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Aim To investigate what cell death mode is dominat in non-small cell lung cancer (NSCLC) tissue and cell line, and the role played byMDM2-p53 pathway in the transition of pyroptosis to apoptosis during chemotherapy Materials and Methods Patients with NSCLC were consecutively recruited in Gansu Provincial Hospital from December 2016 to January 2018. The protein expressions of GSDMD, GSDME, and MDM2 were compared between cancer and adjacent tissues in NSCLC patients, as well as between normal human respiratory epithelium HBE cells and A549 carcinoma cells. A549 and HBE cells were treated with Nutlin-3 to inhibit the MDM2 function in the presence of 5-Fluorouracil (5-FU). Results Both GSDMD and GSDME were expressed in NSCLC tissues, while only GSDME was expressed in A549 and HBE cells. The execution effective N-terminal of GSDME, but not of GSDMD was expressed in NSCLC tissue, and A549 and HBE cells after chemotherapeutic drug treatments. GSDME overexpression in both A549 and HBE cells increased pyroptosis. The expression of MDM2 measured by IHC was significantly higher in cancer tissues. Nutlin-3, a specific inhibitor of MDM2 binding to P53, significantly decreased the total cell survival rate and pyroptosis, but increased apoptosis in A549 cells treated with 5-FU. Nutlin-3 did not show any effect on HBE cells. Conclusions GSDME expression in the lung carcinoma determines pyroptosis sensitivity and the occurrence of severe side effects. MDM2 inhibition shifts pyroptosis to apoptosis, which may be useful in increasing the anti-tumor effects and preventing pyroptosis-induced side effects in lung cancer chemotherapy.

Colorectal cancer (CRC) is a serious threat to human physical and mental health. Due to the novelty of the open reading frame (ORF), ORF has shown a wide range of new genetic associations in cancer. The purpose of this study was to explore the association between the C2orf71 SNPs and CRC susceptibility.We recruited 1419 participants to perform an association analysis between C2orf71 SNPs and CRC risk through SNPStats online solftware. Genotyping was completed by the AgenaMassARRAY. In addition, we used false-positive report probability analysis to detect whether the positive findings were noteworthy observations. We also used Haploview 4.2 software and SNPStats online software to conduct the haplotype analysis and analysis of linkage disequilibrium (LD). Finally, the interaction of SNP-SNP in CRC risk was evaluated by multi-factor dimensionality reduction (MDR).The overall analysis showed thatC2orf71-rs17744093, -rs10200693, and -rs13385188 were significantly associated with the CRC susceptibility. C2orf71-rs17744093 was associated with CRC risk under dominant model (OR = 1.25, p = 0.048). -rs10200693 was associated with CRC risk under allele (OR = 1.17, p = 0.041) and log-additive model (OR = 1.16, p = 0.045). -rs13385188 had significant association with CRC risk under multiple genetic models (allele: OR = 1.19, p = 0.023; log-additive: OR = 1.18, p = 0.026). Multiple stratified analyses showed that except for the three candidate SNPS mentioned above, -rs10166913 (age 60 years and drinking) and -RS17007544 ( 60 years) were associated with increased CRC risk.C2orf71-rs17744093, -rs10200693, -rs10166913, -rs17007544, and -rs13385188 were associated with CRC susceptibility.

Macrophages, which are highly plastic, can be polarized to M1 or M2 subtypes according to the diverse signals in complex microenvironment. Studies have shown the activation of YAP, an oncogenic transcriptional co-activator, increased macrophage recruitment. However, its role in macrophage polarization remains to be elucidated, especially in triple-negative breast cancer (TNBC) progression. Here we found TNBC cells increased YAP expression in macrophages, which depended on OTUD5-mediated deubiquitination and stabilization of YAP, then the high expression of YAP polarized macrophage to the M2-like phenotype. Moreover, the elevation of YAP in M2-like macrophage promotes the pro-metastatic potential of TNBC cells via MCP-1/CCR2 pathway. We also observed high expression of YAP in M2 macrophage was negatively related to survival. Collectively, our finding suggested the therapeutic strategy that targets YAP+ M2 macrophage could be a novel option for TNBC treatment.

To construct a prediction model of solitary pulmonary nodules (SPNs), to predict the possibility of malignant SPNs in patients aged 15-85 years in northwest China for clinical diagnostic and therapeutic decision-making.The features of SPNs were assessed by multivariate logistic regression, followed by visualization using a nomogram. Hosmer lemeshow was applied to evaluate the fitting degree of the model. The area under the receiver operating characteristic (ROC) curve was identified to determine the discriminative ability of the model.Lobulation, spiculation, pleural-tag, carcinoembryonic antigen, neuron-specific enolase, and total serum protein were independent predictors of malignant pulmonary nodules (p .05). Lobulation (100 points) scored the highest in the nomogram, and the Hosmer-Lemeshow goodness-of-fit statistic was 0.805 (p .05). The area under curve (AUC) of the modeling and validation groups using logistic regression were 0.859 (95% CI, 0.805-0.903) and 0.823 (95% CI, 0.738-0.890), respectively. Moreover, the AUC of our model was higher than that of the Mayo model, VA model, and Peking University (AUC 0.823 vs. 0.655 vs. 0.603 vs. 0.521).Our prediction model is more suitable for predicting the possibility of malignant SPNs in northwest China, and can be calculated using a nomogram to determine further treatments.

