Molecular pathogenesis of pancreatic ductal adenocarcinoma: Impact of passenger strand of pre‐<i>miR‐148a</i> on gene regulation

Idichi, Tetsuya; Seki, Naohiko; Kurahara, Hiroshi; Fukuhisa, Haruhi; Toda, Hiroko; Shimonosono, Masataka; Okato, Atsushi; Aoki, Takayuki; Kita, Yoshiaki; Mataki, Yuko; Kijima, Yuko; Maemura, Kosei; Natsugoe, Shoji

doi:10.1111/cas.13610

Cited by 41 publications

(48 citation statements)

References 49 publications

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“…Contrary to this theory, recent studies have shown that some miRNA passenger strands have tumor-suppressive functions, and their target genes can contribute to cancer progression, metastasis, and drug resistance in several types of cancers [ 18 , 19 , 20 , 21 , 22 , 23 ]. Our recent studies of PDAC cells revealed that miR-216a-3p , miR-216b-3p, miR-148a-5p, and miR-130b-5p were significantly downregulated in PDAC tissues using our RNA-sequencing based signature expression patterns [ 24 , 32 , 33 ]. Ectopic expression assays demonstrated that their expression attenuated the malignant phenotypes of PDAC cells and that the genes they regulate were aberrantly expressed in PDAC clinical specimens.…”

Section: Discussionmentioning

confidence: 99%

Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes

Tanaka

Okada

Hozaka

et al. 2020

Cancers

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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.

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Section: Discussionmentioning

confidence: 99%

Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes

Tanaka

Okada

Hozaka

et al. 2020

Cancers

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“…Analyses of the miRNA expression signatures demonstrated that certain miRNA passenger strands were downregulated and acted as antitumor miRNAs in several cancers, e.g., miR-145-3p, miR-150-3p, miR-148a-5p and miR-99a-3p (20,24,35,36). Our previous studies demonstrated that antitumor miR-145-3p directly targeted oncogenes, e.g., MTDH in lung adenocarcinoma, UHRF1 in bladder cancer, MYO1B in head and neck cancer and MELK, NCAPG, BUB1 and CDK1 in prostate cancer (17)(18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

Molecular pathogenesis of esophageal squamous cell carcinoma: Identification of the antitumor effects of miR‑145‑3p on gene regulation

et al. 2018

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Although miR-145-5p (the guide strand of the miR-145 duplex) is established as a tumor suppressive microRNA (miRNA or miR), the functional significance of miR-145-3p (the passenger strand of the miR-145 duplex) in cancer cells and its targets remains obscure. In our continuing analysis of esophageal squamous cell carcinoma (ESCC) pathogenesis, the aim of the present study was to identify important oncogenes and proteins that are controlled by miR-145-3p. Overexpression of miR-145-3p significantly reduced cancer cell proliferation, migration and invasive abilities, and further increased apoptotic abilities. In ESCC cells, 30 possible oncogenic targets were identified that might be regulated by miR-145-3p. Among these targets, dehydrogenase/reductase member 2 (DHRS2) and myosin IB (MYO1B) were focused on to investigate their functional roles in ESCC cells. DHRS2 and MYO1B were directly regulated by miR-145-3p in ESCC cells by dual luciferase reporter assays. Aberrantly expressed DHRS2 and MYOIB were detected in ESCC clinical specimens, and their overexpression enhanced cancer cell aggressiveness. Genes regulated by antitumor miR-145-3p were closely associated with the molecular pathogenesis of ESCC. The approach based on antitumor miRNAs may contribute to the understanding of ESCC molecular pathogenesis.

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“…miRNAs serve roles in numerous physiological and pathological processes including apoptosis, the cell cycle, cellular growth, proliferation, differentiation, metabolism and aging (6). Accumulating evidence reveals that miRNA dysfunction influences the metastasis, chemo-radioresistance and overall survival time of patients with cancer, including patients with PDAC (7)(8)(9)(10). Previous reports have revealed miRNA involvement in PDAC progression, including roles of miR-216b (11), miR-10a-5p (10), miR-374b-5p (12), miR-1271 (13), miR-7-5p (14), miR-4295 (15) and miR-185 (16).…”

Section: Introductionmentioning

confidence: 99%

miR‑212 regulated by HIF‑1α promotes the progression of pancreatic cancer

2019

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MicroRNA-212 (miR-212) is dysregulated in numerous tissues and cancer types and serves a role in the progression of human cancer. However, the function and mechanism of miR-212 in the development of pancreatic ductal adenocarcinoma (PDAC) remain unknown, particularly in a hypoxic microenvironment. In the present study, miR-212 expression was observed to be significantly upregulated in PDAC tissues compared with normal tissues. Clinical data analysis indicated that miR-212 was positively associated with a large tumor size, Tumor-Node-Metastasis stage, lymph node metastasis and vessel invasion, and influenced the overall survival time. Notably, there was a positive association between the expression of hypoxia-inducible factor-1α (HIF-1α) and miR-212 in vivo and in vitro in hypoxic conditions. Mechanistically, HIF-1α bound directly to a hypoxia response element in the miR-212 promoter region and activated miR-212 expression in PDAC cells. Collectively, these results demonstrated that HIF-1α positively regulated miR-212 expression and resulted in PDAC progression.

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Molecular pathogenesis of pancreatic ductal adenocarcinoma: Impact of passenger strand of pre‐miR‐148a on gene regulation

Cited by 41 publications

References 49 publications

Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes

Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes

Molecular pathogenesis of esophageal squamous cell carcinoma: Identification of the antitumor effects of miR‑145‑3p on gene regulation

miR‑212 regulated by HIF‑1α promotes the progression of pancreatic cancer

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