AimClinical resistance is a complex phenomenon in major human cancers involving multifactorial mechanisms, and hypoxia is one of the key components that affect the cellular expression program and lead to therapy resistance. The present study aimed to summarize the role of hypoxia in cancer therapy by regulating the tumor microenvironment (TME) and to highlight the potential of hypoxia-targeted therapy.MethodsRelevant published studies were retrieved from PubMed, Web of Science, and Embase using keywords such as hypoxia, cancer therapy, resistance, TME, cancer, apoptosis, DNA damage, autophagy, p53, and other similar terms.ResultsRecent studies have shown that hypoxia is associated with poor prognosis in patients by regulating the TME. It confers resistance to conventional therapies through a number of signaling pathways in apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux.ConclusionHypoxia targeting might be relevant to overcome hypoxia-associated resistance in cancer treatment.

Background: Circular RNAs (circRNAs) play important regulatory roles in the development of various cancers. However, biological functions and the underlying molecular mechanism of circRNAs in gastric cancer (GC) remain obscure. Methods: Differentially expressed circRNAs were identified by RNA sequencing. The biological functions of circSHKBP1 in GC were investigated by a series of in vitro and in vivo experiments. The expression of circSHKBP1 was evaluated using quantitative real-time PCR and RNA in situ hybridization, and the molecular mechanism of circSHKBP1 was demonstrated by western blot, RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments. Lastly, mouse xenograft and bioluminescence imaging were used to exam the clinical relevance of circSHKBP1 in vivo. Results: Increased expression of circSHKBP1(hsa_circ_0000936) was revealed in GC tissues and serum and was related to advanced TNM stage and poor survival. The level of exosomal circSHKBP1 significantly decreased after gastrectomy. Overexpression of circSHKBP1 promoted GC cell proliferation, migration, invasion and angiogenesis in vitro and in vivo, while suppression of circSHKBP1 plays the opposite role. Exosomes with upregulated circSHKBP1 promoted cocultured cells growth. Mechanistically, circSHKBP1 sponged miR-582-3p to increase HUR expression, enhancing VEGF mRNA stability. Moreover, circSHKBP1 directly bound to HSP90 and obstructed the interaction of STUB1 with HSP90, inhibiting the ubiquitination of HSP90, resulting in accelerated GC development in vitro and in vivo. Conclusion: Our findings demonstrate that exosomal circSHKBP1 regulates the miR-582-3p/HUR/VEGF pathway, suppresses HSP90 degradation, and promotes GC progression. circSHKBP1 is a promising circulating biomarker for GC diagnosis and prognosis and an exceptional candidate for further therapeutic exploration.

Epithelial-mesenchymal transition (EMT) has an important function in cancer.Recently, microRNAs have been reported to be involved in EMT by regulating target genes. miR-942 is considered a novel oncogene in esophageal squamous cell carcinoma. However, its role in non-small-cell lung cancer (NSCLC) has not been investigated. In this study, the expression of miR-942 in NSCLC patients tumor and paired adjacent tissues were assessed by quantitative real-time polymerase chain reaction and in situ hybridization. Transwell, wound healing, tube formation, and tail vein xenograft assays were conducted to assess miR-942′s function in NSCLC.Potential miR-942 targets were confirmed using dual-luciferase reporter assays, immunohistochemistry, immunoblot, and rescue experiments. The results showed miR-942 is relatively highly expressed in human NSCLC tissues and cells. In vitro assays demonstrated that overexpression of miR-942 promoted cell migration, invasion, and angiogenesis. Tail vein xenograft assays suggested that miR-942 contributed to NSCLC metastasis in vivo. Three bioinformatics software was searched, and BARX2 was predicted as a downstream target of miR-942. Direct interaction between them was validated by dual-luciferase assays. Rescue experiments further confirmed that BARX2 overexpression could reverse functional changes caused by miR-942. Moreover, miR-942 increased EMT-associated proteins N-cadherin and vimentin by inhibiting BARX2, while E-cadherin expression is reduced. In summary, this study reveals that miR-942 induces EMT-related metastasis by directly targeting BARX2, which may provide a potential therapeutic strategy for NSCLC. K E Y W O R D S BARX2, epithelial-mesenchymal transition, metastasis, miR-942, NSCLC *Fengming Yang, Chuchu Shao, and Ke Wei contributed equally to this work. SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Yang F, Shao C, Wei K, et al. miR-942 promotes tumor migration, invasion, and angiogenesis by regulating EMT via BARX2 in non-small-cell lung cancer.

