Syndecan-2, negatively regulated by miR-20b-5p, contributes to 5-fluorouracil resistance of colorectal cancer cells via the JNK/ERK signaling pathway.

5-Fluorouracil (5-FU) resistance has been long considered as an obstacle to the efficacy of chemotherapy in colorectal cancer (CRC). In this study, we demonstrated the role of miR-20b-5p-regulated syndecan-2 (SDC2) in 5-FU resistance of CRC cells. 5-FU-resistant SW480 CRC cells were established by treatment of SW480 cells with stepwise increase of 5-FU concentration. The results showed that SDC2 was expressed significantly higher in SW480/5-FU cells than in SW480/WT cells as revealed by quantitative real-time polymerase chain reaction and western blot analysis. MTT assay and BrdU assay showed that SDC2 overexpression led to increased cell survival rate, while SDC2 knockdown reversed the drug resistance of SW480/5-FU cells. Wound healing and transwell invasion assays revealed that knockdown of SDC2 inhibited the migratory and invasive ability of SW480/5-FU cells. Moreover, animal experiments indicated that si-SDC2 plays a suppressive role in tumor growth in vivo. We also confirmed that miR-20b-5p interacted with SDC2, which reversed the effect of SDC2 in SW480/5-FU cells via the c-Jun N-terminal kinase (JNK)/extracellular regulated protein kinases (ERK) signaling pathway. These findings showed that JNK/ERK signaling pathway is involved in miR-20b-5p/SDC2 axis-mediated 5-FU resistance in SW480/5-FU cells, indicating that the miR-20b-5p/SDC2 axis is a potential target for reversing 5-FU resistance in CRC.

DNA hypomethylation promotes invasion and metastasis of gastric cancer cells by regulating the binding of SP1 to the CDCA3 promoter.

BACKGROUND: Cell division cycle associated protein-3 (CDCA3) has been reported frequently upregulated in various cancers. It has been progressively realized that changed DNA methylations occur in diverse carcinomas. However, the concrete involvement of CDCA3 and DNA methylation in gastric cancer (GC) still needs to be further elucidated. METHODS: In this study, quantitative reverse-transcription polymerase chain reaction (PCR) was utilized to determine the relative expressions of CDCA3 in GC and normal tissue samples. The methylation condition of CDCA3 was determined by bisulfite-sequencing PCR (BSP) and methylation-specific PCR (MSP). A chromatin immunoprecipitation (ChIP) assay and luciferase activity assay was used for the interaction between transcription factors and promoters and binding site determination, respectively. The effects of knockdown or overexpression of specificity protein 1 (SP1) or CDCA3 on GC cells in vitro were further assessed via wound healing assay, colony formation assay, and matrigel invasion assay. RESULTS: In comparison to paired normal tissues, CDCA3 expressions were significantly increased in the GC tissues. The CDCA3 expression was regulated by DNA methylation, with the CpG island hypomethylation responsible for CDCA3 upregulation of GC. ChIP assays verified that the activity of SP1 binding to the CDCA3 promoter was dramatically increased. When the CDCA3 expression was downregulated in MKN45 cells by knockdown SP1, the proliferation ability, healing ability, and invasive ability were significantly suppressed. CONCLUSION: The process by which SP1 bound to the nearest promoter region was expedited in GC cells, by which DNA was hypomethylated and CDCA3 expression was promoted. The effect on cell proliferation and invasion by CDCA3 was under the regulation of SP1 and also affected by hypomethylation of DNA.

MiR-660-5p promotes the progression of hepatocellular carcinoma by interaction with YWHAH via PI3K/Akt signaling pathway.

