase report system. A xenograft animal model was established to examine in vivo tumor growth and lung metastasis. Our data indicated that circN4BP2L2 expression was increased in CRC tissues and cell lines. Notably, inhibition of circN4BP2L2 effectively inhibited proliferation, migration, and invasion of LoVo cells, and inhibited tumor growth and metastasis in vivo, whereas the forced expression of circN4BP2L2 facilitated the proliferation, migration, and invasion of HT-29 cells. Mechanistic studies revealed that circN4BP2L2 acted as a molecular sponge of miR-340-5p to competitively promote CXCR4 expression. Furthermore, inhibition of miR-340-5p reversed the anti-cancer effects of circN4BP2L2 or CXCR4 silencing. Our data indicated an oncogenic role of circN4BP2L2 in CRC via regulation of the miR-340-5p/CXCR4 axis, which may be a promising biomarker and target for CRC treatment. This study determined that circN4BP2L2 acts as an oncogene that promotes tumor growth and metastasis of colorectal cancer (CRC) by regulating the miR-340-5p/CXCR4 axis. The authors reveal a novel mechanism for the ceRNA regulatory network in CRC progression and identify a potential therapeutic target for CRC treatment.

The protein-coding ability of circular RNAs (circRNAs) has recently been a hot topic, but the expression and roles of protein-coding circRNAs in triple-negative breast cancer (TNBC) remain uncertain. By intersecting circRNA sequencing data from clinical samples and cell lines, we identified a circRNA, termed circ-EIF6, which predicted a poorer prognosis and correlated with clinicopathological characteristics in a cohort of TNBC patients. Functionally, we showed that circ-EIF6 promoted the proliferation and metastasis of TNBC cells in vitro and in vivo. Mechanistically, we found that circ-EIF6 contains a 675-nucleotide (nt) open reading frame (ORF) and that the -150-bp sequence from ATG functioned as an internal ribosome entry site (IRES), which is required for translation initiation in 5' cap-independent coding RNAs. circ-EIF6 encodes a novel peptide, termed EIF6-224 amino acid (aa), which is responsible for the oncogenic effects of circ-EIF6. The endogenous expression of EIF6-224aa was further examined in TNBC cells and tissues by specific antibody. Moreover, EIF6-224aa directly interacted with MYH9, an oncogene in breast cancer, and decreased MYH9 degradation by inhibiting the ubiquitin-proteasome pathway and subsequently activating the Wnt/beta-catenin pathway. Our study provided novel insights into the roles of protein-coding circRNAs and supported circ-EIF6/EIF6-224aa as a novel promising prognostic and therapeutic target for tailored therapy in TNBC patients.

Background Long non-coding RNAs (lncRNAs) are essential indicators for hepatocellular carcinoma. LncRNAs can exert the same functions as their antisense mRNAs. ILF3 is an oncogene in hepatocellular carcinoma. ILF3 divergent transcript (ILF3-AS1) is the antisense RNA of ILF3, and has been reported as an oncogene in various cancers. Aims To explore the role of lncRNA ILF3-AS1 in malignant phenotypes of hepatocellular carcinoma cells. Methods and results RT-qPCR analysis revealed that ILF3-AS1 was significantly upregulated in hepatocellular carcinoma cells. The hepatocellular carcinoma cell viability was suppressed by silenced ILF3-AS1. Transwell and wound healing assays showed that ILF3-AS1 downregulation inhibited cell invasion and migration. The levels of proteins associated with epithelial-mesenchymal transition (EMT) process and the Notch pathway were detected by western blot analysis. Luciferase reporter, RNA pull down and RIP assays were used to investigate the relationship between ILF3-AS1 and downstream target genes. ILF3-AS1 competed with meis homeobox 2 (MEIS2) for miR-628–5p in hepatocellular carcinoma cells. ILF3-AS1 elevated the levels of key proteins on the Notch pathway. Rescue assays demonstrated that MEIS2 reversed the antitumor effects of silenced ILF3-AS1 on hepatocellular carcinoma. In vivo assays demonstrated that ILF3-AS1 silencing inhibited the hepatocellular carcinoma tumor growth. Conclusions ILF3-AS1 promoted hepatocellular carcinoma progression via the Notch pathway and miR-628–5p/MEIS2 axis.

The dysregulation of circular RNAs (circRNAs) has been proved to be involved in the carcinogenesis of various cancers. Nevertheless, the biological function of circSLC7A6 remains unclear in Wilms’ tumor (WT). In our study, we found that circSLC7A6 was upregulated in cancerous WT tissues and cells. Cell apoptosis was increased while cell viability, migration, and invasion were repressed by circSLC7A6 silencing. Besides, circSLC7A6 knockdown suppressed WT tumor growth in vivo. miR-107 was identified as a direct target of circSLC7A6, and circSLC7A6 could negatively regulate miR-107 expression. In addition, circSLC7A6 knockdown inhibited WT progression, while the effect was partially abolished by the downregulation of miR-107. Additionally, ABL proto-oncogene 2 axis (ABL2) was verified as a downstream gene of miR-107, and circSLC7A6 could upregulate ABL2 expression by serving as a ceRNA of miR-107. Moreover, functional assays revealed that ABL2 overexpression reversed the impact of circSLC7A6 depletion on cell proliferation, migration, invasion, and apoptosis of WT. In conclusion, the present study demonstrated that circSLC7A6 facilitated WT progression by upregulating ABL2 through inhibiting miR-107 expression. These results suggested that circSLC7A6 might serve as a potential therapeutic target for WT.

Gastric cancer (GC) is the most frequent malignant tumor in the digestive system, with high metastasis potential and poor prognosis. This study aimed to investigate the prognostic value and biological function of thioredoxin domain-containing protein 9 (TXNDC9) in GC. The expression of TXNDC9 was analyzed based on The Cancer Genome Atlas (TCGA) database. The prognostic value of TXNDC9 was evaluated by Kaplan-Meier curves and Cox regression analysis. The mRNA and protein expression of TXNDC9 were analyzed using quantitative real-time PCR and western blot analysis. The effects of TXNDC9 on GC cell invasion and EMT were assessed in vitro, and its effects on tumorigenesis were confirmed using animal experiments. The activity of the NF-κB signaling pathway was examined by both in vitro and in vivo experiments. TXNDC9 was highly expressed in GC tissues and cell lines. A high level of TXNDC9 was associated with poor overall survival and served as an independent prognostic biomarker in GC patients. The knockdown of TXNDC9 led to restrained GC cell invasion, microtubule formation, and EMT in vitro, and suppressed tumorigenesis in vivo. In addition, the NF-κB signaling pathway was demonstrated to mediate the functional role of TXNDC9 in GC. In conclusion, this study found that high TXNDC9 predicted poor prognosis in GC, and served as an oncogene by enhancing tumor cell invasion and EMT through the NF-κB signaling pathway.

