MicroRNA-101-3p suppresses proliferation and migration in hepatocellular carcinoma by targeting the HGF/c-Met pathway.

MicroRNAs are involved in each stage of tumor development. Activation of the hepatocyte growth factor (HGF)/c-Met axis facilitates the proliferation and migration of cancer cells, and the HGF/c-MET pathway provides potential targets for anticancer treatment. However, the interaction between HGF and miRNAs in hepatocellular carcinoma (HCC) remains unknown. Previous studies have shown that miR-101 is downregulated in various types of cancer and acts as a tumor suppressor, but the role of miR-101 in HCC has not yet been well defined. Here, we show that HGF is upregulated while microRNA-101-3p is significantly downregulated in the tumor tissues of HCC. By combining bioinformatics analysis and luciferase reporter assays, we demonstrated that HGF is a direct target of miR-101. In vitro experiments indicated that miR-101 inhibits the migration and proliferation of HCC cells by targeting the HGF/c-MET axis, and in vivo studies showed that overexpressed miR-101 dramatically suppresses tumor growth. Therefore, the present study identifies miR-101 as a negative regulator of HGF/c-MET and suggests that miRNAs can be used as targeted drugs for the clinical treatment of HCC.

Diagnostic accuracy of circulating exosomal circRNAs in malignances: A meta-analysis and systematic review.

BACKGROUND: Pathogenesis of malignant tumors are often accompanied by aberrant expression of circular RNAs (circRNAs), indicating the potential diagnostic value of circRNAs in tumors. CircRNAs have been found to be enriched, stable and ubiquitous in serum and plasma exosomes. The study aims at evaluating the diagnostic performance of circulating (plasma and serum) exosomal circRNA in different types of cancer by synthesis of published data. METHODS: A comprehensive literature search was conducted in PubMed, Embase, Medline and the Web of Science databases to identify potentially eligible studies published before April 2021. We conducted the meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. RESULTS: Eleven articles comprising 21 studies were included, and a total of 1609 cases and 1498 controls were evaluated. Six types of cancer were involved in these studies, including lung cancer, hepatocellular carcinoma, colorectal cancer, gastric cancer, multiple myeloma and osteosarcoma. The pooled sensitivity and specificity were 0.72 (95% confidence interval [CI], 0.62-0.81) and 0.83 (95% CI, 0.78-0.88), respectively. Summary receiver operating characteristic curve was constructed and the pooled value of area under curve was 0.86 (95% CI, 0.83-0.89), indicating a favorable diagnostic efficacy of circulating exosomal circRNAs in malignancies. CONCLUSIONS: In conclusion, our study evaluated the diagnostic power of circulating exosomal circRNAs in 6 types of cancer by synthesis of published data comprising 21 studies from eleven articles. The pooled analysis provided the evidence supporting circulating exosomal circRNAs as a promising noninvasive diagnostic biomarkers for malignancies.

m6A Methyltransferase METTL14-Mediated Upregulation of Cytidine Deaminase Promoting Gemcitabine Resistance in Pancreatic Cancer.

OBJECTIVE: Pancreatic cancer is one of the most lethal human malignancies. Gemcitabine is widely used to treat pancreatic cancer, and the resistance to chemotherapy is the major difficulty in treating the disease. N 6-methyladenosine (m6A) modification, which regulates RNA splicing, stability, translocation, and translation, plays critical roles in cancer physiological and pathological processes. METTL14, an m6A Lmethyltransferase, was found deregulated in multiple cancer types. However, its role in gemcitabine resistance in pancreatic cancer remains elusive. METHODS: The mRNA and protein level of m6A modification associated genes were assessed by QRT-PCR and western blotting. Then, gemcitabine-resistant pancreatic cancer cells were established. The growth of pancreatic cancer cells were analyzed using CCK8 assay and colony formation assay. METTL14 was depleted by using shRNA. The binding of p65 on METTL14 promoter was assessed by chromatin immunoprecipitation (ChIP) assay. Protein level of deoxycytidine kinase (DCK) and cytidine deaminase (CDA) was evaluated by western blotting. In vivo experiments were conducted to further confirm the critical role of METTL14 in gemcitabine resistance. RESULTS: We found that gemcitabine treatment significantly increased the expression of m6A methyltransferase METTL14, and METTL14 was up-regulated in gemcitabine-resistance human pancreatic cancer cells. Suppression of METTL14 obviously increased the sensitivity of gemcitabine in resistant cells. Moreover, we identified that transcriptional factor p65 targeted the promoter region of METTL14 and up-regulated its expression, which then increased the expression of cytidine deaminase (CDA), an enzyme inactivates gemcitabine. Furthermore, in vivo experiment showed that depletion of METTL14 rescue the response of resistance cell to gemcitabine in a xenograft model. CONCLUSION: Our study suggested that METTL14 is a potential target for chemotherapy resistance in pancreatic cancer.

