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

• Published in: Cancer science 2018-06, Vol.109 (6), p.2013-2026
• Main Authors: Idichi, Tetsuya, Seki, Naohiko, Kurahara, Hiroshi, Fukuhisa, Haruhi, Toda, Hiroko, Shimonosono, Masataka, Okato, Atsushi, Arai, Takayuki, Kita, Yoshiaki, Mataki, Yuko, kijima, Yuko, Maemura, Kosei, Natsugoe, Shoji
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Cancer; cancer genome/genetics; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell adhesion & migration; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement - genetics; characteristics and pathology of human cancer; Ectopic expression; Female; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Gene regulation; Genomes; Humans; information; invasion and metastasis; Kaplan-Meier Estimate; Male; Medical prognosis; MicroRNAs; MicroRNAs - genetics; Middle Aged; miRNA; Neoplasm Invasiveness; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; oncogenes and tumor‐suppressor genes; Original; Pancreas; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pathogenesis; RNA Interference; Studies; Therapeutic applications
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13610

We previously used RNA sequencing to establish the microRNA (miRNA) expression signature of pancreatic ductal adenocarcinoma (PDAC). We found that both strands of pre‐miR‐148a (miR‐148a‐5p: the passenger strand and miR‐148a‐3p: the guide strand) were downregulated in cancer tissues. Ectopic expression of miR‐148a‐5p and miR‐148a‐3p significantly inhibited cancer cell migration and invasion, indicating that both strands of pre‐miR‐148a had tumor‐suppressive roles in PDAC cells. In silico database and genome‐wide gene expression analyses identified a total of 15 genes that were putative targets regulated by these miRNAs. High expression of miR‐148a‐5p targets (PHLDA2, LPCAT2 and AP1S3) and miR‐148a‐3p targets (SMA, ENDOD1 and UHMK1) was associated with poor prognosis of patients with PDAC. Moreover, knockdown of PHLDA2 expression inhibited cancer cell aggressiveness, suggesting PHLDA2 acted as an oncogene in PDAC cells. Involvement of the passenger strand of pre‐miR‐148a (miR‐148‐5p) is a new concept in cancer research. Novel approaches that identify tumor‐suppressive miRNA regulatory networks in lethal PDAC might provide new prognostic markers and therapeutic targets for this disease. Pre‐miR‐148a involved in PDAC pathogenesis.