ARID1A belongs to a class of chromatin regulatory proteins that function by maintaining accessibility at most promoters and enhancers, thereby regulating gene expression. The high frequency of ARID1A alterations in human cancers has highlighted its significance in tumorigenesis. The precise role of ARID1A in cancer is highly variable since ARID1A alterations can have a tumor suppressive or oncogenic role, depending on the tumor type and context. ARID1A is mutated in about 10% of all tumor types including endometrial, bladder, gastric, liver, biliopancreatic cancer, some ovarian cancer subtypes, and the extremely aggressive cancers of unknown primary. Its loss is generally associated with disease progression more often than onset. In some cancers, ARID1A loss is associated with worse prognostic features, thus supporting a major tumor suppressive role. However, some exceptions have been reported. Thus, the association of ARID1A genetic alterations with patient prognosis is controversial. However, ARID1A loss of function is considered conducive for the use of inhibitory drugs which are based on synthetic lethality mechanisms. In this review we summarize the current knowledge on the role of ARID1A as tumor suppressor or oncogene in different tumor types and discuss the strategies for treating ARID1A mutated cancers.

Dysregulation of mitochondrial calcium uniporter (MCU) exerts a carcinogenic effect in several cancers. Nevertheless, the roles of MCU in oral squamous cell carcinoma (OSCC) remain elusive. It has been reported that Dihydroartemisinin (DHA) may suppress the progression of OSCC but its associated mechanisms have been not investigated. The purpose of our research was to observe the biological function of MCU on OSCC and its regulatory relationship with DHA. MCU, MICU1, MICU2, N-cadherin, TGF-β and Vimentin expression was detected in OSCC and peritumoral tissues by immunohistochemistry and western blot. Following DHA treatment, the expression of above proteins was detected in CAL-27 cells transfected with shMCU or pcDNA3.1-MCU by western blot or immunofluorescence. Furthermore, clone formation, mitochondrial membrane potential (MMP), wound healing and transwell assays were presented in CAL-27 cells treated with DHA, shMCU or pcDNA3.1-MCU. Our results showed that the members of MCU complex including MCU, MICU1 and MICU2 were overexpressed in OSCC compared to peritumoral tissues. Furthermore, TGF-β and epithelial to mesenchymal transition (EMT) proteins (N-cadherin and Vimentin) exhibited higher expression in OSCC. DHA treatment significantly lowered the expression of MCU in CAL-27 cells. MCU overexpression reversed the inhibitory effects of DHA on MICU1, MICU2, N-cadherin, TGF-β and Vimentin expression. Furthermore, MCU knockdown or DHA suppressed proliferation, MMP and migration of CAL-27 cells. DHA treatment could reverse the effects of MCU overexpression. Collectively, our study demonstrated that MCU was an oncogene of OSCC and DHA exerted a suppressive role on proliferation and migration of OSCC cells by suppressing MCU expression.

Cervical cancer (CC) is the fourth leading cancer in women in the age group of 15-44 years globally. Experimental as well as epidemiological studies identified that type16 and 18 HPV cause 70% of precancerous cervical lesions as well as cervical cancer worldwide by bringing about genetic as well as epigenetic changes in the host genome. The insertion of the HPV genome triggers various defense mechanisms including the silencing of tumor suppressor genes as well as activation of oncogenes associated with cancer metastatic pathway. E6 and E7 are small oncoproteins consisting of 150 and 100 amino acids, respectively. These oncoproteins affect the regulation of the host cell cycle by interfering with p53 and pRb. Further, these oncoproteins adversely affect the normal functions of the host cell by binding to their signaling proteins. Recent studies demonstrated that E6 and E7 oncoproteins are potential targets for CC. Therefore, this review discusses the role of E6 and E7 oncoproteins in metastasis and drug resistance as well as their regulation, early oncogene mediated signaling pathways. This review also uncovers recent updates on molecular mechanisms of E6 and E7 mediated phytotherapy, gene therapy, immune therapy, and vaccine strategies as well as diagnosis through precision testing. Therefore, understanding the potential role of E6/E7 in metastasis and drug resistance along with targeted treatment, vaccine, and precision diagnostic strategies, could be useful for the prevention and treatment of cervical cancer.

Long-chain non-coding RNA ASB16-AS1 has been proven to be an oncogene for many cancer types. However, the relationship between ASB16-AS1 and immunity is still under studied. This study aims to explore the expression and prognostic potential of ASB16-AS1, and to visualize the relationship between ASB16-AS1 expression and immune infiltration in pan-cancer. We clarified ASB16-AS1 expression patterns in pan-cancer and its relationship with prognosis through multi-platform and multi-database sources (TCGA, GEO, GTEx, ArrayExpress, and SRA), and verified the function of ASB16-AS1 in liver hepatocellular carcinoma (LIHC). Then, a variety of immune cell content evaluation methods were used to mutually verify the correlation between ASB16-AS1 and immune infiltration. Finally, the relationships between ASB16-AS1 and some molecular characteristics (immune checkpoints, tumor mutation burden, microsatellite instability, oncogenic signaling pathways) were further explored. In terms of comprehensive analysis, compared with non-tumor tissues, ASB16-AS1 was highly expressed in tumor tissues, and indicated the value of poor prognosis in multiple cancer types. Functional assays, such as CCK8 assay, transwell assay and wound scratch assay, verified that high ASB16-AS1 expression promoted tumor progression in LIHC. ASB16-AS1 was positively correlated with B cells, T cell CD4+ and T cell CD8+ in most cancer types, and negatively correlated with macrophages, dendritic cells and neutrophils in some cancer types, especially in neutrophils. In addition, there were different interaction modes between ASB16-AS1 and molecular features, such as the relationship with oncogenic signaling pathways, showing that the high ASB16-AS1 expression was related to alterations in oncogenic signaling pathways. Our study emphasizes that ASB16-AS1 is a potential pan-cancer prognostic marker, whichs is associated with the immune infiltration in multiple cancer types.