Background: Recently, a growing number of studies have reported the coorelation between miR-155 and the diagnosis and prognosis of lung cancer, but results of these researches were still controversial due to insufficient sample size. Thus, we carried out the systematic review and meta-analysis to figure out whether miR-155 could be a screening tool in the detection and prognosis of lung cancer. Methods: A meta-analysis of 13 articles with 19 studies was performed by retrieving the PubMed, Embase and Web of Science. We screened all correlated literaters until December 1st, 2018. For the diagnosis analysis of miR-155 in lung cancer, sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the ROC curve (AUC) were pooled to evaluate the accuracy of miRNA-155 in the diagnosis of lung cancer. For the prognosis analysis of miR-155 in lung cancer, the pooled HRs and 95% CIs of miR-155 for overall survival/disease free survival/progression-free survival (OS/DFS/PFS) were calculated. In addition, Subgroup and meta-regression analyses were performed to distinguish the potential sources of heterogeneity between studies. Results: For the diagnostic analysis of miR-155 in lung cancer, the pooled SEN and SPE were 0.82 (95% CI: 0.72-0.88) and 0.78 (95% CI: 0.71-0.84), respectively. Besides, the pooled PLR was 3.75 (95% CI: 2.76-5.10), NLR was 0.23 (95% CI: 0.15-0.37), DOR was 15.99 (95% CI: 8.11-31.52) and AUC was 0.87 (95% CI: 0.84-0.90), indicating a significant value of miR-155 in the lung cancer detection. For the prognostic analysis of miR-155 in lung cancer, upregulated miRNA-155 expression was not significantly associated with a poor OS (pooled HR = 1.26, 95% CI: 0.66-2.40) or DFS/PFS (pooled HR = 1.28, 95% CI: 0.82-1.97). Conclusions: The present meta-analysis demonstrated that miR-155 could be a potential biomarker for the detection of lung cancer but not an effective biomarker for predicting the outcomes of lung cancer. Furthermore, more well-designed researches with larger cohorts were warranted to confirm the value of miR-155 for the diagnosis and prognosis of lung cancer.

Background Cisplatin resistance is the main cause of poor clinical prognosis in patients with gastric cancer (GC). Yet, the exact mechanism underlying cisplatin resistance remains unclear. Recent studies have suggested that exocrine miRNAs found in the tumor microenvironment participate in tumor metastasis and drug resistance. Methods Exosomes isolated from BGC823 and BGC823/DDP culture medium were characterized by transmission electron microscopy and differential ultracentrifugation, and miRNA expression profiles of BGC823 and BGC823/DDP cells derived exosomes were analyzed using miRNA microarray. In vivo and in vitro assays were used to identify roles of exosomal miR‐769‐5p and clarify the mechanism of exosomal miR‐769‐5p regulated the crosstalk between sensitive and resistant GC cells. Results In this study, we found that cisplatin‐resistant GC cells communicated with the tumor microenvironment by secreting microvesicles. MiR‐769‐5p was upregulated in GC tissues and enriched in the serum exosomes of cisplatin‐resistant patients. The biologically active miR‐769‐5p could be integrated into exosomes and delivered to sensitive cells, spreading cisplatin resistance. Underlying cellular and molecular mechanism was miR‐769‐5p targeting CASP9, thus inhibiting the downstream caspase pathway and promoting the degradation of the apoptosis‐related protein p53 through the ubiquitin‐proteasome pathway. Targeting miR‐769‐5p with its antagonist to treat cisplatin‐resistant GC cells can restore the cisplatin response, confirming that exosomal miR‐769‐5p can act as a key regulator of cisplatin resistance in GC. Conclusions These findings indicate that exosome‐transmitted miR‐769‐5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53. These findings reveal exosomal miR‐769‐5p derived from drug‐resistant cells can be used as a potential therapeutic predictor of anti‐tumor chemotherapy to enhance the effect of anti‐cancer chemotherapy, which provides a new treatment option for GC.