Currently, more and more studies show that aberrantly expressed microRNAs (miRNAs) are important driving factors for the pathogenesis of hepatocellular carcinoma (HCC). Based on the TCGA and GEO databases, miR-660-5p was identified as a possible target for HCC in this study.In HCC tissues, miR-660-5pexpressionwasparticularly high, and this was confirmed inHCC cell lines. The upregulatedmiR-660-5p showed correlations with tumor size, tumor number, TNM stage and histological grade. In vitro experimental data, aswellas in vivo evidence showed that miR-660-5p has the ability to significantly enhance the cell proliferation rate, clone formation, migration, invasion, and tumorigenic capacity of HCC cells. YWHAH is validated that targeted by miR-660-5p using dual luciferase reporter assay. Knockdown of YWHAH has been shown to partially reverse the tumor suppressive function of miR-660-5p inhibitor. Furthermore, miR-660-5p/YWHAH axis could activate PI3K/AKT pathway, which promoted EMT and cell cycle processes. In conclusion, this study illustrated the function of miR-660-5p/YWHAH axis in HCC and provided potential targets for treating HCC.

MicroRNA-92a promotes proliferation and invasiveness of gastric cancer cell by targeting FOXO1 gene.

The aim of this study is to   investigate the effect of miRNA-92a on GC cell proliferation, migration and invasiveness, and the mechanism(s) involved.  Four GC cell lines (SGC-7901, BGC-823, MKN45 and HGC-27) and normal human gastric epithelial cells (GES1) were used in this study. MicroRNA-92a mimics or inhibitor were transfected into the cells. The results of transfection were assessed using real-time quantitative polymerase chain reaction (qRT-PCR). Cell proliferation, migration, invasiveness and apoptosis were determined using cell counting kit 8 (CCK-8), scratch test, Transwell invasion assay, and flow cytometric analysis, respectively. The protein target of miRNA-92a was predicted using Bioinformatics. The expression of FOXO1 protein was measured using Western blotting. The expression of miRNA-92a was significantly upregulated in GC cells, relative to normal gastric epithelial cells (p < 0.05). Overexpression of miRNA-92a significantly promoted the proliferation, migration and invasiveness of GC cells, but significantly inhibited their apoptosis (p < 0.05). MicroRNA-92a directly targeted FOXO1 gene, and significantly reduced its protein expression. Overexpression of miRNA-92a promotes the proliferation, migration and invasiveness of GC cells, and plays a role similar to that of oncogene. It directly targets FOXO1 gene by inhibiting its protein expression.

Prediction of potential drugs and targets based on meibomian gland dysfunction module classification to guide individualized treatment.

Meibomian gland dysfunction (MGD) is an epidemic chronic ocular inflammation. However, little is known about its effective treatment. Here, this study identified important MGD-related genes, core regulators, and potential drugs and their targets though integrating a series of bioinformational analyses. First, there were 665 differentially expression genes (DEGs) were identified. Then, 56 coexpression modules were exacted based on the expression of DEGs and their interactors. Moreover, core transcription factors (TF) significantly regulated modules were identified, including RELA, HIF1A, SIRT1, and MYC, which related to variety of eye diseases. Finally, the prediction of potential drugs and the identification of their target were performed. The results showed that artenimol, copper, and glutathione may have the remarkable curative effect or the toxicology to MGD. Moreover, their targets module gene LDHA (lactate dehydrogenase A), ENO1 (enolase 1), ALB (albumin), and PKM (pyruvate kinase M) are play important role in eye diseases. It suggests that these potential drugs may be useful for the treatment of MGD by acting on their targets. It provides valuable references for drug redirection and new drug development for drug developers, and provides individualized treatment strategies for tarsal gland dysfunction.

The microRNA-146a/b attenuates acute small-for-size liver graft injury in rats.