Brother of Regulator of Imprinted Sites (BORIS) or CCCTC-Binding Factor Like (CTCFL) is a nucleotide-binding protein, aberrantly expressed in various malignancies. Expression of BORIS has been found to be associated with the expression of oncogenes which regulate the reactive oxygen species (ROS) biogenesis, DNA double-strand break repair, regulation of stemness, and induction of cellular senescence. In the present study, we have analyzed the effects of knockdown of BORIS, a potential oncogene, on the induction of senescence and tumor suppression. Loss of BORIS downregulated the expression of critical oncogenes such as BMI1, Akt, MYCN, and STAT3, whereas overexpression increased their respective expression levels in MYCN-amplified neuroblastoma cells. BORIS knockdown exhibited high levels of ROS biogenesis, indicating an upregulated mitochondrial superoxide production and thereby induction of senescence. Our study also showed that the loss of BORIS facilitated cellular senescence through the disruption of telomere integrity via altering the expression of various proteins required for telomere capping (POT1, TRF2, and TIN1). In addition to affecting ROS production and DNA damage, BORIS knockdown sensitized the cells towards chemotherapeutic drugs and induced apoptosis. Tumor induction studies on in-vivo xenograft mouse models showed that cells with loss of BORIS/CTCFL failed to induce tumors. From our study, we conclude that silencing BORIS/CTCFL influences tumor growth and proliferation by regulating key oncogenes. The results also indicated that the BORIS knockdown can cause cellular senescence and upon a combinatorial treatment with chemotherapeutic drugs can induce enhanced drug sensitivity in MYCN amplified neuroblastoma cells.

Thyroid carcinoma is one of the most common endocrine malignancies, in which papillary thyroid carcinoma (PTC) is the main pathotype. ANXA1 plays a significant role in many cancer types, but how it works in PTC has not been identified. MYC is a common transcript factor involved in tumorigenesis, development, invasion, and metastasis. The relation between ANXA1 and MYC has not been proved in PTC. In this study, firstly, we analyzed the expression and prognostic value of ANXA1 in pan-cancer using the data from the UCSC database. Then we explore the role of ANXA1 in PTC, including expression, prognostic value, and immune infiltration. In addition, we evaluated the relation between ANXA1 and the transcription factor MYC. Finally, we identified the expression of ANXA1 and MYC and then evaluated their function associated with proliferation and apoptosis in PTC cell lines by CCK8 proliferation and flow cytometry apoptosis experiment. We found that ANXA1 is up-regulated in PTC comparing with normal patients. High expression of ANXA1 was associated with adverse overall survival of PTC. ANXA1 may be regulated by MYC to promote the proliferation of PTC. MYC may regulate the expression of ANXA and thus affect the proliferation of PTC.

Distant metastasis is, unfortunately, the leading cause of death in colorectal cancer (CRC). Approximately 50% of CRC patients develop liver metastases, while 10–30% of patients develop pulmonary metastases. The occurrence of metastasis is considered to be almost exclusively driven by cancer stem cells (CSCs) formation. However, the key molecules that confer the transformation to stem cells in CRC, and subsequent metastasis, remain unclear. Far upstream element‐binding protein 1 (FUBP1), a transcriptional regulator of c‐Myc, was screened in CSCs of CRC by mass spectrometry and was examined by immunohistochemistry in a cohort of CRC tissues. FUBP1 was upregulated in 85% of KRAS‐mutant and 25% of wild‐type CRC patients. Further, whether in KRAS‐mutant or wild‐type patients, elevated FUBP1 was positively correlated with CRC lymph node metastasis and clinical stage, and negatively associated with overall survival. Overexpression of FUBP1 significantly enhanced CRC cell migration, invasion, tumor sphere formation, and CD133 and ALDH1 expression in vitro, and tumorigenicity in vivo. Mechanistically, FUBP1 promoted the initiation of CSCs by activating Wnt/β‐catenin signaling via directly binding to the promoter of DVL1, a potent activator of β‐catenin. Knockdown of DVL1 significantly inhibited the transformation to stem cells in, as well as the tumorigenicity of, CRC. Activation of Wnt/β‐catenin signaling by DVL1 increased pluripotent transcription factors, including c‐Myc, NANOG, and SOX2. Moreover, FUBP1 was upregulated at the post‐transcriptional level. Elevated FUBP1 levels in KRAS wild‐type CRC patients is due to the decrease in Smurf2, which promotes ubiquitin‐mediated degradation of FUBP1. In contrast, FUBP1 was upregulated in KRAS‐mutant patients through both inhibition of caspase 3‐dependent cleavage and decreased Smurf2. Our results demonstrate, for the first time, that FUBP1 is an oncogene, initiating the development of CSCs, as well as a new powerful endogenous Wnt‐signaling agonist that could provide an important prognostic factor and therapeutic target for metastasis in both KRAS‐mutant and wild‐type CRC., Distant metastasis represents the leading cause of death in colorectal cancer (CRC). Cancer stem cells (CSCs) formation is considered to drive metastasis in patients with CRC; however, the key molecules guiding CSC formation remain elusive. Here, we investigated the role of the FUBP1 oncogene and DVL1, a novel agonist of endogenous Wnt signaling in CSCs development. Our data indicate that FUBP1 acts in initiating the development of CSC and could serve as a prognostic factor, as well as a potential therapeutic target in both KRAS‐mutant and wild‐type patients with CRC metastasis.

Deregulation of long non-coding RNAs (lncRNAs) has been implicated in tumorigenesis. FALEC is a lncRNA upregulated in multiple cancer types. FALEC functions as an oncogene through various mechanisms, such as competitively binding miRNAs and regulation of PI3K/AKT, Tp53 and phosphatase and tensin homolog signaling pathways. Pertinent to clinical practice, the use of FALEC as a putative biomarker has been identified. These findings suggested that FALEC might play a pivotal role in human cancers. Further studies are warranted to examine the diagnostic and prognostic performance of FALEC as a noninvasive biomarker in liquid biopsy samples and promote its development to be a clinically utilizable prognostic cancer biomarker and molecular therapeutic target.

TAS-115 is an oral multikinase inhibitor targeting the MET proto-oncogene, vascular endothelial growth factor receptor, and colony-stimulating factor 1 receptor. We evaluated the efficacy and safety of TAS-115 in castration-resistant prostate cancer (CRPC) patients with bone metastases.This phase II study, conducted in Japan, comprised 2 cohorts of CRPC patients. Cohort A included patients with bone metastasis and no history of docetaxel; TAS-115 200 to 400 mg/d was administered with abiraterone and prednisone. Cohort B included patients with symptomatic multiple bone metastases, post- or unfit for docetaxel, randomized 1:1 to receive TAS-115 400 or 600 mg/d orally, once daily, in a repeated weekly schedule of 5 days on/2 days off. The primary endpoint was bone scan index (BSI) response rate at Week 12 in each dose group.Cohorts A and B included 24 and 26 patients, respectively. The 12-week BSI response rates for 200, 300, and 400 mg were 0%, 33.3%, and 16.7% in Cohort A, and for 400 and 600 mg were 7.1% and 25.0% in Cohort B. The best BSI response rates for 200, 300, and 400 mg were 0%, 66.7%, and 16.7% in Cohort A, and for 400 and 600 mg were 7.1% and 33.3% in Cohort B. A ≥ 30% reduction in BPI-SF score was shown in 57.7% of patients in Cohort B. The most frequent Grade ≥ 3 adverse drug reactions were hypophosphatemia (20.8%) in Cohort A and anemia (23.1%) in Cohort B.TAS-115 appears to demonstrate anti-tumor activity and acceptable tolerability in CRPC patients with bone metastases.