The Notch1 (Notch1 receptor) and yes-associated protein 1 (YAP1) signaling can regulate breast cancer metastasis. This study aimed at investigating whether and how these two signal pathways crosstalk to promote breast cancer lung metastasis. Here, we show that YAP1 expression was positively correlated with Notch1 in breast cancer according to bioinformatics and experimental validation. Mechanistically, YAP1 with TEA domain transcription factors (TEADs) enhanced Jagged1(JAG1)-Notch1 signaling. Meanwhile, Notch1 promoted YAP1 stability in breast cancer cells by inhibiting the β-TrCP-mediated degradation, thereby, forming a YAP1- JAG1/Notch1 positive feedback loop in breast cancer. Furthermore, YAP1 enhanced the mammosphere formation and stemness of MDA-MB-231 cells by attenuating the inhibition of the BMP4-SMAD1/5 signaling. In vivo, the YAP1- JAG1/Notch1 positive feedback loop promoted the lung colonization of MDA-MB-231 cells. Our data for the first time indicate that the YAP1-Notch1 positive feedback loop promotes lung metastasis of breast cancer by modulating self-renewal and inhibiting the BMP4-SMAD1/5 signaling.

The tumor microenvironment (TME) is a crucial factor in cancer progression. In breast cancer, cancer-associated fibroblasts (CAFs) and the derived stromal components have been recognized as comprising the majority of the pathological structure of the TME. In this study, we show that metformin (Met), a diabetes drug, transforms CAFs in the TME. Met disrupts tumor-stromal cross talk by preventing breast cancer cell transforming growth factor-β (TGF-β) signaling and the production of stromal-derived factor-1 (SDF-1) and interleukin-8 (IL-8) by CAFs. The suppression of bidirectional signaling between tumor cells and CAFs by Met is attributed to increased phospho-AMP kinase (p-AMPK) levels. By upregulating p-AMPK in CAFs, Met induces prolyl hydroxylases (PHDs), leading to the degradation of hypoxia-inducible factor-1α (HIF-1α) in CAFs. Moreover, interruption of HIF-1α-driven SDF-1 signaling in CAFs by Met leads to decreased breast cancer cell invasion. These findings suggest that Met may be used to target tumor-promoting signaling between CAFs and breast cancer cells in the TME.

Gastric cancer (GC) is the most deadly gastrointestinal malignancy with high incidence and mortality. Although, molecular mechanisms which drive gastric cancer progression are extensively investigated, the roles of long noncoding RNA (lncRNA) in gastric cancer growth and drug sensitivity remain unclear. Platinum is a mainstay to treat gastric cancer, and platinum resistance always leads to the local recurrence of gastric cancer. Therefore, it is important to identify biomarkers or therapeutic targets to sensitize gastric cancer to platinum. In this study, we employ noncoding RNA sequencing and found that lncRNA PITPNA-AS1 is overexpressed in gastric cancer tissues and associated with poor survival of gastric cancer patients. Kockdown of PITPNA-AS1 in gastric cancer cells significantly inhibited cell growth and triggered apoptotic cell death in gastric cancer cells. Also, cisplatin treatment could decrease PITPNA-AS1 levels in gastric cancer cells through inhibiting H3K27ac. Besides, PITPNA-AS1 is elevated in cisplatin-resistant gastric cancer cells and tissues, PITPNA-AS1 knockdown could sensitize gastric cancer cells to cisplatin treatment. Furthermore, we identified that PITPNA-AS1 directly interacts and inhibits miR-98-5p. Therefore, PITPNA-AS1 could be served as a potential biomarkers and curative therapeutic targets for gastric cancer progression.

Nanostructured multilayer thin films (Ag/W, Cu/Ru, Cu/W), consisting of alternating ductility/brittle layers with wide ranges of modulation period (Λ) and modulation ratio (η), were prepare...

The recurrence and metastasis of breast cancer limit the effectiveness of clinical treatments, making them important issues for clinicians to address. Tumor‑associated macrophages (TAMs) contribute to regulating the immune system. C‑C motif chemokine ligand 5 (CCL5) is an inflammatory chemokine that promotes chemotaxis on cells involved in the immune/inflammatory response. Breast cancer cells that secrete CCL5 act on THP‑1 cells, influencing the invasion and metastasis of tumors. However, knowledge remains limited regarding the mechanism underlying the effects of CCL5 on breast cancer cells and TAMs, as well as the mechanisms promoting the migration and invasion of breast cancer. The present study demonstrated that the positive expression of CCL5 was associated with lymph node status and tumor‑node‑metastasis stage. Treatment with ≥20 ng/ml CCL5 significantly promoted the migration and invasion of MCF‑7 and MDA‑MB‑231 cells. CCL5‑small interfering RNA intervention significantly decreased the migration and invasion of the two cell types. In vitro, THP‑1 cells were successfully induced to become TAMs, which were then recruited via the chemotactic effects of CCL5. This process was achieved through the co‑stimulation of phorbol‑12‑myristate‑13‑​acetate, interleukin‑4 (IL‑4) and IL‑13. The nuclear factor‑κB (NF‑κB) signaling pathway was activated to regulate EMT, as well as the migration and invasion process of MCF‑7 cells, when co‑cultured with TAMs. We also reported that blocking the expression of CCL5 in vivo may significantly inhibit the growth of human breast cancer xenografts. Therefore, targeting CCL5 may be considered as a novel therapeutic strategy for suppressing the invasion and metastasis of breast cancer.