BACKGROUND & AIMS: A critical role of the Toll-like receptor (TLR)-4 and its downstream mediators in the pathogenesis of small-for-size liver graft injury has been documented. Recently, the microRNA-146 (miR-146) was identified as a potent negative regulator of the TLR4 signalling pathway. In this study, the role of miR-146a and miR-146b in the attenuation of TLR-4 signalling and small-for-size liver graft injury was investigated. METHODS: The expression levels of miR-146a and miR-146b during small-for-size liver graft injury were studied in vivo. In addition, the effects of miR-146a and miR-146b on the expression of IRAK1 and TRAF6 in the rat macrophage cell line NR8383 and rat liver kupffer cells were studied in vitro. The in vivo effect of miR-146a and miR-146b on small-for-size liver graft injury was studied by the tail vein injection of miR-146a mimics and miR-146b mimics. RESULTS: The levels of miR-146a and miR-146b decreased with a small-for-size liver graft. MiR-146a and miR-146b inhibited IRAK1 and TRAF6 expression by binding to the 3'UTR of IRAK1 or TRAF6, respectively, in the rat macrophage cell line NR8383. The administration of miR-146a mimics and miR-146b mimics prevented liver graft injury in small-for-size liver graft injury via the inactivation of IRAK1 and TRAF6 in vivo. CONCLUSIONS: miR-146a and miR-146b prevent liver injury in small-for-size liver graft injury via the inactivation of IRAK1 and TRAF6.

Exosomal lncRNA HCG18 contributes to cholangiocarcinoma growth and metastasis through mediating miR-424-5p/SOX9 axis through PI3K/AKT pathway.

Cholangiocarcinoma is a highly aggressive malignant tumor disease with the increasing incidence and mortality. It's urgent to identify specific biomarkers for cholangiocarcinoma treatment and diagnosis. Recent studies have noted the importance of lncRNAs in cancer and the following downstream mechanism with miRNAs network has been a hotspot. This work aimed to discover the role of lncRNA HCG18 and its possible downstream mechanism in cholangiocarcinoma tumor progression. Initially, through bioinformatics tools, we observed abnormal expression of lncRNA HCG18 in cholangiocarcinoma. In vitro experiments like (CCK-8, EdU, colony formation, flow cytometry, transwell, wound healing assays) and animal study confirmed that lncRNA HCG18 served as a cancer-promoting gene, promoted cancer proliferation, migration and invasion abilities. Besides, we found cancer cell-secreted exosomes transitted HCG18 to surrounding tumor cells and accelerated tumor growth and metastasis. After that, we confirmed HCG18 directly interacted with miR-424-5p through FISH, RIP and dual luciferase reporter assays with negative modulation. The inhibition of miR-424-5p reversed the HCG18 knockdown induced suppression on cholangiocarcinoma cancer cells. More specific, miR-424-5p targeted to SOX9 contributed to cholangiocarcinoma growth and metastasis through mediating PI3K/AKT pathway. In conclusion, these findings provide solid evidence of lncRNAs/miRNAs regulation in cholangiocarcinoma progression.

Correction: miR-146a Ameliorates Liver Ischemia/Reperfusion Injury by Suppressing IRAK1 and TRAF6.

[This corrects the article DOI: 10.1371/journal.pone.0101530.].

Exosomal microRNA-23a-3p contributes to the progression of cholangiocarcinoma by interaction with Dynamin3.

Cholangiocarcinoma (abbreviated as CCA) accounts for about 3% of digestive tract tumors, which is a rare disease with relatively low incidence. Herein, we firstly discovered overexpression of microRNA-23a-3p (abbreviated as miR-23a-3p) in CCA tissues, as well as cell lines via bioinformatics prediction. Next, by conducting miR-23a-3p knockdown system in HUCCT1 cells and miR-23a-3p overexpression system in RBE cells, we investigated the biological effects of miR-23a-3p. Based on our findings, inhibition of miR-23a-3p was able to prevent cancer cell proliferation via colony formation, CCK-8, as well as EdU assays. Moreover, invasion as well as migration abilities of cells was examined by transwell assay and wound healing test. Animal study further verified that knockdown miR-23a-3p slowed down tumor growth and lung metastasis. In addition, we identified cholangiocarcinoma cells transferred miR-23a-3p through exosomes by a series of assays. Functional experiments have confirmed that exosomal miR-23a-3p could benefit for cancer cell growth and metastasis, serving as a cancer promoting gene. Furthermore, we found Dynamin3 (abbreviated as DNM3) turned out to be a target of miR-23a-3p, while DNM3 was down-regulated in cholangiocarcinoma. Knockdown DNM3 accelerated cancer cell development. Collectively, our findings firstly pointed out that exosomal miR-23a-3p was conducive to the progression of cholangiocarcinoma by interaction with DNM3, which provided potential evidence for cancer treatment.

