Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer

Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Hiromasa Yamamoto, Yuho Maki, Takayuki Muraoka, Kazuhiko Shien, Masashi Furukawa, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Keisuke Aoe, Shinichiro Miyoshi

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Small-cell lung cancer (SCLC) is an aggressive tumor with a dismal prognosis among primary lung cancers. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family is comprised of tumor-suppressive miRNAs, and its reduced expression by methylation has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the alteration and tumor-suppressive impact of miR-34s in SCLC. The methylation of miR-34a and miR-34b/c was observed in 4 (36%) and 7 (64%) of 11 SCLC cell lines, respectively. Among the 27 SCLC clinical specimens, miR-34a and miR-34b/c were methylated in 4 (15%) and 18 (67%), respectively. In contrast, 13 (28%) miR-34a methylated cases and 12 (26%) miR-34b/c methylated cases were found in 47 NSCLC primary tumors. The frequency of miR-34b/c methylation was significantly higher in SCLC than in NSCLC (p<. 0.001). The expressions of miR-34s were reduced in methylated cell lines and tumors and restored after 5-aza-2'-deoxycytidine treatment, indicating that methylation was responsible for the reduced expression of miR-34s. Because the frequency of methylation was higher in miR-34b/c, we focused on miR-34b/c for a functional analysis. We examined the effect of miR-34b/c introduction on cell proliferation, migration and invasion. The transfection of miR-34b/c to two SCLC cell lines (H1048 and SBC5) resulted in the significant inhibition of cell growth, migration, and invasion, compared with control transfectants. Our results indicate that the aberrant methylation of miR-34b/c plays an important role in the pathogenesis of SCLC, implying that miR-34b/c may be a useful therapeutic target for SCLC.

Original languageEnglish
Pages (from-to)32-38
Number of pages7
JournalLung Cancer
Volume76
Issue number1
DOIs
Publication statusPublished - Apr 2012

Keywords

  • Methylation
  • MicroRNA
  • MicroRNA-34b/c
  • Non-small cell lung cancer
  • P53
  • Small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Fingerprint Dive into the research topics of 'Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer'. Together they form a unique fingerprint.

  • Cite this

    Tanaka, N., Toyooka, S., Soh, J., Kubo, T., Yamamoto, H., Maki, Y., Muraoka, T., Shien, K., Furukawa, M., Ueno, T., Asano, H., Tsukuda, K., Aoe, K., & Miyoshi, S. (2012). Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer. Lung Cancer, 76(1), 32-38. https://doi.org/10.1016/j.lungcan.2011.10.002