Human epidermal growth factor receptor (HER)‑2‑positive breast cancer accounts for ~25% of all breast cancer cases, has a high propensity for relapse, metastasis and drug resistance, and is associated with a poor prognosis. Therefore, it is necessary to develop more effective therapeutic targets for the treatment of HER‑2‑positive breast cancer. CD44+/CD24‑/low is currently the most commonly used marker for breast cancer stem cells (CSCs), which are considered the main cause of drug resistance, relapse and metastasis. In the present study, the ratio of CD44+/CD24‑/low cells was almost zero in SK‑BR‑3 cells; however, it was >90% in MDA‑MB‑231 cells, as determined by flow cytometry. Since SK‑BR‑3 and MDA‑MB‑231 cells both exhibit a strong propensity for invasion and migration, it was hypothesized that there may be other markers of CSCs in SK‑BR‑3 cells. Therefore, transcriptome sequencing was performed for SK‑BR‑3 and MDA‑MB‑231 cells. It was observed that several leukocyte differentiation antigens and other CSC markers were significantly more highly expressed in SK‑BR‑3 cells. Furthermore, the expression of aldehyde dehydrogenase (ALDH)1A3, CD164 and epithelial cell adhesion molecule (EpCAM) was higher in SK‑BR‑3 cells compared with in other subtypes of breast cell lines, as determined by reverse transcription‑polymerase chain reaction and western blot analysis. In addition, the expression levels of ALDH1A3, ALDH3B2 and EpCAM were higher in HER‑2‑positive breast cancer compared with in paracancerous tissues and other subtypes of breast cancer, as determined by immunohistochemistry. The expression of β‑catenin in the Wnt signaling pathway was lower in SK‑BR‑3 cells compared with in MDA‑MB‑231 cells, which may be used as a prognostic indicator for breast cancer. These findings may help identify novel CSC markers and therapeutic targets for HER‑2‑positive breast cancer.

Protein-protein interactions (PPIs) play an important role in almost all vital processes involved in many diseases, especially cancer. Peptides are perfect candidates that modulate PPIs as they can closely mimic principle features of protein. However, the intrinsic drawbacks of peptides, including poor stability and member impenetrability, severely limit the development of peptide-derived therapeutics. Nanotechnology offers a feasible route for anti-cancer peptide delivery, but much remains to be done, especially with respect to the pressing need for a simple method for efficient delivery of peptides into sites of interest towards potent and safe therapy. Herein, we report a one-step method to conjugate lanthanide-doped nanoparticles with p53-activating peptide (PMI: TSFAEYWALLSP), Bcl2-blocking peptide (BIM: IWIAQELRRIGDEFNAYYARR) and CD13-binding peptide (iNGR: CRNGRGPDC) by mercaptogenic self-assembly. The resultant LDN-iNGRPMI-BIM nanoparticles can tumor-specifically accumulate at interest sites, and potently induce apoptosis of cancer cells in vitro and in vivo, while keeping a favorable biosafety profile. Taken together, the general therapeutically viable method reported here will enable us to develop a novel class of peptide-based nanomedicines, and likely reinvigorate peptide drug discovery efforts in general, which will target intracellular protein-protein interactions responsible for initiation and progression of a great variety of human diseases.

Single nucleotide polymorphisms (SNPs) in interleukin-23 receptor (IL23R) are involved in the pathogenesis of many cancers and autoimmune diseases. IL23R gene is still controversial in the study of esophageal cancer. The aim of this research is to investigate the influence of IL23R SNPs on the risk of esophageal cancer. Five hundred six esophageal cancer and 507 controls frequency matched by age and gender were conducted, and the genotypes were determined by the Agena MassARRAY. Logistic regression analysis was used to evaluate the odd ratios (ORs) and 95% confidence intervals (CIs) of rs1884444 and rs6682925 with susceptibility of esophageal cancer. A total of 30 articles are eligible. Pooled ORs and the 95% CI were calculated using the random-effect model. Database predicts the expression of IL23R gene in esophageal cancer. IL23R rs1884444 allele G decreased the risk of esophageal cancer under allele, genotype, and additive models (allele model: OR = 0.82, 95% CI: 0.68-0.98, P = .032; genotype model: OR = 0.65, 95% CI: 0.44-0.97, P = .035; additive model: OR = 0.82, 95% CI: 0.68-0.98, P = .031). Meta-analysis shown that IL23R rs1884444 increased the risk of overall disease in allele model (OR = 1.16, 95% CI: 1.08-1.25, P < .001), and also increased the risk of gastrointestinal tumor (OR = 1.18, 95% CI: 1.05-1.31, P = .005). The database analysis showed that the expression of IL23R gene was upregulated in esophageal cancer tissues. IL23R rs1884444 may play an important role in the susceptibility of esophageal cancer.

Zinc finger protein family is the largest transcription factor family in the human genome. Studies have shown that the aberrant expression of zinc finger protein (ZNF) had a potential role in tumorigenesis. However, due to the high complexity of the ZNF family genes, the role of the ZNF family genes in breast cancer (BRCA) is still lacking in systematic understanding.In the study, we aim to understand the expression profile, prognostic value, immune invasion pattern, tumor microenvironment, epigenetic and pathway relationships, and drug sensitivity of ZNFs using multi-omics data from public databases.We focused on six members of ZNFs, which were upregulated in a variety of cancers. Notably, ZNF750 and ZNF224 were lower expressed in BRCA, and their expressions were significantly associated with BRCA prognosis. We confirmed the observations obtained by analyzing the clinic-pathological data. Otherwise, the expressions of ZNFs were significantly related to stromal and immune scores, and was significantly different among different immune subtypes in BRCA. Here, we found down-regulated methylation of ZNF217 and ZNF750. The relationship between methylation and survival showed the survival was worse for hypo-methylation of ZNF750 in BRCA, which is consistent with the correlation of high expression of ZNF750 in BRCA with worse survival.Collectively, our results provide clues for a better understanding of the characterization of ZNF family genes in BRCA from a multi-omics perspective and show their potential for use as new tumor markers and therapeutic targets.