Chronic neuroinflammation is an important factor in the development of neuropathic pain (NP). Excess microglia activation releases a mass of pro-inflammatory cytokines during neuroinflammation process, leading to a constant painful irritation of the sensory nerve. Src belongs to a non-receptor tyrosine kinase associated with sarcoma, whereas the role of Src in neuropathic pain is controversial. We designed to testify the inflammation-regulatory role of Src in the lipopolysaccharide (LPS)-induced BV2 microglia line and the mouse model of neuropathic pain by partial sciatic nerve ligation (PNL). In BV2 microglia, Src expression was inhibited using a Src family kinase inhibitor PP2 after LPS induced inflammatory response. In vivo, the neuropathic pain in mice was induced by PNL surgery and then treated with PP2. The neuroinflammation level in vitro was detected by enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), trans-well and Western blotting (WB) assays, in vivo was examined in PNL mice using immunohistochemistry (IHC) and IF. Finally, mechanical allodynia and thermal hyperalgesia assays were used to access the functional evaluation. Inhibition of Src was decreased microglial inflammation and migration after LPS stimuli. Mechanistically, the expression of nuclear factor kappa B (NF-κB) pathway decreased after Src inhibition. The data in vivo showed that the decrease expression of Src reduced neuroinflammation and the amount of microglia in spinal dorsal horn (SDH), the mechanical allodynia of mice thereby attenuated after Src inhibition. These results indicated that the inhibition of Src took a protective effect in neuropathic pain mouse models via reducing microglia-induced neuroinflammation.

Aberrant expression of long non-coding RNAs (lncRNAs) has been reported in multiple cancers. However, the underlying mechanisms mediated by super-enhancers remain elusive. Here we sought to define the role of a novel lncRNA termed lncRNA-DAW in tumorigenesis. Our results revealed that lncRNA-DAW was driven by a liver-specific super-enhancer and transcriptionally activated by HNF4G, leading to frequent elevation in hepatocellular carcinoma (HCC) specimens. Ectopic expression of lncRNA-DAW promoted both in vivo and in vitro tumor growth. By using RNA sequencing, Wnt2 was screened out as a downstream effector of lncRNA-DAW. We next found that lncRNA-DAW physically interacted with EZH2, a negative regulator of Wnt2. This interplay subsequently potentiated CDK1-EZH2 interaction, leading to the phosphorylation and ubiquitination of EZH2. The lncRNA-DAW-mediated EZH2 degradation facilitated the de-repression of Wnt2 transcription, which eventually activated the Wnt/β-catenin pathway. Furthermore, we verified that Wnt2 potentiated in vitro and in vivo cancer cell growth by activating the Wnt/β-catenin pathway. Finally, Wnt2 amplification was confirmed as a common event in liver cancer, and the expression of lncRNA-DAW was positively correlated with Wnt2 in HCC specimens. Collectively, we are the first to identify lncRNA-DAW as a novel candidate oncogene in liver cancer, and this lncRNA may serve as a novel clinical diagnosis biomarker for liver cancer., Graphical abstract, lncRNA-DAW was driven by a liver-specific super-enhancer and frequently upregulated in liver cancer. lncRNA-DAW diminished PRC2-mediated repression of Wnt2 by antagonizing the function of EZH2, eventually leading to the activation of the Wnt/β-catenin pathway and cancer cell proliferation.

The transcription factor NANOG regulates self-renewal and pluripotency in embryonic cells, and its downregulation leads to cell differentiation. Recent studies have linked upregulation of NANOG in various cancers and the regulation of expression of different molecules, and vice versa, to induce proliferation, metastasis, invasion and chemoresistance. Thus NANOG is an oncogene that functions by inducing stem cells’ circuitries and heterogeneity in cancers. Understanding NANOG’s role in various cancers may lead to it becoming a therapeutic target to halt cancer progression. The NANOG network can also be targeted to resensitize resistant cancer cells to conventional therapies. The current review focuses on NANOG regulation in the various signaling networks leading to cancer progression and chemoresistance, and highlights the therapeutic aspect of targeting NANOG in various cancers.

The signal transducer and activator of transcription 3 (STAT3) oncogene is a transcription factor with a central role in head and neck cancer. Hypopharyngeal cells (HCs) exposed to acidic bile present aberrant activation of STAT3, possibly contributing to its oncogenic effect. We hypothesized that STAT3 contributes substantially to the bile reflux‐induced molecular oncogenic profile, which can be suppressed by STAT3 silencing or pharmacological inhibition. To explore our hypothesis, we targeted the STAT3 pathway, by knocking down STAT3 (STAT3 siRNA), and inhibiting STAT3 phosphorylation (Nifuroxazide) or dimerization (SI3‐201; STA‐21), in acidic bile (pH 4.0)‐exposed human HCs. Immunofluorescence, luciferase assay, Western blot, enzyme‐linked immunosorbent assay and qPCR analyses revealed that STAT3 knockdown or pharmacologic inhibition significantly suppressed acidic bile‐induced STAT3 activation and its transcriptional activity, Bcl‐2 overexpression, transcriptional activation of IL6, TNF‐α, BCL2, EGFR, STAT3, RELA(p65), REL and WNT5A, and cell survival. Our novel findings document the important role of STAT3 in bile reflux‐related molecular oncogenic events, which can be dramatically prevented by STAT3 silencing. STA‐21, SI3‐201 or Nifuroxazide effectively inhibited STAT3 and cancer‐related inflammatory phenotype, encouraging their single or combined application in preventive or therapeutic strategies of bile reflux‐related hypopharyngeal carcinogenesis.

Hepatocellular carcinoma (HCC) is a very deadly disease. HCC initiation and progression involve multiple genetic events, including the activation of proto-oncogenes and disruption of the function of specific tumor suppressor genes. Activation of oncogenes stimulates cell growth and survival, while loss-of-function mutations of tumor suppressor genes result in unrestrained cell growth. In this review, we summarize the new findings that identified novel proto-oncogenes and tumor suppressors in HCC over the past five years. These findings may inspire the development of novel therapeutic strategies to improve the outcome of HCC patients.