Adipose-derived exosomes deliver miR-23a/b to regulate tumor growth in hepatocellular cancer by targeting the VHL/HIF axis.

Adipose tissue has long been considered to be involved in tumor progression. However, the adipocyte-secreted molecular determinants that regulate hepatocellular cancer progression have not been defined yet. In this study, the expression pattern of exosome miRNAs in hepatocellular carcinoma (HCC) patients with high body fat ratio (BFR) were identified by using low-density microarray. And the targets of exosome-miRNAs in HCC cells were predicted by bioinformatics methods and verified by in vitro as well as in vivo experiments. Here, we show that microRNA-23a/b (miR-23a/b) was significantly upregulated in both serum exosomes and tumor tissues of HCC patients with a high body fat ratio than low BFR. Subsequently, in vitro studies suggested that miR-23a/b was most likely to be derived from adipocytes and was transported into cancer cells via exosomes, thus promoting HCC cell growth and migration. Meanwhile, exosome miR-23a and miR-23b confer chemoresistance by targeting the von Hippel-Lindau/hypoxia-inducible factor axis. Our study provides evidence in that high BFR-related exosome miR23-a/b is a promising target for future treatment of HCC.

Screening of important lncRNAs associated with the prognosis of lung adenocarcinoma, based on integrated bioinformatics analysis.

The study aimed to elucidate the mechanisms underlying the occurrence and development of lung adenocarcinoma, and to reveal long non­coding RNA (lncRNA) prognostic factors to identify patients at high risk of disease recurrence or metastasis. Based on extensive RNA sequencing data and clinical survival prognosis information from patients with lung adenocarcinoma, obtained from The Cancer Genome Atlas and the Gene Expression Omnibus databases, a co­expression network of lncRNAs with different expression levels was built using weighted correlation network analysis and MetaDE.ES. The prognostic lncRNAs were identified using the Cox proportional hazards model and Kaplan­Meier survival curves to construct a risk scoring system. The reliability of the system was confirmed in validation datasets. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed on the genes significantly associated with the prognostic lncRNAs using gene set enrichment analysis. A total of 58 and 1,633 differentially expressed lncRNAs and mRNAs were identified, respectively. Considering the module stability, annotation, correlation between modules and clinical factors, and the differential expression levels of lncRNAs, 32 differentially expressed lncRNAs were selected from the brown, red, blue, green and yellow modules for subsequent survival analysis. A signature­based risk scoring system involving five lncRNAs [DIAPH2 antisense RNA 1, FOXN3 antisense RNA 2, long intergenic non­protein coding RNA 652, maternally expressed 3 and RHPN1 antisense RNA 1 (head to head)] was developed. The system successfully distinguished between low­ and high­risk prognostic samples. System effectiveness was further verified using two independent validation datasets. Further KEGG pathway analysis indicated that the target genes of the five prognostic lncRNAs were associated with a number of cellular processes and signaling pathways, including the cell receptor­mediated signaling and cell adhesion pathways. A five­lncRNA signature predicts the prognosis of patients with lung adenocarcinoma. These prognostic lncRNAs may be potential diagnostic markers. The present results may help elucidate the pathogenesis of lung adenocarcinoma.