The Number of Lymph Nodes Examined is Associated with Survival Outcomes of Neuroendocrine Tumors of the Jejunum and Ileum (siNET): Development and Validation of a Prognostic Model Based on SEER Database.

PURPOSE: The number of neuroendocrine tumors (NETs) is gradually increasing worldwide, and those located in the small intestine (siNETs) are the most common. As some biological and clinical characteristics of tumors of the jejunum and the ileum differ, there is a need to assess the prognosis of individuals with siNETs of the jejunum and ileum separately. We generated a predictive nomogram by assessing individuals with siNETs from the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: We used univariate Cox regression analysis to determine both the overall survival (OS) and the cancer-specific survival (CSS) of 2501 patients with a pathological confirmation of siNETs of the jejunum and ileum. To predict 3-, 5-, and 10-year OS of siNETs, a nomogram was generated based on a training cohort and validated with an external cohort. Accuracy and clinical practicability were evaluated separately by Harrell's C-indices, calibration plots, and decision curves. The correlation was examined between dissected lymph nodes and positive lymph nodes. RESULTS: Dissection of 7 or more lymph nodes significantly improved patient OS and was found to be a protective factor for patients with siNETs. In Cox regression analyses, age, primary site, tumor size, N stage, M stage, and regional lymph node examination were significant predictors in the nomogram. A significant positive correlation was found between dissected lymph nodes and positive lymph nodes. CONCLUSIONS: Patients with 7 or more dissected lymph nodes showed an accurate tumor stage and a better prognosis. Our nomogram accurately predicted the OS of patients with siNETs.

MicroRNA-92b augments sorafenib resistance in hepatocellular carcinoma via targeting PTEN to activate PI3K/AKT/mTOR signaling.

Sorafenib (SOR) resistance is still a significant challenge for the effective treatment of hepatocellular carcinoma (HCC). The mechanism of sorafenib resistance remains unclear. Several microRNAs (miRNAs) have been identified as playing a role in impairing the sensitivity of tumor cells to treatment. We examined the mechanism behind the role of miR-92b in mediating sorafenib resistance in HCC cells. We detected that miR-92b expression was significantly upregulated in SOR-resistant HepG2/SOR cells compared to parental HepG2/WT cells. After transfection with miR-92b inhibitor, the proliferation of HepG2/SOR cells was remarkably weakened and rates of apoptosis significantly increased. PTEN was considered to be a functional target of miR-92b according to a luciferase reporter assay. Knockdown of PTEN significantly impaired the ability of miR-92b inhibitor on increasing sorafenib sensitivity of HepG2/SOR cells. Furthermore, we confirmed by western blotting and immunofluorescence that miR-92b can mediate sorafenib resistance by activating the PI3K/AKT/mTOR pathway in HCC cells by directly targeting PTEN. These findings further validate the mechanism of miR-92b in SOR resistance in HCC treatment.

Transcription factor PAX4 facilitates gastric cancer progression through interacting with miR-27b-3p/Grb2 axis.

