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MiR-1249-3p accelerates the malignancy phenotype of hepatocellular carcinoma by directly targeting HNRNPK.

ABSTRACT: BACKGROUND:microRNAs (miRNAs) have been implicated to play crucial roles in carcinogenesis. miR-1249-3p was reported to be abnormally expressed in multiple human cancers. However, its biological role and the associated underlying mechanisms in hepatocellular carcinoma (HCC) remain largely unknown. METHODS:miR-1249-3p expression level in HCC cell lines and normal cell line was measured by quantitative real-time PCR. Role of miR-1249-3p on HCC cell proliferation, colony formation, and invasion was examined by cell counting kit-8 assay, colony formation assay, and transwell invasion assay, respectively. Luciferase activity reporter assay and western blot were performed to validate whether heterogeneous nuclear ribonucleoprotein K (HNRNPK) was a direct target of miR-1249-3p. Effect of miR-1249-3p on overall survival of HCC patients was analyzed at KM Plotter website. RESULTS:We found miR-1249-3p expression level was increased, while HNRNPK expression level was decreased in HCC cell lines compared with normal cell line. Knockdown miR-1249-3p expression inhibits HCC cell proliferation, colony formation, and cell invasion through regulating HNRNPK in vitro. We also showed high miR-1249-3p expression was a predictor for poor overall survival of HCC patients. CONCLUSIONS:These findings about miR-1249-3p/HNRNPK pair provide a novel therapeutic method for HCC patients.

SUBMITTER: Shu H

PROVIDER: S-EPMC6785437 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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miR-1249-3p accelerates the malignancy phenotype of hepatocellular carcinoma by directly targeting HNRNPK.

Shu Hongchun H Hu Jia J Deng Huiqiu H

Molecular genetics & genomic medicine 20190820 10

<h4>Background</h4>microRNAs (miRNAs) have been implicated to play crucial roles in carcinogenesis. miR-1249-3p was reported to be abnormally expressed in multiple human cancers. However, its biological role and the associated underlying mechanisms in hepatocellular carcinoma (HCC) remain largely unknown.<h4>Methods</h4>miR-1249-3p expression level in HCC cell lines and normal cell line was measured by quantitative real-time PCR. Role of miR-1249-3p on HCC cell proliferation, colony formation, a ...[more]

PMID: 31429522

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Project description:Background:Thyroid cancer is an endocrine malignancy that is growing in incidence worldwide. Despite progress in diagnostics and treatment of thyroid cancer, prognosis remains poor. Emerging research has shown that circular RNAs (circRNAs) have crucial regulatory roles in cancers. However, the possible functions and mechanisms of hsa_circ_0011385 remain undetermined. Materials and methods:Expression levels of hsa_circ_0011385 and miR-361-3p were evaluated by qRT-PCR assay. The interaction between hsa_circ_0011385 and miR-361-3p was verified by dual-luciferase reporter assay. Effects of hsa_circ_0011385 or miR-361-3p on cell viability, proliferation, cell cycle, apoptosis, migration and invasion were confirmed by cell counting kit-8 (CCK-8), carboxyfluoresceinsuccinimidyl ester (CFSE), flow cytometry, and Transwell assays in vitro. The effect of hsa_circ_0011385 on thyroid cancer progression was also determined by in vivo tumor formation assay. Target genes of miR-361-3p were predicted by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and the expression of apoptosis- and metastasis-related proteins were assessed by Western blot assay. Results:Hsa_circ_0011385 upregulated in thyroid cancer; hsa_circ_0011385 knockdown inhibited thyroid cancer cell proliferation, migration and invasion, and promoted cell cycle arrest and apoptosis. In addition, hsa_circ_0011385 could negatively regulate miR-361-3p by functioning as a sponge. Hsa_circ_0011385 promoted thyroid cancer cell proliferation, migration and invasion and suppressed cell cycle arrest and apoptosis by targeting miR-361-3p in vitro. We also found that hsa_circ_0011385 knockdown dramatically inhibited thyroid cancer growth in vivo. Furthermore, hsa_circ_0011385 regulated expression of apoptosis and metastasis-related proteins in thyroid cancer. Conclusions:Hsa_circ_0011385facilitated thyroid cancer cell proliferation, invasion and migration, and inhibited thyroid cancer cell cycle arrest and apoptosis by targeting miR-361-3p, suggesting that the hsa_circ_0011385/miR-361-3p axis might be a promising therapeutic target for thyroid cancer.

Project description:BACKGROUND:Gain-of-function mutations and overexpression of KIT are characteristic features of gastrointestinal stromal tumor (GIST). Dysregulation in miRNA expression may lead to KIT overexpression and tumorigenesis. METHODS:miRNA microarray analysis and real-time PCR were used to determine the miRNA expression profiles in a cohort of 69 clinical samples including 50 CD117IHC+/KITmutation GISTs and 19 CD117IHC-/wild-type GISTs. GO enrichment and KEGG pathway analyses were performed to reveal the predicted targets of the dysregulated miRNAs. Of the dysregulated miRNAs whose expression was inversely correlated with that of KIT miRNAs were predicted by bioinformatics analysis and confirmed by luciferase reporter assay. Cell counting kit-8 (CCK-8) and flow cytometry were used to measure the cell proliferation, cycle arrest and apoptosis. Wound healing and transwell assays were used to evaluate migration and invasion. A xenograft BALB/c nude mouse model was applied to investigate the tumorigenesis in vivo. Western blot and qRT-PCR were used to investigate the protein and mRNA levels of KIT and its downstream effectors including ERK, AKT and STAT3. RESULTS:Of the six miRNAs whose expression was inversely correlated with that of KIT, we found that miR-148b-3p was significantly downregulated in the CD117IHC+/KITmutation GIST cohort. This miRNA was subsequently found to inhibit proliferation, migration and invasion of GIST882 cells. Mechanistically, miR-148b-3p was shown to regulate KIT expression through directly binding to the 3'-UTR of the KIT mRNA. Restoration of miR-148b-3p expression in GIST882 cells led to reduced expression of KIT and the downstream effectors proteins ERK, AKT and STAT3. However, overexpression of KIT reversed the inhibitory effect of miR-148b-3p on cell proliferation, migration and invasion. Furthermore, we found that reduced miR-148b-3p expression correlated with poor overall survival (OS) and disease-free survival (DFS) in GIST patients. CONCLUSION:miR-148b-3p functions as an important regulator of KIT expression and a potential prognostic biomarker for GISTs.

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MiR-1249-3p accelerates the malignancy phenotype of hepatocellular carcinoma by directly targeting HNRNPK.

Publications

miR-1249-3p accelerates the malignancy phenotype of hepatocellular carcinoma by directly targeting HNRNPK.

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