Radiofrequency ablation with systemic chemotherapy in the treatment of colorectal cancer liver metastasis: a 10-year single-center study.

OBJECTIVE: To retrospectively evaluate the long-term efficacy and safety of radiofrequency ablation (RFA) with systemic chemotherapy (CT) in treatment of solitary liver metastasis after surgery for colorectal cancer (CRC). METHODS: This single-center study was conducted at the Hunan Provincial Cancer Hospital from June 2006 to December 2015 with median follow-up time of 26 months. Percutaneous ultrasound-guided RFA was carried out on eligible patients with solitary liver metastasis after surgery for CRC. After a week, ablation status was confirmed by MRI. Post MRI, all patients received systemic CT with or without molecular-targeted therapy. Survival rate was evaluated and survival curve was constructed with Kaplan-Meier analysis. Log-rank test and Cox regression model were used for univariate and multivariate analysis, respectively, to determine the independent prognostic factors for survival rate. RESULTS: A total of 109 eligible patients (mean age, 53.84±11.71; mean tumor mass diameter, 3.4+2.01 cm) were enrolled in this 10-year study. After RFA, 95 patients achieved complete ablation, and 14 patients achieved partial ablation, with median ablation time of 26 minutes (range: 12-120 minutes). The median survival time required for achieving complete and partial ablation was 56.0 and 19.0 months, respectively (P<.01). After RFA and adjuvant systemic CT, the 1-, 3-, and 5-year survival rates were 92.3%, 50.7%, and 41.6%, respectively, with the median (mean) survival time of 39.0 (56.5) months. Age was the only significant independent prognostic factor with better survival rate observed in patients aged ≥50 years than those aged <50 years (P<0.05). The incidence of complications was minimal (1.8%) with only two cases: one biliary fistula and one liver hemorrhage. CONCLUSION: RFA combination with systemic CT was safe; it showed long-term efficacy in patients with solitary liver metastasis after surgery for CRC and can be a preferred treatment.

Long-term outcome of transcatheter arterial chemoembolization after radiofrequency ablation as a combined therapy for Chinese patients with hepatocellular carcinoma.

OBJECTIVE: This study was undertaken to assess the long-term outcome of transcatheter arterial chemoembolization (TACE) after radiofrequency ablation (RFA) combined with a combined therapy for Chinese patients with intermediate (stage B) hepatocellular carcinoma (HCC) of single block type, and evaluate the survival rate for 1, 3, 5, and 7 years. RESEARCH DESIGN AND METHODS: This prospective, single-center study consisted of patients with solitary massive intermediate (stage B) HCC treated by RFA combined with TACE from October 1999 to December 2013. MAIN OUTCOME MEASURES: The survival rate of the patients for 1, 3, 5, and 7 years, and safety of the RFA treatment in the interim, total RFA for each case, and number of TACE cycles were evaluated. RESULTS: Ninety-three patients (aged 54.4 ± 8.0 years) underwent RFA combined with TACE as a combined therapy, and they were analyzed and followed up until December 2013. The mean time for the initial ablation was 1.5-3 h, and, on average, each patient received 1.39 RFA and 1.43 TACE therapies. Overall, complete ablation was achieved in nine patients, and the majority of ablation was seen in 84 patients. The longest survival time was 102 months and, among the survivors the 1, 3, 5, and 7 year survival rate was 94.4%, 52.3%, 26.1%, and 14.1%, respectively. The median survival time was 36 months (95% confidence interval = 32.7-39.3). Serum alpha-fetoprotein (AFP) levels showed significant correlation with tumor size in patients with HCC (r = 0.323, p = 0.0001). There were no major complications related to this therapy. CONCLUSION: This was the first study that performed RFA combined with TACE in Chinese patients with intermediate (stage B) HCC. RFA combined with TACE, as a combined therapy for intermediate (stage B) HCC, seems to be a promising regimen that showed a satisfactory clinical effect, which may become a new therapy mode for HCC. However, a larger cohort and control group(s) reflecting usual standards of care are needed to assess the external validity of these results in a wider population.