Impact of aberrant methylation of microRNA-9 family members on non-small cell lung cancers

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

doi:10.3892/mco.2012.18

Impact of aberrant methylation of microRNA-9 family members on non-small cell lung cancers

Authors:
- Takayuki Muraoka
- Junichi Soh
- Shinichi Toyooka
- Yuho Maki
- Kazuhiko Shien
- Masashi Furukawa
- Tsuyoshi Ueno
- Norimitsu Tanaka
- Hiromasa Yamamoto
- Hiroaki Asano
- Kazunori Tsukuda
- Shinichiro Miyoshi
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Affiliations: Department of Cancer and Thoracic Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama 700-8558, Japan
Published online on: September 3, 2012 https://doi.org/10.3892/mco.2012.18
Pages: 185-189

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Abstract

MicroRNAs (miRs) contribute to cancer development and progression by acting as oncogenes and tumor suppressor genes. miR‑9 family members (miR‑9s), including miR‑9‑1, 9‑2 and 9‑3, have been shown to be oncogenically involved through the downregulation of E‑cadherin expression, which promotes the epithelial-mesenchymal transition. Tumor suppressive roles of miR‑9s have also been reported to silence miR‑9 through methylation, which is associated with an shortened overall survival (OS) period in several types of cancer. In this study, the impact of miR‑9s methylation on non‑small cell lung cancers (NSCLC) was investigated. In total, 293 resected NSCLC samples were examined and the miR‑9s methylation status was determined using a combined bisulfite restriction analysis. miR-9 expression was analyzed by in situ hybridization. Methylation of miR-9-1, 9-2 and 9-3 was present in 20 (7%), 33 (11%) and 34 (12%) of the cases, respectively. Methylation of any miR-9s (miR‑9s methylation) was observed in 76 of the cases (26%), and miR‑9 expression was silenced in cases with miR‑9s methylation. Logistic regression analysis demonstrated that male gender [odds ratio (OR), 2.0; 95% confidence interval (95% CI), 1.1‑3.6; P=0.01] and pathologically negative lymph node metastasis (OR, 4.8; 95% CI, 1.4‑17.2; P=0.002) were independent relative factors for miR‑9s methylation. Additionally, miR‑9s methylation [hazard ratio (HR), 4.2; 95% CI, 1.2-27.0; P=0.026] and early pathological stage (HR, 8.3; 95% CI, 2.1-28.6; P=0.004) were found to be independent predictive factors for prolonged OS time by the Cox proportional hazard test. miR‑9s methylation which induces expression silencing is common in NSCLC cases without lymph nodal metastasis, suggesting that miR‑9s are oncogenically involved in NSCLC carcinogenesis through the promotion of tumor metastasis.

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