Syntaxin-6 (STX6), a vesicular transport protein, is a direct target of the tumor suppressor gene P53, supporting cancer growth dependent on P53. However, STX6’s function in the tumor microenvironment has yet to be reported. In this research, we comprehensively explored the role of the oncogene STX6 in pan-cancer by combining data from several databases, including the Cancer Genome Atlas, CPTAC, cBioPortal, and TIMER. Then, we verified the carcinogenic effect of STX6 in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) through a series of experiments in vitro and in vivo. Bioinformatics analysis demonstrated that STX6 is an oncogene for several cancers and is mainly involved in the cell cycle, epithelial–mesenchymal transition, oxidative phosphorylation, and tumor immune modulation, especially for tumor-associated fibroblasts (CAFs) and NKT cells. Additionally, a high level of STX6 could indicate patients’ resistance to immunotherapy. Our own data indicated that the STX6 level was upregulated in HCC and CRC. Knockdown of the STX6 levels could arrest the cell cycle and restrain cell proliferation, migration, and invasion. RNA-seq indicated that STX6 was significantly involved in pathways for cancer, such as the MAPK signal pathway. In a mouse model, knockdown of STX6 inhibited tumor growth and potentiated anti-PD-1 efficacy. In light of the essential roles STX6 plays in carcinogenesis and cancer immunology, it has the potential to be a predictive biomarker and a target for cancer immunotherapy.

Background Activating point mutations of the RAS gene (NRAS, HRAS, and KRAS) can be seen in benign and malignant thyroid tumors; among these, NRAS mutations are more commonly seen. This study was conducted to evaluate the thyroid risk of malignancy (ROM) associated with RAS mutations in thyroid fine-needle aspiration (FNA) at the authors' institution. Methods The authors searched their electronic database system between January 2015 and May 2021 for thyroid FNA cases with any type of RAS mutation. Molecular alterations were identified with the ThyroSeq Genomic Classifier, ThyGeNEXT (thyroid oncogene panel)/ThyraMIR (miRNA classifier), or ThyroSure gene panel. Results A total of 127 cases (age, 51 ± 14 years; 100 females and 27 males) were identified, and 72 had histologic follow-up. The overall ROM associated with RAS mutations (with or without any other molecular alterations) was 29%, whereas the ROM was lower (18%) with RAS mutations only. Isolated NRAS, HRAS, and KRAS mutation-associated ROMs were 15%, 27%, and 14%, respectively. Among these RAS-mutated cases, the cases with a Bethesda category IV cytologic diagnosis had a higher ROM than the cases with a category III diagnosis (38% vs 17%). Twenty-one histologically confirmed malignant cases were mostly classified on cytology as category IV lesions (14 of 34; 41%), and the remainder were either category III (6 of 35; 17%) or V lesions (1 of 1; 100%). Conclusions This study demonstrated that the overall RAS mutation-associated ROM in thyroid FNA was intermediate (29%), and isolated HRAS mutations appeared to have a higher ROM (27%) than NRAS and KRAS mutations (15% and 14%, respectively).

Transcriptome expression profiles of laryngeal squamous cell carcinoma (LSCC) are altered, and we aimed to investigate expression and role of hsa_circ_0005033 (circ_0005033), microRNA (miR)-107 and insulin-like growth factor 1 receptor (IGF1R) in LSCC. Real-time PCR, western blotting and immunohistochemistry detected RNA and protein expression levels. Functional assays were performed using MTT assay, EdU assay, apoptosis assay, flow cytometry, Transwell assay, and xenograft tumor model. Direct interaction was predicted by Starbase algorithm and validated by dual-luciferase reporter assay and RNA immunoprecipitation. Expression of circ_0005033 was substantially upregulated in LSCC tissues and cells, and allied with miR-107 downregulation and IGF1R upregulation. Circ_0005033 showed a closed-loop structure and long half-life. Essentially, circ_0005033 and IGF1R were competing endogenous RNAs for miR-107 via target binding. Silencing circ_0005033 facilitated apoptosis rate and lowered cell viability, proliferation, migration and invasion of LSCC cells, as well as delayed xenograft tumor growth. Allied with that, cleaved-caspase 3/8/9 expression was elevated via death receptor-mediated and mitochondrial pathways, and expression of matrix metalloproteinase-2 (MMP2), MMP9, cyclin D1 and proliferating cell nuclear antigen was decreased. Moreover, Cisplatin-induced inhibition of cell viability was exacerbated by inhibiting circ_0005033. These functional effects of circ_0005033 depression were consistent with those of miR-107 overexpression. Furthermore, depleting miR-107 and restoring IGF1R abated the effects of circ_0005033 knockdown and miR-107 overexpression, respectively. Circ_0005033 was oncogenic in LSCC by regulating cell progression and Cisplatin sensitivity at least via miR-107/IGF1R axis.

The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells, which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. As an important component of the Hh signaling pathway, glioma-associated oncogene (GLI) acts as a key signal transmission hub for various signaling pathways in many tumors. Here, we review direct and indirect inhibitors of GLI; summarize the abundant active structurally diverse natural GLI inhibitors; and discuss how to better develop and utilize GLI inhibitors to solve the problem of drug resistance in tumors of interest. In summary, GLI inhibitors will be promising candidates for various cancer treatments.