Citron kinase (CIT-K), as a key Rho effector, functions to maintain proper structure of the midbody during cell mitosis. This study assessed CIT-K expression and its role in breast cancer cells. Paraffin-embedded breast cancer and para-tumor tissues from 43 invasive breast cancer patients and 33 normal mammary glands were collected for immunohistochemistry. CIT-K expression knockdown was achieved using lentivirus carrying CIT-K shRNA in a wide range of breast cancer cell lines. Cells were then subjected to Western blot, qRT-PCR, cell proliferation, colony formation, transwell, and flow cytometric assays. The tumorigenicity of CIT-K knocked-down breast cancer cells was assessed using the nude mouse xenograft assay. Microarray analysis was performed to elucidate the underlying gene regulation after CIT-K silencing. CIT-K protein was overexpressed in breast cancer tissues, which is associated with advanced tumor stage, HER-2 expression and Ki-67 expression, whereas knockdown of CIT-K expression reduced breast cancer cell proliferation and colony formation, but promoted tumor cell apoptosis and cell-cycle arrest. Knockdown of CIT-K expression also inhibited breast cancer cell migration and invasion capacity. Moreover, CIT-K knockdown suppressed the tumorigenicity of breast cancer cells in nude mice. Molecularly, the expression of a variety of signaling genes, such as cyclin D1, EGFR, JAK1, TGF-α, PTK2, RAF1, RALB, SOS1, mTOR, and PTGS2, were altered after CIT-K knockdown. This study demonstrated that CIT-K is associated with aggressive breast cancer behavior and targeting CIT-K may be a novel strategy for the future control of breast cancer.

The pre-metastatic niche has been shown to play a critical role in tumor metastasis, and its formation is closely related to the tumor microenvironment. However, the underlying molecular mechanisms remain unclear. In the present study, we successfully established a mouse model of lung metastasis using luciferase-expressing MDA-MB-435s cells. In this model, recruitment of vascular endothelial growth factor receptor-1 (VEGFR1)+CD133+ hematopoietic progenitor cells (HPCs) was gradually increased in lung but gradually decreased after the formation of tumor colonies in lung. We also established a highly metastatic MDA-MB-435s (MDA-MB-435s-HM) cell line from the mouse model. Changes in protein profiles in different culture conditions were investigated by protein microarray analysis. The levels of CXC chemokine ligand 16, interleukin (IL)-2Rα, IL-2Rγ, matrix metalloproteinase (MMP)-1, MMP-9, platelet-derived growth factor receptor (PDGFR)-α, stromal cell-derived factor (SDF)-1α, transforming growth factor (TGF)-β, platelet endothelial cell adhesion molecule (PECAM)-1 and vascular endothelial (VE)-cadherin were significantly greater (> fivefold) in the culture medium from MDA-MB-435s-HM cells than in that from MDA-MB-435s cells. Moreover, the levels of MMP-9, PDGFR-α, and PECAM-1 were significantly greater in the co-culture medium of MDA-MB-435s-HM cells and CD133+ HPCs than in that from MDA-MB-435s-HM cells. Differentially expressed proteins were validated by enzyme-linked immunosorbent assay, and expression of their transcripts was confirmed by quantitative real-time polymerase chain reaction. Moreover, inhibition of MMP-9, PDGFR-α, and PECAM-1 by their specific inhibitors or antibodies significantly decreased cell migration, delayed lung metastasis, and decreased recruitment of VEGFR1+CD133+ HPCs into lung. Intra-hepatic growth of HPCs enhanced the invasive growth of MDA-MB-435s-HM cells in the liver. Our data indicate that VEGFR1+CD133+ HPCs contribute to lung metastasis.

Background Interleukin 7 receptor (IL-7R) is a member of the type I cytokine receptor family, which affects the occurrence of various tumors by forming a signaling complex with its ligand Interleukin 7 (IL-7). This study aimed to explore the potential relationships of IL-7R polymorphisms with breast cancer susceptibility in the Chinese Han women. Methods Five polymorphisms of IL-7R gene (rs969129, rs10213865, rs10053847, rs118137916, and rs6451231) form 553 patients and 550 healthy individuals among the Chinese Han women were genotyped using Agena MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to evaluate the relationship. Results The resulted of this study showed that rs10213865 was related to an increased breast cancer risk in allele (P = 0.045), dominant (P = 0.040), and log-additive (P = 0.029) models. As for rs969129, an increased risk of breast cancer was found in the allele (P = 0.018), co-dominant (P = 0.017), recessive (P = 0.034), and additive (P = 0.019) models. Rs6451231 was related to an increased risk of breast cancer under allele (P = 0.018), co-dominant (P = 0.021), and log-additive (P = 0.019) models. Age stratified analysis revealed that rs6451231 could enhance risk of breast cancer among the individuals older than 52 years. Furthermore, there was a significant correlation between haplotype Crs969129Grs10213865Ars10053847Grs118137916 and the decreased risk of breast cancer (P = 0.010). Conclusions This study firstly proved that IL-7R polymorphisms were significantly correlated with an increased susceptibility of breast cancer in the Chinese Han women.

The NR5A2 and RYR2 genes are important players in steroid metabolism and play an important role in cancer research. In this research, we want to evaluate the effect of NR5A2 and RYR2 polymorphisms on breast cancer (BC). Four single nucleotide polymorphisms on NR5A2 and RYR2 were selected to genotype by Agena MassARRAY in 379 BC patients and 407 healthy controls. Using the PLINK software to calculate the Odds ratio (OR) and 95% confidence intervals (CIs) via the logistic regression analysis to evaluate the risk for BC. We found that NR5A2 rs2246209 significantly decreased the risk of BC with the AA genotype (OR 0.58, 95%CI 0.34–0.99, p = 0.049), and recessive model (OR 0.59, 95%CI 0.35–0.99, p = 0.046); rs12594 in the RYR2 gene significantly decreased the risk of BC in the GG genotype (OR 0.44, 95%CI 0.22–0.88, p = 0.020), and recessive model (OR 0.43, 95%CI 0.21–0.85, p = 0.016). Further stratification analysis showed that NR5A2 rs2246209 was related to a lower incidence of BC affected by age, lymph nodes metastasis, and tumor stage; RYR2 rs12594 was related to a decreased BC risk restricted by age, estrogen receptor (ER), progesterone receptor (PR), menopausal status, tumor size, and tumor stage. Rs12594 in the RyR2 gene remained significant on the genetic susceptibility of PR-positive BC after Bonferroni correction (p