Gastric cancer (GC) is one of the most common aggressive cancers. The discovery of an effective biomarker is necessary for GC diagnosis. In this study, we confirmed that Paired box gene 4 (PAX4) is up-regulated in GC tissues and cells via quantitative real time polymerase chain reaction (qRT-PCR), western blot and immunohistochemical staining. It was also identified that PAX4 contributed to GC cell proliferation, migration and invasion through Cell Counting Kit-8, BrdU, flow cytometry assay, colony formation assay, transwell assays, and wound healing assay. miR-27b-3p was confirmed with the binding site with PAX4 using ChIP assay and served as a tumor suppressor that inhibiting GC cell growth and metastasis, and reversed the effect of PAX4. Bioinformatics prediction and dual luciferase assay results demonstrated that miR-27b-3p targeted Grb2, which could alter the function of miR-27b-3p. Furthermore, the transcriptional control of PAX4-regulated miR-27b-3p activated the Ras-ERK pathway. Taken together, the PAX4/miR-27b-3p/Grb2 loop is known to be involved in GC cell promotion, and can be seen as a promising target for GC therapy.

MicroRNA-95-3p serves as a contributor to cisplatin resistance in human gastric cancer cells by targeting EMP1/PI3K/AKT signaling.

MicroRNAs (miRNAs) are thought to be involved in the development of cisplatin (DDP) resistance in gastric cancer (GC). Using RNA sequencing analysis (RNA-seq), we found that miR-95-3p is associated with DDP resistance in GC. We discovered that miR-95-3p is highly expressed in DDP-resistant GC tissues and cell lines (SGC7901/DDP and AGS/DDP). Furthermore, results from the BrdU and MTT assays indicated that miR-95-3p promotes GC cell proliferation. Additionally, data from transwell chamber assay, wound healing test and in vivo experiments illustrated that miR-95-3p can effectively promote invasion, migration and tumorigenic capacity, respectively, of DDP-resistant GC cells. Subsequently, results from dual luciferase assay and qRT-PCR collectively indicated that EMP1 is a target of miR-95-3p with inhibitory function through suppression of the EMT process and drug-resistance proteins. Furthermore, PI3K/AKT was identified as a downstream pathway of miR-95-3p, which promotes DDP resistance in GC. In summary, miR-95-3p helped develop DDP-resistance through down-regulation of EMP1 and increasing phosphorylation of the PI3K/Akt pathway in GC.

Protective effects of upregulated HO-1 gene against the apoptosis of human retinal pigment epithelial cells in vitro.

AIM: To investigate the protective effect of heme oxygenase-1 (HO-1) against H2O2-induced apoptosis in human ARPE-19 cells. METHODS: The lentiviral vector expressing HO-1 was prepared and transfected into apoptotic ARPE-19 cells induced by H2O2. Functional experiments including cell counting kit-8 (CCK-8) assay, flow cytometry (FCM) and mitochondrial membrane potential assay were conducted. RESULTS: The ultrastructure of ARPE-19 cells was observed using transmission electron microscope (TEM). It was found that exogenous HO-1 significantly ameliorated H2O2-induced loss of cell viability, apoptosis and intracellular levels of reactive oxygen species (ROS) in ARPE-19 cells. The overexpression of HO-1 facilitated the transfer of nuclear factor erythroid-2-related factor 2 (Nrf2) from cytoplasm to nucleus, which in turn upregualted expressions HO-1 and B-cell lymphoma-2 (Bcl-2). Furthermore, HO-1 upregulation further inhibited H2O2-induced release of cysteinyl aspartate specific proteinase-3 (caspase-3). CONCLUSION: Exogenous HO-1 protect ARPE-19 cells against H2O2-induced oxidative stress by regulating the expressions of Nrf2, HO-1, Bcl-2, and caspase-3.

miR-92b promotes gastric cancer growth by activating the DAB2IP-mediated PI3K/AKT signalling pathway.