Long non‐coding RNAs (LncRNAs), which are more than 200 nucleotides in length and with limited protein‐coding potential, play vital roles in the pathogenesis, tumorigenesis, and angiogenesis of cancers. Aberrant expression of lncRNAs has been detected in various carcinomas and may be correlated with oncogenesis by affecting related genes expression. Recently, an increasing number of studies have reported on long intergenic non‐protein coding RNA 460 (LINC00460) in human tumor fields. LINC00460 is upregulated in diverse cancer tissues and cells. The upregulated expression level of LINC00460 is correlated with larger tumor size, tumor node metastasis (TNM) stage, lymph node metastasis, and shorter overall survival. The regulatory mechanism of LINC00460 was complex and diverse. LINC00460 could act as a competitive endogenous RNA (ceRNA), directly bind with proteins or regulate multiple pathways, which affected tumor progression. Moreover, LINC00460 was also identified to increase drug resistance, and therefore, weaken the effectiveness of tumor treatment. It has become increasingly important to investigate the roles of LINC00460 in various cancers by different mechanisms. Therefore, a more comprehensive understanding of LINC00460 is crucial to expound on the cellular function and molecular mechanism of human cancers. In this review, we refer to studies concerning LINC00460 and provide the basis for the evaluation of LINC00460 as a predicted biomarker or potential therapeutic target in malignancies, and also provide ideas for the future research of lncRNAs similar to LINC00460., In recent years, the regulatory role of long noncoding RNAs (lncRNAs) in human tumors has been gradually recognized. In this review, we respectively showed how lncRNA LINC00460 affected progression of human tumors in different types by multiple mechanisms. A large number of previous researches have demonstrated that LINC00460 as an oncogene plays important roles in tumor growth, development, and metastasis. In view of the important role of LINC00460 in tumorigenesis and development as well as its significance as a biomarker, we summarized the specific role and molecular mechanism of LINC00460 in various tumors, convenient for readers integrally learning about the effect of LINC00460 on diverse cancers. We believe this review is valuable for all the researchers who are interested in human cancers and noncoding RNAs.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects newborns who need oxygen therapy, and high-concentration oxygen therapy may cause neonatal morbidity and mortality in newborns. E26 oncogene homologue 1 (ETS1) and transglutaminase 2 (TGM2) have been reported to be associated with lung cell injury. However, the mechanism of ETS1 in regulating BPD is still unclear. Hyperoxia-induced A549 cells to simulate hyperoxia-induced alveolar epithelial cell injury. MTT assays and colony formation assays were performed to investigate the proliferation of A549 cells. Flow cytometry was carried out to quantify the apoptosis of A549 cells. The expression levels of ETS1 and TGM2 were quantified by qRT–PCR. The protein expression levels of ETS1, TGM2, β-catenin, c-Jun and MET were measured by western blot. Overexpression of ETS1, overexpression of TGM2, overexpression of ETS1 with downregulation of TGM2 and overexpression of TGM2 with inhibition of Wnt/β-catenin pathway were performed to investigate the role of ETS1, TGM2 and Wnt/β-catenin pathways in hyperoxia-induced alveolar epithelial cell injury. Hyperoxia decreased the proliferation and promoted the apoptosis of cells in a time-dependent manner. Moreover, overexpression of ETS1 rescued the effect of hyperoxia on proliferation and apoptosis. In addition, overexpression of TGM2 participated in the regulation of hyperoxia-induced proliferation and apoptosis. ETS1 regulated hyperoxia-induced alveolar epithelial cell injury through the Wnt/β-catenin pathway via TGM2. ETS1 ameliorates hyperoxia-induced alveolar epithelial cell injury through the TGM2-mediated Wnt/β-catenin pathway.

BACKGROUND AND AIMS Intertumoral accumulation of regulatory T cells (Tregs) has been implicated in the pathogenesis of HCC. Because of poor understanding of the immunosuppression mechanism(s) in HCC, immunotherapy is largely unsuccessful for the treatment of HCC. APPROACH AND RESULTS Hydrodynamic injection (HDI) of c-Myc into mice resulted in enlarged spleens and lethal HCC associated with an increase in hepatic Tregs and depletion of CTLs (cytotoxic T lymphocytes). Malignant hepatocytes in c-Myc mice overproduced TGFβ1, which enhanced the suppressor function of Tregs and impaired the proliferation and cytotoxicity of CTLs. In addition to activating TGFβ signaling, c-Myc synergized with Yin Yang 1 to impair microRNA-206 (miR-206) biogenesis. HDI of miR-206 fully prevented HCC and the associated enlargement of the spleen, whereas 100% of control mice died from HCC within 5-9 weeks postinjection. Mechanistically, by directly targeting errant kirsten ras oncogene (KRAS) signaling, miR-206 impeded the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) axis that drives expression of Tgfb1. By blocking the KRAS/MEK/ERK axis, miR-206 prevented TGFβ1 overproduction, thereby impairing the suppressor function and expansion of Tregs, but enhancing the expansion and cytotoxic program of CTLs. Disrupting the interaction between miR-206 and Kras offset the roles of miR-206 in inhibiting immunosuppression and HCC. Depletion of CD8+ T cells impaired the ability of miR-206 to inhibit HCC. CONCLUSIONS c-Myc-educated hepatocytes promoted immunosuppression by overproducing TGFβ1, which promoted HCC development. miR-206, by attenuating TGFβ1 overproduction, disrupted the communication of malignant hepatocytes with CTLs and Tregs, which prevented HCC. miR-206 represents a potential immunotherapeutic agent against HCC.

Recent studies have reported that MLST8 is upregulated in many malignant tumors. Nevertheless, the underlying molecular mechanism is still unclear. The aim of this work was to investigate how MLST8 contributes to the development and progression of clear cell renal cell carcinoma (ccRCC). MLST8 is an oncogenic protein in the TCGA database and ccRCC clinical specimens. We also ascertain that MLST8 interacts with FBXW7, which was universally regarded as an E3 ubiquitin ligase. MLST8 can be degraded and ubiquitinated by tumor suppressor FBXW7. FBXW7 recognizes a consensus motif (T/S) PXX (S/T/D/E) of MLST8 and triggers MLST8 degradation via the ubiquitin‐proteasome pathway. Strikingly, the activated cyclin dependent kinase 1 (CDK1) kinase engages in the MLST8 phosphorylation required for FBXW7‐mediated degradation. In vitro, we further prove that MLST8 is an essential mediator of FBXW7 inactivation‐induced tumor growth, migration, and invasion. Furthermore, the MLST8 and FBXW7 proteins are negatively correlated in human renal cancer specimens. Our findings suggest that MLST8 is a putative oncogene that functions via interaction with FBXW7, and inhibition MLST8 could be a potential future target in ccRCC treatment., Schematic diagram of the CDK1‐FBXW7α signaling axis in the regulation of MLST8 protein degradation.

Tissue inhibitor matrix metalloproteinase 1 (TIMP1) has been reported to act as a tumor oncogene in colon cancer. However, little is known about the biological role of TIMP1 in gastric cancer. In this study, we found that the expression of TIMP1 in GC tissues was upregulated compared with the normal gastric tissues. TIMP1 was confirmed as a direct target of miR-6745 and silencing TIMP1 mimicked the effects of miR-6745 in GC cells. Further mechanism studies have shown that miR-6745 inhibits the Wnt/β-catenin pathway by targeting TIMP1, thereby inhibiting cell proliferation, migration and invasion. In addition, through the analysis of GC tissues, a negative correlation between miR-6745 and TIMP1 was found in 42 GC tissues. Our findings indicate that the miR-6745-TIMP1 axis regulates Wnt/βcatenin signaling and participates in GC tumorigenesis and provide a potential therapeutic target for preventing GC progression.