Introduction IL-7R is involved in the occurrence and development of breast cancer by binding to its ligand IL-7. This study aimed to explore the potential relationships of IL-7R polymorphisms with breast cancer susceptibility in Chinese Han women.Methods Five polymorphisms (rs969129, rs10213865, rs10053847, rs118137916, and rs6451231) of IL-7R genewere genotyped in 553 patients and 550 healthy healthy individuals from the in Chinese Han women using the Agena MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated used to evaluate the relationship.Results IL-7R rs10213865, rs969129 and rs6451231 was correlated with an increased the risk of breast cancer in multiple genetic models. Age stratified analysis revealed that rs6451231 was correlated with an increased breast cancer risk at age > 52 years. Additionally, rs10213865 was correlated with tumor site and ER expression, rs969129 was related to tumor size and Ki67 expresses status, and rs6451231was related to tumor size. Haplotype CGAG (rs969129, rs10213865, rs10053847 and rs118137916) were observed to a decrease breast cancer risk.Conclusions IL-7R polymorphism were significantly correlated with an increased breast cancer susceptibility in Chinese Han women.

[This corrects the article DOI: 10.1371/journal.pone.0103482.].

Thymoquinone (TQ, 2‐methyl‐5‐isopropyl‐1,4‐benzoquinone), a bioactive constituent extracted from the seeds of Nigella sativa, has been proved to exert anti‐tumor efficiency in various cancers. Autophagy is a self‐digestion phenomenon, and its role in tumor formation and progression remains controversial. In the present study, we investigated the effects of TQ on renal cell cancer (RCC) cell lines (786‐O and ACHN) using wound healing assay, transwell assay and western blot analysis. We found that TQ effectively inhibited the metastatic capacity of RCC cells in vitro, which was also verified in a xenograft model. Meanwhile, we observed LC3 puncta and detected the expression of LC3 in TQ‐treated RCC cells, and then found that autophagy was induced by TQ in 786‐O and ACHN cell lines. In addition, TQ inhibited the migration and invasion as well as the EMT in RCC cells in an autophagy‐dependent manner. To further explore the underlying mechanism, we detected the AMPK/mTOR signaling pathway. The results indicated that TQ inhibited the metastasis of RCC cells by inducing autophagy via AMPK/mTOR signaling pathway. In conclusion, our findings provide a novel therapeutic strategy that aims at TQ‐induced autophagy in RCC treatment.

Abnormal activation of the Wnt/β-catenin signaling pathway, which underlies multiple malignancies, promotes tumor progression; drugs that can block this pathway are therefore highly attractive candidates for anticancer therapy. Using a therapeutic peptide derived from E-cadherin region V (cECRV), we sought to develop a potent and selective antagonist of β-catenin that can disrupt the carcinogenic interaction between β-catenin and BCL9. More importantly, to overcome the pharmacological obstacles of peptide-derived therapeutics (poor nuclease stability and low membrane permeability), a gold nanoparticle (AuNP)-based nanocarrier was designed to deliver cECRV into the cytoplasm to modulate the intracellular interaction of β-catenin and BCL9. The resultant nanoparticle, pAuNP-cECRV, showed no cytotoxicity towards normal peripheral blood mononuclear cells and induced cycle arrest and subsequent apoptosis of Wnt-hyperactive cancer cells by antagonizing β-catenin to inhibit the Wnt pathway. Our results indicate that pAuNP-cECRV is very promising for application as an efficient and safe peptide delivery vector for cancer therapy.

Distinguishing the surface markers of cancer stem cells (CSCs) is a useful method for early diagnosis and treatment of tumors, as CSCs may participate in tumorigenesis and metastasis by migrating into the circulatory system. However, the potential targets of CSCs are expressed at low levels in the natural state and are always changing. Thus, dynamic screening has been reported to be an effective measure for exploring CSC markers. In recent years, diverse single-chain variable fragments (scFvs) have been widely used in immunotherapy. In this study, we determined that the scFvs, screened using RD, had a high affinity to microspheres and could inhibit their progression. We also observed that the selected scFvs underwent evolution in vitro, and antitumor-associated proteins were successfully expressed. Combined with chemotherapy, the scFvs had a synergistic effect on the inhibition of the microspheres' progression in vitro and in vivo, which could be ascribed to their high affinity for stem-like cells and the inhibition of the microspheres' collective behaviors. In addition, proteins inhibiting CD44+ /CD24+ and MAPK were involved. Our data indicated that dynamic screening of the scFvs in a natural state was of great significance in the inhibition of the microspheres in vitro and in vivo.

// Xiaoxiao Zuo 1, * , Miao Li 2, * , Ya Yang 1 , Tiansong Liang 1 , Hongyao Yang 1 , Xinhan Zhao 2 and Daoke Yang 1 1 Department of Radiation Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450000, People's Republic of China 2 Department of Internal Medicine Oncology, The Fifth People’s Hospital of Qinghai Province, Xining, Qinghai 810007, China * These authors contribute equally to this work Correspondence to: Daoke Yang, email: ydk8666@126.com Xinhan Zhao, email: zhaoxinhan@mail.xjtu.edu.cn Keywords: cytokines; IL1; breast cancer; case-control; polymorphisms Received: September 06, 2017 Accepted: November 15, 2017 Epub: December 11, 2017 Published: April 06, 2018 ABSTRACT Cytokines are known as important regulators of the cancer involved in inflammatory and immunological responses. This fact and plethora of gene polymorphism data prompted us to investigate IL1 gene polymorphisms in breast cancer (BC) patients. Totally, 530 patients with BC and 628 healthy control women were studied. The genetic polymorphisms for IL1 were analyzed by Massarray Sequencing method. Three single nucleotide polymorphisms (SNPs) identified in IL1B, IL1R1 gene are thought to influence breast cancer risk. The results of the association between IL-1B, IL1R1 polymorphisms and breast cancer risk have significant. We found that the variant TT genotype of rs10490571 was associated with a significantly increased breast cancer risk (TT vs. CC: OR = 2.82, 95% CI = 1.12–7.08, P = 0.047 for the codominant model). For rs16944 (AG vs. GG: OR = 0.60, 95% CI = 0.41–0.90, P = 0.034 for the codominant model) and rs1143623 (CG vs. CC: OR = 0.65, 95% CI = 0.45–0.94, P = 0.023 for the codominant model) have significant associations were found in genetic models. In conclusion, the present analysis suggests a correlation of polymorphic markers within the IL-1 gene locus with the risk in developing breast cancer. Taken together with our finding that IL1B, IL1R1 gene three SNP are also associated with the risk for the disease, we suggest that inflammation via innate and adaptive immunity contributes to multifactorial hereditary predisposition to pathogenesis of the breast cancer.