OBJECTIVES: miR-92b has been reported to play critical roles in several carcinomas; however, our understanding of the mechanisms by which miR-92b stimulates gastric cancer (GC) is incomplete. The aim of this study was to investigate the clinical significance and functional relevance of miR-92b in GC. MATERIALS AND METHODS: Expression of miR-92b in GC and peritumoural tissues was determined using qRT-PCR, in situ hybridization and bioinformatics. CCK-8, colony formation and fluorescence-activated cell sorting assays were utilized to explore the effect of miR-92b on GC cells. A luciferase reporter assay and Western blotting were employed to verify miR-92b targeting of DAB2IP. Furthermore, Western blotting was used to evaluate the levels of DAB2IP and PI3K/Akt signalling pathway-related proteins. RESULTS: In this study, we found that miR-92b was upregulated in GC tissues compared with peritumoural tissues. Overexpression of miR-92b promoted cell proliferation, colony formation, and G0 /G1 transition and decreased apoptosis. Our results indicated that miR-92b repressed the expression of DAB2IP and that loss of DAB2IP activated the PI3K/AKT signalling pathway. Overexpression of DAB2IP rescued the effects of miR-92b in GC cells. Finally, our results demonstrated a significant correlation between miR-92b expression and DAB2IP expression in GC tissues. CONCLUSIONS: Our results suggest that miR-92b promotes GC cell proliferation by activating the DAB2IP-mediated PI3K/AKT signalling pathway. The miR-92b/DAB2IP/PI3K/AKT signalling axis may be a potential therapeutic target to prevent GC progression.

Syndecan-2 in colorectal cancer plays oncogenic role via epithelial-mesenchymal transition and MAPK pathway.

PURPOSE: In this study, we aimed to elucidate the biological roles of Syndecan-2 (SDC2) in colorectal cancer (CRC), thereby further understanding its clinical role. METHODS: The expression of SDC2 was assessed by qRT-PCR and Western blot analysis. To understand the potential biological role of SDC2, we also explored the correlation between its expression level and clinicopathologic parameters. By using MTT, plate colony formation assay, Transwell invasion assays, and flow cytometry in vitro, the biological impact of SDC2 on CRC cell proliferation, migration, invasion, and apoptosis. In addition, the related signaling pathways were investigated. RESULTS: SDC2 expression was significantly upregulated in CRC tissues. The expression of SDC2 was highly associated with four parameters, i.e., stage (P < 0.01), vascular invasion (P = 0.0045), lymph node metastasis (P=0.0018), and distant metastasis (P = 0.0019). Knockdown of SDC2 significantly reduced proliferation, migration, and invasion of HCT116 and SW480 cells, and induced cell apoptosis. Moreover, SDC2 promoted epithelial-mesenchymal transition (EMT) in CRC cells, whereas the ratio of p-MEK/MEK and p-ERK/ERK markedly reduced after depleting SDC2. CONCLUSION: During CRC development, overexpression of SDC2 plays a carcinogenic role in CRC. Therapeutic solutions targeting SDC2 may provide potential insights into CRC prevention and treatment.

CDCA3 is a potential prognostic marker that promotes cell proliferation in gastric cancer.

Gastric cancer (GC) is an aggressive and highly lethal gastrointestinal cancer, with an exceedingly poor prognosis. In the present study, the carcinogenic mechanism of human GC and the role of cell division cycle­associated 3 (CDCA3) were investigated. The expression levels of CDCA3 were investigated in GC samples and matched, peritumoral tissues by reverse transcription­quantitative polymerase chain reaction and immunohistochemical analysis. The effects of CDCA3 on cell proliferation were explored by Cell Counting Kit­8, colony formation, flow cytometric analysis and western blotting in vitro, and in vivo tumorigenesis in nude mice. The results demonstrated that CDCA3 expression was increased in human GC tissues compared with those in adjacent non­tumor tissues. Evaluation of the clinicopathological significance indicated that CDCA3 was closely associated with features of GC and patients with unfavorable overall survival times. CDCA3 overexpression resulted in the stimulation of cell growth and colony formation in vitro and xenograft tumors in vivo. Conversely, knockdown of CDCA3 inhibited these effects. Furthermore, the ectopic expression of CDCA3 in SGC7901 cells consistently promoted the cell cycle transition from the G0/G1 phase to the S phase; whereas knockdown of CDCA3 in BGC823 cells blocked the transition from the G0/G1 phase. Additionally, the present study revealed that the Ras signaling pathway was involved in CDCA3­mediated regulation of GC cell proliferation. CDCA3 activated the Ras signaling pathway to promote cell proliferation in vitro and in vivo in GC cells. Levels of CDCA3 greatly accelerated the progression of human GC. CDCA3 served as an oncogene, and may be a significant prognostic predictor and a novel therapeutic target for patients with GC.

