The miR-106b-25 Polycistron, Activated by Genomic Amplification, Functions as an Oncogene by Suppressing p21 and Bim

Takatsugu Kan, Fumiaki Sato, Tetsuo Ito, Nobutoshi Matsumura, Stefan David, Yulan Cheng, Rachana Agarwal, Bogdan C. Paun, Zhe Jin, Alexandru V. Olaru, Florin M. Selaru, James P. Hamilton, Jian Yang, John M. Abraham, Yuriko Mori, Stephen J. Meltzer

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aims: Barrett's esophagus (BE) is a highly premalignant disease that predisposes to the development of esophageal adenocarcinoma (EAC); however, the involvement of microRNAs (miRs) in BE-EAC carcinogenic progression is not known. Methods: Esophageal cultured cells (HEEpiC, QhTRT, ChTRT, GihTRT, and OE-33) and esophageal tissues (22 normal epithelia, 24 BE, and 22 EAC) were studied. MiR microarrays and quantitative reverse-transcription polymerase chain reaction (RT-PCR) were employed to explore and verify differentially expressed miRs. Quantitative genomic PCR was performed to study copy number variation at the miR-106b-25 polycistron and MCM7 gene locus on chromosome 7q22.1. In vitro cell proliferation, cell cycle, and apoptosis assays and in vivo tumorigenesis experiments were performed to elucidate biologic effects of the miR-106b-25 polycistron. Western blotting and luciferase assays were performed to confirm direct messenger RNA (mRNA) targeting by the miR-106b-25 polycistron. Results: The miR-106b-25 polycistron exerted potential proliferative, antiapoptotic, cell cycle-promoting effects in vitro and tumorigenic activity in vivo. MiRs-93 and -106b targeted and inhibited p21, whereas miR-25 targeted and inhibited Bim. This polycistron was up-regulated progressively at successive stages of neoplasia, in association with genomic amplification and overexpression of MCM7. In addition, miRs-93 and -106b decreased p21 mRNA, whereas miR-25 did not alter Bim mRNA, suggesting the following discrete miR effector mechanisms: (1) for p21, mRNA degradation; (2) for Bim, translational inhibition. Conclusions: The miR-106b-25 polycistron is activated by genomic amplification and is potentially involved in esophageal neoplastic progression and proliferation via suppression of 2 target genes: p21 and Bim.

Original languageEnglish (US)
Pages (from-to)1689-1700
Number of pages12
JournalGastroenterology
Volume136
Issue number5
DOIs
StatePublished - May 2009

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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