Breast cancer is a heterogeneous disease that can be classified into several molecular intrinsic subtypes according to hormone markers, including estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2. Breast cancer cases with different hormone status vary with respect to patient morbidity, metastasis organotropism and disease progression. It is well known that the most preferential relapse site of breast cancer is in the bone, but the metastatic incidence is markedly higher in hormone receptor-positive cancer compared with that in hormone receptor-negative cancers. Bone marrow-derived mesenchymal stem cells (BMSCs) perform important roles at the site of metastasis; however, the effects in different tumors or tumor subtypes are controversial. The present study aimed to explore the various effects of BMSCs on the biological characteristics of different hormone receptor statuses. BMSCs were obtained from female rats and characterized by cell lineage-specific antigens. The MCF-7 and MDA-MB-231 breast cancer cell lines, which are hormone receptor-positive and -negative, respectively, were employed in the present study. The cancer cells were co-cultured with BMSCs, and changes in the biological characteristic of cell growth, apoptosis, migration and epithelial-mesenchymal transition (EMT) were assessed. BMSCs exhibited chemotactic attraction to MCF-7, promoted the proliferation of MCF-7 cells and reduced MCF-7 cell apoptosis. By contrast, BMSCs exerted no marked effects on these behaviors of MDA-MB-231 cells. However, following co-culture with BMSCs, the migratory ability was enhanced in the two cell lines. Furthermore, the expression of epithelial markers (epithelial-cadherin and occludin) was decreased, and mesenchymal marker vimentin was markedly increased in the two cell lines. Notably, the migratory ability of MDA-MB-231 cells was attenuated compared with that of MCF-7 cells. The results from the present study indicated that BMSCs may favor receptor-positive cancer cell proliferation in bone and promote enhanced invasiveness of receptor-negative compared with receptor-positive cancer cells.

Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the effect of Celecoxib, a COX-2 inhibitor on two molecular breast cancer subtypes-MDA-MB-231 and SK-BR-3. Firstly, MDA-MB-231 and SK-BR-3 cells were treated with various concentration of Celecoxib for 24 and 48 h. Celecoxib-inhibition of NF-κB (p52 and p65) transcriptional activity and effect of Caspase 3 pathway were examined by western blotting. COX-2 mRNA was assessed by RT-PCR. Cell viability was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazoliumbromide (MTT) assay. Both cell cycle profiles and apoptosis were analyzed using flow cytometry. We found that Celecoxib inhibited the proliferation of the MDA-MB-231 cell line in a dose-time dependent manner versus SK-BR-3 in a dose dependent manner only (p

// Chuang Li 1, 2 , Zixuan Zhao 3 , Jun Zhou 2 , Ying Liu 2 , Hao Wang 2 and Xinhan Zhao 1 1 Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China 2 Department of Interventional Therapy, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, China 3 Elite Property Management Ltd, Saskatoon, SK S7H 0S6, Canada Correspondence to: Xinhan Zhao, email: zhaoxinhanprof@163.com Keywords: colorectal cancer, polymorphism, TERT, TNIP1, OBFC1 Abbreviations: CRC: colorectal cancer; SNP: single nucleotide polymorphism; OR: odds ratio; CI: confidence interval; LD: linkage disequilibrium Received: March 29, 2017 Accepted: April 27, 2017 Published: June 06, 2017 ABSTRACT Colorectal cancer (CRC) is one of the most common diseases worldwide, and telomere length has been reported correlate with CRC. This study aimed to investigate whether polymorphisms of telomere length related genes are associated with susceptibility to CRC in Chinese Han population. 11 SNPs from TERT , TNIP1 and OBFC1 genes were selected and genotyped, in addition odds ratio (OR) and 95% confidence intervals (CI) were used to evaluate association between the SNPs and CRC risk in 247 patients clinically and 300 controls in a Chinese Han population. Our results showed that minor allele “G” of rs7708392 and minor allele “C” of rs10036748 in TNIP1 gene were significantly associated with an increased the CRC risk in genotype model, dominant model and additive model after Bonferroni’s multiple adjusted ( P