The development of innate and/or acquired resistance to human epidermal growth factor receptor type-2 (HER2)-targeted therapy in HER2-positive breast cancer (HER2 + BC) is a major clinical challenge that needs to be addressed. One of the main mechanisms of resistance includes aberrant activation of the HER2 and phosphatidylinositol 3-kinase/AKT8 virus oncogene cellular homolog/mammalian target of rapamycin (PI3K/Akt/mTOR) pathways. In the present work, we propose to use a triple combination therapy to combat this resistance phenomenon. Our strategy involves evaluation of two targeted small molecule agents, everolimus and dasatinib, with complementary inhibitory circuitries in the PI3K/Akt/mTOR pathway, along with a standard cytotoxic agent, paclitaxel. Everolimus inhibits mTOR, while dasatinib inhibits Src, which is a protein upstream of Akt. An over-activation of these two proteins has been implicated in approximately 50% of HER2 + BC cases. Hence, we hypothesize that their simultaneous inhibition may lead to enhanced cell-growth inhibition. Moreover, the potent apoptotic effects of paclitaxel may help augment the overall cytotoxicity of the proposed triple combination in HER2 + BC cells. To this end, we investigated experimentally and assessed computationally the in vitro pharmacodynamic drug-drug interactions of the various dual and triple combinations to assess their subsequent combinatorial effects (synergistic/additive/antagonistic) in a HER2-therapy resistant BC cell line, JIMT-1. Our proposed triple combination therapy demonstrated synergism in JIMT-1 cells, thus corroborating our hypothesis. This effort may form the basis for further investigation of the triple combination therapy in vivo at a mechanistic level in HER2-therapy resistant BC cells.

Cancer is one of the most devastating diseases worldwide and definitive therapeutics for treating cancer are not yet available despite extensive research efforts. The key challenges include limiting factors connected with traditional chemotherapeutics, primarily drug resistance, low response rates, and adverse side-effects. Therefore, there is a high demand for novel anti-cancer drugs that are both potent and safe for cancer prevention and treatment. Gallic acid (GA), a natural botanic phenolic compound, can mediate various therapeutic properties that are involved in anti-inflammation, anti-obesity, and anti-cancer activities. More recently, GA has been shown to exert anti-cancer activities via several biological pathways that include migration, metastasis, apoptosis, cell cycle arrest, angiogenesis, and oncogene expression. This review discusses two aspects, one is the anti-cancer potential of GA against different types of cancer and the underlying molecular mechanisms, the other is the bibliometric analysis of GA in cancer and tumor research. The results indicated that lung cancer, prostate cancer, stomach cancer, and colon adenocarcinoma may become a hot topic in further research. Overall, this review provides evidence that GA represents a promising novel, potent, and safe anti-cancer drug candidate for treating cancer.

Background: Prostate cancer (PCa) is a commonly diagnosed malignant cancer and is the second- highest cause of cancer death in men worldwide. Enzalutamide is the second-generation inhibitor of androgen receptor signaling and is the fundamental drug for the treatment of advanced PCa. However, the disease will eventually progress to metastatic castration-resistant prostate cancer (CRPC) and aggressive neuroendocrine prostate cancer (NEPC) because of androgen-deprivation therapy (ADT) resistance. The aim of the study was to investigate the role of long non-coding RNA (lncRNA) AFAP1-AS1 in ADT resistance. Methods: Quantitative real-time PCR analysis (qPCR) was used to assess the expression of AFAP1-AS1 in PCa cell lines and tissues. Cell proliferation and invasion were assessed after AFAP1-AS1 knockdown using Cell Counting Kit (CCK)-8 and Transwell assay, respectively. A dual-luciferase reporter gene assay was carried out to validate the regulatory relationship among AFAP1-AS1, microRNA (miR)-15b, and insulin-like growth factor1 receptor (IGF1R). Results: AFAP1-AS1 level was markedly increased in castration-resistant C4-2 cells and NE-like cells (PC3, DU145, and NCI-H660), compared with androgen-sensitive LNCaP cells. Enzalutamide treatment increased the expression of AFAP1-AS1 in vitro and in vivo. Functionally, AFAP1-AS1 knockdown repressed tumor cell proliferation and invasion. Mechanistically, AFAP1-AS1 functioned as an oncogene in PCa through binding to miR-15b and destroying its tumor suppressor function. Finally, we identified that AFAP1-AS1 up-regulated IGF1R expression by competitively binding to miR-15b to de-repress IGF1R. Conclusion: AFAP1-AS1 facilitates PCa progression by regulating miR-15b/IGF1R axis, indicating that AFAP1-AS1 may serve as a diagnostic biomarker and therapeutic target for PCa.

Background Rearranged during transfection (RET) is a targetable oncogene. RET fusions have been reported in patients with metastatic colorectal cancer (mCRC). However, RET mutations in mCRC are less studied. Here, we aimed to characterize the clinical, pathological, and molecular landscape of RET‐mutated mCRC. Methods Five hundred and eighty‐two patients were included in this study. Next‐generation sequencing was performed to detect RET mutations and calculate tumor mutation burden (TMB). We compared the clinical, pathological, and molecular characteristics of mCRC cases with tumors that harbored somatic RET mutations (N = 16, 2.7%) or had wild‐type RET (N = 566, 97.3%). Results Males comprised the absolute majority of cases with RET mutations (15/16 [93.8%]) compared to their fraction among cases with wild‐type RET (339/566 [59.9%]). Furthermore, all patients with RET mutations were younger than 60 years (16/16 [100%]), whereas such patients were less predominant in the group with wild‐type RET (379/566 [67.0%]). Individuals with tumors positive for RET mutations more frequently exhibited mucinous histology (5/16 [31.2%] vs. 55/566 [9.7%]), exhibited a lower incidence of liver metastasis (4/16 [25.0%] vs. 335/566 [59.2%]), and higher incidence of peritoneal metastasis (9/16 [56.2%] vs.161/566 [28.4%]), expressed wild‐type TP53 (8/16 [50.0%] vs.120/566 [21.2%]), and showed an increased frequency of MSI‐high (6/16 [37.5%] vs. 18/566 [3.2%]). In those with microsatellite‐stable mCRC, patients with RET mutations had a higher median TMB than patients with wild‐type RET (9.4 vs. 6.7 mutations/Mb, respectively, p = 0.001). The median progression‐free survival was similar in individuals with mutated and wild‐type RET on the oxaliplatin‐based regimen (7.1 vs. 8.7 months, p = 0.516). Conclusions Our study suggests that cases with RET mutations represent a separate mCRC subtype. Further studies are needed to evaluate the efficacy of RET inhibitors in mCRC patients with RET mutations., RET mutations were enriched in male patients and those younger than 60 years.