Background N6‐methyladenosine (m6A) RNA modification is known as a common epigenetic regulation form in eukaryotic cells. Emerging studies show that m6A in noncoding RNAs makes a difference, and the aberrant expression of m6A‐associated enzymes may cause diseases. The demethylase alkB homologue 5 (ALKBH5) plays diverse roles in different cancers, but its role during gastric cancer (GC) progression is not well known. Methods The quantitative real‐time polymerase chain reaction, immunohistochemistry staining and western blotting assays were used to detect ALKBH5 expression in GC tissues and human GC cell lines. The function assays in vitro and xenograft mouse model in vivo were used to investigate the effects of ALKBH5 during GC progression. RNA sequencing, MeRIP sequencing, RNA stability and luciferase reporter assays were performed to explore the potential molecular mechanisms involved in the function of ALKBH5. RNA binding protein immunoprecipitation sequencing (RIP‐seq), RIP and RNA pull‐down assays were performed to examine the influence of LINC00659 on the ALKBH5–JAK1 interaction. Results ALKBH5 was highly expressed in GC samples and associated with aggressive clinical features and poor prognosis. ALKBH5 promoted the abilities of GC cell proliferation and metastasis in vitro and in vivo. The m6A modification on JAK1 mRNA was removed by ALKBH5, which resulted in the upregulated expression of JAK1. LINC00659 facilitated ALKBH5 binding to and upregulated JAK1 mRNA depending on an m6A‐YTHDF2 manner. Silencing of ALKBH5 or LINC00659 disrupted GC tumourigenesis via the JAK1 axis. JAK1 upregulation activated the JAK1/STAT3 pathway in GC. Conclusion ALKBH5 promoted GC development via upregulated JAK1 mRNA expression mediated by LINC00659 in an m6A‐YTHDF2‐dependent manner, and targeting ALKBH5 may be a promising therapeutic method for GC patients.

Systemic chemotherapy with multiple drug regimens is the main therapy option for advanced gastric cancer (GC) patients. However, many patients develop relapse soon. Here, we evaluated the therapeutic potential of targeting interleukin-8 (IL8) to overcome resistance to chemotherapy in advanced GC. RNA sequencing revealed crucial molecular changes after chemotherapy resistance, in which the expression of IL8 was significantly activated with the increase in drug resistance. Subsequently, the clinical significance of IL8 expression was determined in GC population specimens. IL8-targeted by RNA interference or reparixin reversed chemotherapy resistance with limited toxicity in vivo and vitro experiments. Sequential treatment with first-line, second-line chemotherapy and reparixin inhibited GC growth, reduced toxicity and prolonged survival. Collectively, our study provides a therapeutic strategy that targeting IL8 as a sequential therapy after chemotherapy resistance in advanced GC.

Background Chronic inflammation is a well-known risk factor for the development of gastric cancer (GC). Nevertheless, the molecular mechanisms underlying inflammation-related GC progression are incompletely defined. Methods Bioinformatic analysis was performed based on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and the expression of miR-26b-5p in GC cells and tissues was validated by quantitative real-time PCR (qRT-PCR). Cell proliferation was examined through Cell Counting Kit-8 (CCK8), 5-Ethynyl-2’-deoxyuridine (EdU), colony formation, flow cytometry, and tumor xenografts. Correlation between miR-26b-5p and Cyclin dependent kinase 8 (CDK8) or Phosphodiesterase 4B (PDE4B) was analyzed by dual-luciferase reporter assays, qRT-PCR, and Western blot. The effect of miR-26b-5p on the Signal transducer and activator of transcription 3 (STAT3) pathway was investigated using Western blot, immunofluorescence (IF), and immunohistochemistry (IHC). The impact of STAT3 on miR-26b-5p was determined by dual-luciferase reporter assays and qRT-PCR. Results The expression of miR-26b-5p was significantly downregulated in Helicobacter Pylori (H. pylori)-infected GC cells. The decreased expression of miR-26b-5p was also detected in GC cells and tissues compared to normal gastric epithelium cells (GES1) and normal adjacent gastric tissues. The low expression of miR-26b-5p promoted GC proliferation in vitro and in vivo and was related to the poor outcome of GC patients. In terms of mechanism, miR-26b-5p directly targeted PDE4B and CDK8, resulting in decreased phosphorylation and nuclear translocation of STAT3, which was associated with the regulation of GC proliferation by miR-26b-5p. Notably, miR-26b-5p was transcriptionally suppressed by STAT3, thus forming the miR-26b-5p-PDE4B/CDK8-STAT3 positive feedback loop. Conclusion The newly identified miR-26b-5p-PDE4B/CDK8-STAT3 feedback loop plays an important role in inflammation-related GC progression and may serve as a promising therapeutic target for GC.