// Chenli Yue 1, 2, * , Miao Li 3, * , Chenxing Da 4 , Hongtao Meng 5 , Shaomin Lv 2 and Xinhan Zhao 1 1 Department of Internal Medicine Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China 2 Department of Respiratory Medicine, Shaanxi Provincial Crops Hospital of Chinese People’s Armed Police Force, Xi’an, Shaanxi 710054, China 3 Department of Internal Medicine Oncology, The Fifth People’s Hospital of Qinghai Province, Xining, Qinghai 810007, China 4 Department of Gastroenterology, Shaanxi Provincial Crops Hospital of Chinese People’s Armed Police Force, Xi’an, Shaanxi 710054, China 5 Medical Department, Shaanxi Provincial Crops Hospital of Chinese People’s Armed Police Force, Xi’an, Shaanxi 710054, China * These authors have contributed equally to this work Correspondence to: Xinhan Zhao, email: zhaoxinhanprof@163.com Keywords: esophageal cancer, genetic polymorphism, NAF1, han chinese, case-control Received: October 27, 2016 Accepted: February 17, 2017 Published: April 10, 2017 ABSTRACT We investigated whether single nucleotide polymorphisms (SNPs) in the nuclear assembly factor 1 ( NAF1 ) and TNFAIP3-interacting protein 1 ( TNIP1 ) gene were associated with susceptibility to esophageal cancer in a Chinese Han population. Five SNPs were genotyped and their relationship with esophageal cancer risk was analyzed in a sample of 386 esophageal cancer patients and 495 unrelated healthy controls recruited from the First Affiliated Hospital of Xi’an Jiaotong University. Patients with the AG genotype of rs2320615 were at lower risk of developing esophageal cancer than those with the GG genotype (adjusted odds ratio [OR] = 0.64, 95% confidence interval [CI] = 0.46-0.90, P = 0.009). The rs2320615 SNP was found to be associated with a decreased the risk of esophageal cancer in the dominant model (adjusted OR = 0.70, 95% CI = 0.51-0.96, P = 0.026). These results provide the first evidence that the rs2320615 in NAF1 was associated with reduced risk of esophageal cancer. Further studies with larger samples are warranted to confirm our findings.

Vascular endothelial growth factor (VEGF)165 is one of the most abundant and potent angiogenic factors in both physiological and pathological conditions. However, the function and mechanism of VEGF165 in tumors and their environment remain to be elucidated. In the present study, a lentivirus vector (LV) that contained the VEGF165-enhanced green fluorescent protein (EGFP) fusion gene was constructed and transfected into the human breast cancer cell line MCF-7. Following transfection, the expression of VEGF165 in MCF-7 cells was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Further cellular localization of VEGF165 was observed through fluorescence microscopy. The titer of the recombinant lentivirus was 5.44×107 TU/ml in the LV-VEGF165-EGFP group and 5.00×108 TU/ml in the LV-EGFP negative control group. RT-qPCR and western blotting demonstrated that the expression of VEGF165 was significantly increased in the LV-VEGF165-EGFP group compared with the control group. The present study lays the foundation for in vitro and in vivo studies on tumor cell derived-VEGF165. Furthermore, the present fusion gene expression vector may provide a potential approach for gene therapy treatment of cancer and other diseases that require regulation of angiogenesis.

Gene therapy is one of the most promising potential therapeutic strategies for many types of cancer. Cell apoptosis is an active, programmed physiological process of the body, and its disruption has been closely associated with the occurrence of tumor development. Apoptin is known to induce tumor cell apoptosis. In the present study, the MCF-7 breast cancer cell line was transfected with a human serum albumin (HSA) and apoptin expressing plasmid [HSA-polyethylenimine (PEI)-pcDNA-Apoptin]. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to detect the expression of apoptin in the transfected MCF-7 cells, while MTT assays and flow cytometry were conducted to detect cell viability and apoptosis. Furthermore, hematoxylin and eosin staining was used to observe the morphology of xenografts from mice injected with MCF-7 cells. It was demonstrated that the HSA-PEI-pcDNA-Apoptin expression plasmid resulted in the upregulation of apoptin in MCF-7 cells, and efficiently suppressed breast tumor growth in vivo. These findings indicated that the use of HSA as an apoptin expression vector has potential therapeutic benefits for cancer and confirms the requirement for the further evaluation of apoptin in clinical trials.

// Xu Li 1, 2, * , Wenjing Zou 3, * , Ming Liu 4 , Wei Cao 5 , Yonghong Jiang 6 , Gaili An 7 , Yuzheng Wang 2 , Shangke Huang 1 , Xinhan Zhao 1 1 Department of Oncology, First Affiliated Hospital, Xi’an Jiatong University, Xi’an, Shannxi 710061, China 2 Department of The First of Internal Medicine, Tumor Hospital of Shaanxi Province Affiliated Hospital, Medical College of Xi’an Jiao Tong University, Xi’an, Shannxi 710061, China 3 Department of The Fifth of Internal Medicine, Xi’an No5 Hospital, Xi’an, Shannxi 710082, China 4 Department of Obstetrics and Gynecology, Second Affiliated Hospital, Xi’an Jiatong University, Xi’an, Shannxi 710003, China 5 Department of Oncological Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068, China 6 Department of Oncological Surgery, Weinan Central Hospital, Weinan, Shaanxi 714000, China 7 Department of Oncology, Shaanxi Provincial People’s Hospital, Xi’an 710068, China * The authors are joint first authors Correspondence to: Xinhan Zhao, email: zhaoxinhanjiaoda@163.com Keywords: breast cancer, single nucleotide polymorphism (SNP), case-control study, Chinese population Received: July 27, 2016 Accepted: October 19, 2016 Published: November 16, 2016 ABSTRACT We selected 13 tag single nucleotide polymorphisms (tSNPs) to investigate whether they were associated with breast cancer risk in the Chinese Han population. Upon statistical analyses of clinical data from 551 patients and 577 controls, we found that six of the 13 SNPs were associated with breast cancer; namely, rs4973768(Odds ratio (OR) = 1.30, 95% confidence interval (CI) =1.01-1.67), rs981782(OR =1.30, 95% CI=1.01-1.66), rs1432679(OR =0.84, 95% CI=0.70-0.99), rs10759243(OR=1.30, 95%CI=1.09-1.55), rs10822013(OR =1.18, 95% CI=1.00-1.39) and rs704010(OR =1.63, 95% CI=1.04-2.56). When stratified based on breast cancer subtype, our analyses revealed that three SNPs (rs981782, rs10759243 and rs704010) correlated with ER+ breast cancer, while another three (rs4973768, rs1432679 and rs10822013) correlated with ER- breast cancer. We obtained similar results while investigating the correlation of SNPs with PR status or clinical stage. Our results suggest that associations identified between SNPs and breast cancer through genome-wide association studies (GWAS) may not always be generalizable across races.

