Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes
| Autor: | Masumi Wada, Yuto Hozaka, Souichi Satake, Takao Ohtsuka, Takako Tanaka, Naohiko Seki, Reona Okada, Shogo Moriya, Hiroshi Kurahara, Tetsuya Idichi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research endocrine system diseases pancreatic ductal adenocarcinoma Biology lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine microRNA Gene expression TOP2A medicine skin and connective tissue diseases Gene Gene knockdown Cell growth Cancer medicine.disease tumor-suppressor lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens digestive system diseases miR-30c-2-3p miR-30c-5p 030104 developmental biology Oncology 030220 oncology & carcinogenesis YWHAZ Cancer research Ectopic expression |
| Zdroj: | Cancers, Vol 12, Iss 2731, p 2731 (2020) Cancers Volume 12 Issue 10 |
| ISSN: | 2072-6694 |
| Popis: | Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer, and its prognosis is abysmal only 25% of patients survive one year, and 5% live for five years. MicroRNA (miRNA) signature analysis of PDAC revealed that both strands of pre-miR-30c (miR-30c-5p, guide strand miR-30c-2-3p, passenger strand) were significantly downregulated, suggesting they function as tumor-suppressors in PDAC cells. Ectopic expression assays demonstrated that these miRNAs attenuated the aggressiveness of PDAC cells, e.g., cell proliferation, migration, and invasiveness. Through a combination of in silico analyses and gene expression data, we identified 216 genes as putative oncogenic targets of miR-30c-5p and miR-30c-2-3p regulation in PDAC cells. Among these, the expression of 18 genes significantly predicted the 5-year survival rates of PDAC patients (p < 0.01). Importantly, the expression levels of 10 genes (YWHAZ, F3, TMOD3, NFE2L3, ENDOD1, ITGA3, RRAS, PRSS23, TOP2A, and LRRFIP1) were found to be independent prognostic factors for patient survival (p < 0.01). We focused on TOP2A (DNA Topoisomerase II Alpha) and investigated its potential as a therapeutic target for PDAC. The overexpression of TOP2A and its transcriptional activators (SP1 and HMGB2) was detected in PDAC clinical specimens. Moreover, the knockdown of TOP2A enhanced the sensitivity of PDAC cells to anticancer drugs. Our analyses of the PDAC miRNA signature and tumor-suppressive miRNAs provide important insights into the molecular pathogenesis of PDAC. |
| Databáze: | OpenAIRE |
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