Nectin-4 promotes gastric cancer progression via the PI3K/AKT signaling pathway.

Nectin-4, a member of the Nectin family that includes 4 Ca+-independent immunoglobulin-like cell adhesion molecules, plays a carcinogenic role in multiple cancers. However, Nectin-4 expression and its biological role in gastric cancer (GC) remain largely unknown. In this study, quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry were used to evaluate the expression patterns of Nectin-4 in GC specimens and cell lines. We observed that high expression of Nectin-4 in GC patients was associated with TNM stage and lymph node metastasis status, and poor prognosis. In addition, cell proliferation and cell migration assays in vitro and tumorigenicity in vivo were performed to observe the effects of up-regulation and down-regulation of Nectin-4 expression on GC cell phenotypes. In further studies, the PI3K/AKT signaling pathway was revealed to be involved in Nectin-4-mediated GC progression. These results demonstrated that Nectin-4 had a promoter effect on human GC cell growth and motility, indicating that Nectin-4 may serve as an effective therapeutic target in GC.

High expression of Nectin-4 is associated with unfavorable prognosis in gastric cancer.

Nectins are Ca2+-independent immunoglobulin-like cell adhesion molecules that belong to a family of four members that function in a number of biological cellular activities. Nectin-4 is overexpressed in several types of human cancer; however, the functional and prognostic significance of Nectin-4 in gastric cancer (GC) remains unclear. In the present study, the reverse transcription-quantitative polymerase chain reaction and tissue microarray immunohistochemical analysis were used to investigate the expression of Nectin-4 in GC as well as its function in the prognosis of patients with GC. The results indicated that mRNA and protein expression of Nectin-4 were increased in tumor tissues compared with the matched non-tumor tissues. Expression of Nectin-4 was closely associated with differentiation (P=0.004), primary tumor (P=0.001), lymph node metastasis (P<0.001) and tumor-node-metastasis (TNM) stage (P<0.001). Positive Nectin-4 expression (P=0.001) and advanced TNM stage (P<0.001) were demonstrated to be associated with overall survival time in multivariate analyses. These results suggest that Nectin-4 may serve a significant function in GC and may serve as a novel clinic pathological biomarker and therapeutic target in GC.

MicroRNA-92b augments sorafenib resistance in hepatocellular carcinoma via targeting PTEN to activate PI3K/AKT/mTOR signaling

Sorafenib (SOR) resistance is still a significant challenge for the effective treatment of hepatocellular carcinoma (HCC). The mechanism of sorafenib resistance remains unclear. Several microRNAs (miRNAs) have been identified as playing a role in impairing the sensitivity of tumor cells to treatment. We examined the mechanism behind the role of miR-92b in mediating sorafenib resistance in HCC cells. We detected that miR-92b expression was significantly upregulated in SOR-resistant HepG2/SOR cells compared to parental HepG2/WT cells. After transfection with miR-92b inhibitor, the proliferation of HepG2/SOR cells was remarkably weakened and rates of apoptosis significantly increased. PTEN was considered to be a functional target of miR-92b according to a luciferase reporter assay. Knockdown of PTEN significantly impaired the ability of miR-92b inhibitor on increasing sorafenib sensitivity of HepG2/SOR cells. Furthermore, we confirmed by western blotting and immunofluorescence that miR-92b can mediate sorafenib resistance by activating the PI3K/AKT/mTOR pathway in HCC cells by directly targeting PTEN. These findings further validate the mechanism of miR-92b in SOR resistance in HCC treatment.