Background The Estrogen receptor-1 (ESR1) gene encodes estrogen receptor-α which is a major biomarker in the development of breast cancer. This research aimed to investigate the effect of ESR1 polymorphisms on breast cancer in Chinese Han women.Methods Four candidate single nucleotide polymorphisms (SNPs) in ESR1 gene among 503 breast cancer patients and 503 healthy people were genotyped using Agena MassARRAY platform. The association between ESR1 polymorphisms and breast cancer risk was evaluated using odds ratio (OR) and 95% confidence intervals (95% CIs) in four genetic models. The HaploReg v4.1 and GEPIA database were used for SNP functional annotation and ESR1 expression analysis respectively.Results The allele T of rs9383938 in ESR1 was significantly associated with an increased breast cancer risk (OR = 1.26, 95% CI = 1.05 – 1.50, p = 0.013). In genetic models, rs9383938 increased breast cancer risk in codominant model (OR = 1.54, 95% CI = 1.07 – 2.22, p = 0.021), dominant model (OR = 1.31, 95% CI = 1.01 – 1.68, p = 0.040), and additive model (OR = 1.24, 95% CI = 1.04 – 1.48, p = 0.017). Stratification analysis showed that rs9383938 and rs2228480 raised the breast cancer susceptibility at age < 50 years. Rs1801132 of ESR1 was also associated with the status of ER, PR, and Her-2 in allele model and genetic models significantly.Conclusion This study demonstrated that ESR1 polymorphisms might influence breast cancer susceptibility in Chinese Han population. Further mechanisms studies are needed to confirm the contribution of ESR1.

Deregulation of microRNAs (miRNAs) leads to malignant growth and aggressive invasion during cancer occurrence and progression. miR-147b has emerged as one of the cancer-related miRNAs that are dysregulated in multiple cancers. Yet, the relevance of miR-147b in non-small-cell lung cancer (NSCLC) remains unclear. In the present study, we aimed to report the biological function and signalling pathways mediated by miR-147b in NSCLC. Our results demonstrate that miR-147b expression is significantly downregulated in NSCLC tissues and cell lines. Overexpression of miR-147b decreased the proliferative ability, colony-forming capability, and invasive potential of NSCLC cells. Notably, our study identified ribosomal protein S15A (RPS15A), an oncogene in NSCLC, as a target gene of miR-147b. Our results showed that miR-147b negatively modulates RPS15A expression in NSCLC cells. An inverse correlation between miR-147b and RPS15A was evidenced in NSCLC specimens. Moreover, miR-147b overexpression downregulated the activation of Wnt/β-catenin signalling via targeting of RPS15A. Overexpression of RPS15A partially reversed the miR-147b-mediated antitumour effect in NSCLC cells. Collectively, these findings reveal that miR-147b restricts the proliferation and invasion of NSCLC cells by inhibiting RPS15A-induced Wnt/β-catenin signalling and suggest that the miR-147b/RPS15A/Wnt/β-catenin axis is an important regulatory mechanism for malignant progression of NSCLC.

Protein-protein interactions (PPIs) play an important role in almost all vital processes involved in many diseases, especially cancer. Peptides are perfect candidates that modulate PPIs as they can closely mimic principle features of protein. However, the intrinsic drawbacks of peptides, including poor stability and member impenetrability, severely limit the development of peptide-derived therapeutics. Nanotechnology offers a feasible route for anti-cancer peptide delivery, but much remains to be done, especially with respect to the pressing need for a simple method for efficient delivery of peptides into sites of interest towards potent and safe therapy. Herein, we report a one-step method to conjugate lanthanide-doped nanoparticles with p53-activating peptide (PMI: TSFAEYWALLSP), Bcl2-blocking peptide (BIM: IWIAQELRRIGDEFNAYYARR) and CD13-binding peptide (iNGR: CRNGRGPDC) by mercaptogenic self-assembly. The resultant LDN-iNGRPMI-BIM nanoparticles can tumor-specifically accumulate at interest sites, and potently induce apoptosis of cancer cells

Background: Single-nucleotide polymorphisms (SNPs) are important indicators of susceptibility to breast cancer. Objective: To assess the associations between SNPs in the FAM13A, PHLDB1, and CYP24A1 gene and breast cancer risk in the Chinese Han population. Methods: We performed a case-control study including 379 female breast cancer patients and 407 female healthy controls. The three SNPs were genotyped using Agena MassARRAY platform. The χ2 test was used to compare alleles and genotypes frequencies of polymorphisms between case and control groups. Genetic models analyses to assess the associations between SNPs and breast cancer risk by computing odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. RegulomeDB and HaploReg databases were used to calculate possible functional effects of polymorphisms. Results: Overall analysis results showed that rs4809957 was associated with an increased risk of breast cancer (allele A: OR = 1.27, 95% CI: 1.03-1.55, p = 0.024; AA vs. GG: OR = 1.80, 95% CI: 1.15–2.82, p = 0.010; recessive model: OR = 1.70, 95% CI: 1.12–2.58, p = 0.012); and rs1059122 was found to be associated with a reduced breast cancer risk in the recessive model (OR = 0.71, 95% CI: 0.51–0.98, p = 0.039). Stratification analysis found significant associations between the three SNPs (rs1059122, rs17748, and rs4809957) and breast cancer risk. Conclusion: Our results suggested that rs1059122 (FAM13A), rs17748 (PHLDB1), and rs4809957 (CYP24A1) might contribute to breast cancer susceptibility in the Chinese Han population. Future studies with large samples are required to confirm our findings, as well as functional studies are needed to explore their function in the breast cancer development.