Long noncoding RNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1) is abnormally expressed in numerous tumors and functions as an oncogene, but the role of NEAT1 in laryngocarcinoma is largely unknown. Our study validated that NEAT1 expression was markedly upregulated in laryngocarcinoma tissues and cells. Downregulation of NEAT1 dramatically suppressed cell proliferation and invasion through inhibiting miR-524-5p expression. Additionally, NEAT1 overexpression promoted cell growth and metastasis, while overexpression of miR-524-5p could reverse the effect. NEAT1 increased the expression of histone deacetylase 1 gene (HDAC1) via sponging miR-524-5p. Mechanistically, overexpression of HDAC1 recovered the cancer-inhibiting effects of miR-524-5p mimic or NEAT1 silence by deacetylation of tensin homolog deleted on chromosome ten (PTEN) and inhibiting AKT signal pathway. Moreover, in vivo experiments indicated that silence of NEAT1 signally suppressed tumor growth. Taken together, knockdown of NEAT1 suppressed laryngocarcinoma cell growth and metastasis by miR-524-5p/HDAC1/PTEN/AKT signal pathway, which provided a potential therapeutic target for laryngocarcinoma.

Burkitt lymphoma/leukemia (BL/L) is an aggressive mature B-cell malignancy cytogenetically characterized by the translocation t(8;14)(q24;q32) or its variants, which determines the juxtaposition of the MYC oncogene to one of the three immunoglobulin loci. In addition to MYC translocations, different secondary genetic abnormalities have been described, some of them with prognostic significance. However, dual translocations of chromosome 14, except those involving chromosome 18, are very rare events in this pathology. Herein, we present the coexistence of translocations t(8;14) and t(14;15) in a pediatric BL/L patient. To our knowledge, this is the first report of a translocation t(14;15)(q32;q22) as a secondary alteration in a BL/L patient. The patient had multiple complications at diagnosis but he evolved favorably reaching complete remission. The description of new secondary alterations in this pathology as well as their impact on clinical evolution, add information to the biological characterization of BL, contributing to a higher accuracy in the diagnosis and/or prognosis of the disease.

Background Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Its therapy has not significantly improved during the past four decades despite intense research efforts. New molecularly targeted therapies are in great need. The proto-oncogene c-Myc (MYC) is an attractive target due to its transactivation role in multiple signaling cascades. Deregulation of the MYC is considered one of a series of oncogenic events required for tumorigenesis. However, limited knowledge is available on which mechanism underlie MYC dysregulation and how long non-coding RNAs (lncRNAs) are involved in MYC dysregulation in AML. Methods AML microarray chips and public datasets were screened to identify novel lncRNA GAS6-AS1 was dysregulated in AML. Gain or loss of functional leukemia cell models were produced, and in vitro and in vivo experiments were applied to demonstrate its leukemogenic phenotypes. Interactive network analyses were performed to define intrinsic mechanism. Results We identified GAS6-AS1 was overexpressed in AML, and its aberrant function lead to more aggressive leukemia phenotypes and poorer survival outcomes. We revealed that GAS6-AS1 directly binds Y-box binding protein 1 (YBX1) to facilitate its interaction with MYC, leading to MYC transactivation and upregulation of IL1R1, RAB27B and other MYC target genes associated with leukemia progression. Further, lentiviral-based GAS6-AS1 silencing inhibited leukemia progression in vivo. Conclusions Our findings revealed a previously unappreciated role of GAS6-AS1 as an oncogenic lncRNA in AML progression and prognostic prediction. Importantly, we demonstrated that therapeutic targeting of the GAS6-AS1/YBX1/MYC axis inhibits AML cellular propagation and disease progression. Our insight in lncRNA associated MYC-driven leukemogenesis may contribute to develop new anti-leukemia treatment strategies.

Drug resistance is a huge challenge during the management of diseases. MicroRNA (miRNA) dys-regulation is known to contribute to tumor progression. Herein we aimed to explore miR-1254’s role in drug resistance in lung cancer. In the present study, we used Pabolizumab to treat drug-resistant and non-drug resistant lung cancer cells followed by analysis of miR-1254 expression by RT-qPCR, epithelial-mesenchymal transition (EMT) related protein and c-Myc expression by western blot, E-cadherin and N-cadherin level by immunofluorescence. Additionally, mouse model of lung cancer was treated with miR-1254 mimic and/or Pabolizumab to assess miR-1254’s role in lung cancerin vivo. Drug-resistant lung cancer cells exhibited significantly increased viability upon treatment with Pabolizumab with decreased miR-1254 expression. Besides, Pabolizumab upregulated E-caderin and downregulated N-cadherin. Importantly, miR-1254 bound to c-Myc in cancer cells. In the presence of miR-1254 mimic or siRNA (si)-c-Myc, the chemosensitivity of lung cancer cells was increased whereas miR-1254 inhibitor augmented cell resistance to Pabolizumab. Furthermore, the chemosensitivity induced by c-Myc could be depleted by miR-1254 inhibitor. Combined treatment of miR-1254 mimic and Pabolizumab significantly decreased tumor weight and volume, and reduced c-Myc level. In conclusion, miR-1254 might suppress EMT by inhibiting c-Myc expression in lung cancer and decrease drug resistance.

Graphical abstract, Highlights • PIK3CB is highly expressed in PAAD. • PIK3CB is involved in PAAD progression and metastasis. • PIK3CB-depletion does not significantly affect cell viability, migration or invasion capabilities of human PAAD cells in vitro. • PIK3CB-depletion does not significantly influence growth or hepatic colonization abilities of human PAAD cells in vivo. • PIK3CB influences cell invasiveness via cell-to-collagen I interaction in human PAAD cells in vitro., Introduction Pancreatic adenocarcinoma (PAAD) is an aggressive malignancy, with a major mortality resulting from the rapid progression of metastasis. Unfortunately, no effective treatment strategy has been developed for PAAD metastasis to date. Thus, unraveling the mechanisms involved in PAAD metastatic phenotype may facilitate the treatment for PAAD patients. Objectives PIK3CB is an oncogene implicated in cancer development and progression but less is known about whether PIK3CB participates in PAAD metastasis. Therefore, the objective of this study is to explore the mechanism(s) of PIK3CB in PAAD metastasis. Methods In our study, we examined the PIK3CB expression pattern using bioinformatic analysis and clinical material derived from patients with PAAD. Subsequently, a series of biochemical experiments were conducted to investigate the role of PIK3CB as potential mechanism(s) underlying PAAD metastasis in vivo using nude mice and in vitro using cell lines. Results We observed that PIK3CB was involved in PAAD progression. Notably, we identified that PIK3CB was involved in PAAD metastasis. Downregulation of PIK3CB significantly reduced PAAD metastatic potential in vivo. Furthermore, a series of bioinformatic analyses showed that PIK3CB was involved in cell adhesion in PAAD. Notably, PIK3CB depletion inhibited invasion potential specifically via suppressing cell adhesion to collagen I in PAAD cells. Conclusion Collectively, our findings indicate that PIK3CB is involved in PAAD metastasis through cell-matrix adhesion. We proposed that PIK3CB is a potential therapeutic target for PAAD therapy.