Gene regulation by antitumor miR-130b-5p in pancreatic ductal adenocarcinoma: the clinical significance of oncogenic EPS8

Haruhi Fukuhisa, Naohiko Seki, Tetsuya Idichi, Hiroshi Kurahara, Yasutaka Yamada, Hiroko Toda, Yoshiaki Kita, Yota Kawasaki, Kiyonori Tanoue, Yuko Mataki, Kosei Maemura, Shoji Natsugoe

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Our ongoing analyses identifying dysregulated microRNAs (miRNAs) and their controlled target RNAs have shed light on novel oncogenic pathways in pancreatic ductal adenocarcinoma (PDAC). The PDAC miRNA signature obtained by RNA sequencing showed that both strands of pre-miR-130b (miR-130b-5p, the passenger strand and miR-130b-3p, the guide strand) were significantly downregulated in cancer tissues. Our functional assays revealed that miR-130b-5p significantly blocked the malignant abilities of PDAC cell lines (PANC-1 and SW1990), e.g., cancer cell proliferation, migration, and invasion. A total of 103 genes were identified as possible oncogenic targets by miR-130b-5p regulation in PDAC cells based on genome-wide gene expression analysis and in silico database search. Among the possible targets, high expression of 9 genes (EPS8, ZWINT, SMC4, LDHA, GJB2, ZCCHC24, TOP2A, ANLN, and ADCY3) predicted a significantly poorer prognosis of PDAC patients (5-year overall survival, p < 0.001). Furthermore, we focused on EPS8 because its expression had the greatest impact on patient prognosis (overall survival, p < 0.0001). Overexpression of EPS8 was detected in PDAC clinical specimens. Knockdown assays with siEPS8 showed that its overexpression enhanced cancer cell proliferation, migration, and invasion. Analysis of downstream RNA networks regulated by EPS8 indicated that MET, HMGA2, FERMT1, RARRES3, PTK2, MAD2L1, and FLI1 were closely involved in PDAC pathogenesis. Genes regulated by antitumor miR-130b-5p were closely involved in PDAC molecular pathogenesis. Our approach, discovery of antitumor miRNAs and their target RNAs, will contribute to exploring the causes of this malignant disease.

Original languageEnglish
Pages (from-to)521-534
Number of pages14
JournalJournal of Human Genetics
Volume64
Issue number6
DOIs
Publication statusPublished - 01-06-2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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