miR-29b, miR-205 and miR-221 Enhance Chemosensitivity to Gemcitabine in HuH28 Human Cholangiocarcinoma Cells

Abstract

Background and AimsCholangiocarcinoma (CCA) is highly resistant to chemotherapy, including gemcitabine (Gem) treatment. MicroRNAs (miRNAs) are endogenous, non-coding, short RNAs that can regulate multiple genes expression. Some miRNAs play important roles in the chemosensitivity of tumors. Here, we examined the relationship between miRNA expression and the sensitivity of CCA cells to Gem.MethodsMicroarray analysis was used to determine the miRNA expression profiles of two CCA cell lines, HuH28 and HuCCT1. To determine the effect of candidate miRNAs on Gem sensitivity, expression of each candidate miRNA was modified via either transfection of a miRNA mimic or transfection of an anti-oligonucleotide. Ontology-based programs were used to identify potential target genes of candidate miRNAs that were confirmed to affect the Gem sensitivity of CCA cells.ResultsHuCCT1 cells were more sensitive to Gem than were HuH28 cells, and 18 miRNAs were differentially expressed whose ratios over ± 2log2 between HuH28 and HuCCT1. Among these 18 miRNAs, ectopic overexpression of each of three downregulated miRNAs in HuH28 (miR-29b, miR-205, miR-221) restored Gem sensitivity to HuH28. Suppression of one upregulated miRNA in HuH28, miR-125a-5p, inhibited HuH28 cell proliferation independently to Gem treatment. Selective siRNA-mediated downregulation of either of two software-predicted targets, PIK3R1 (target of miR-29b and miR-221) or MMP-2 (target of miR-29b), also conferred Gem sensitivity to HuH28.ConclusionsmiRNA expression profiling was used to identify key miRNAs that regulate Gem sensitivity in CCA cells, and software that predicts miRNA targets was used to identify promising target genes for anti-tumor therapies.

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

“…In AML, the differential expression of a number of miRNAs has been reported to be associated with the malignant phenotype but as yet the upstream mechanisms by which this is controlled are yet to be described. [29][30][31][32] As we have previously identified NRF2 as an important regulator of cell survival in AML, the aim of the present study was to investigate the ability of NRF2 to affect miRNA expression and furthermore define the function of these miRNAs in human AML both in a resting state and in response to front-line chemotherapeutic agents. Through gene expression data and multiple transcription factor binding assays, we found that NRF2 upregulates mir-125B1 and downregulates miR-29B1 though binding to specific ARE sites in the miR-125B1 and miR-29B1 regulatory regions.…”

Expression Profiles of microRNAs in Drug-Resistant Non-Small Cell Lung Cancer Cell Lines Using microRNA Sequencing

“…miR-194 is dysregulated in doxorubicin, carboplatin, and mitomycin-resistant hepatocellular carcinoma cells and docetaxel-resistant lung cancer [19,20]. Downregulation of miR-205 confers glioma cells with DDP resistance and pancreatic cancer cells with gemcitabine resistance [21,22]. miR-30a influences chemoresistance in melanoma cells by targeting insulin-like growth factor 1 [23], regulates etoposide/DDP resistance in small cell lung cancer by targeting Beclin-1 [24], sensitizes NSCLC cells to paclitaxel through B-cell lymphoma 2 inhibition [25], and enables acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors to be overcome in NSCLC cells by reducing phosphoinositide-3-kinase regulatory Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry submit 2 [26].…”

Epigenetic regulation in the carcinogenesis of cholangiocarcinoma

“…Some of the miRNAs have been proposed as either therapeutic targets, diagnostic or predictive biomarkers for CCAs. For example, miR200c, miR204 and miR-214, which directly target on EMT-related NCAM1, Slug and Twist, respectively, are frequently downregulated in ICC and potential therapeutic targets for preventing postoperative recurrence (Piontek and Selaru, 2015); while miR-29b, miR-221, miR-21 and miR-200b, which have been linked to gemcitabine sensitivity through their modulation effects on survival or apoptosis responses (Haga et al, 2014;Okamoto et al, 2013), can be potential markers for treatment response prediction. Recently, study of the miRNAs in the extracellular vesicles isolated from bile demonstrated that these vesicles contain more than 100 miRNAs .…”