HOXA11 hypermethylation is associated with progression of non-small cell lung cancer

// Jung-Ah Hwang 1 , Bo Bin Lee 2 , Yujin Kim 2 , Seong-Eun Park 2 , Kyun Heo 1 , Seung-Hyun Hong 1 , Young-Ho Kim 3 , Joungho Han 4 , Young Mog Shim 5 , Yeon-Su Lee 1 , and Duk-Hwan Kim 2 1 Cancer Genomics Branch, Research Institute, National Cancer Center, Goyang-si, Korea 2 Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea 3 Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul, Korea Correspondence: Yeon-Su Lee, email: // Duk-Hwan Kim, email: // Keywords : HOXA11; Hypermethylation; Non-small cell lung cancer; Progression; Migration Received : October 3, 2013 Accepted : October 27, 2013 Published : October 28, 2013 Abstract This study was aimed at understanding the functional significance of HOXA11 hypermethylation in non-small cell lung cancer (NSCLC). HOXA11 hypermethylation was characterized in six lung cancer cell lines, and its clinical significance was analyzed using formalin-fixed paraffin-embedded tissues from 317 NSCLC patients, and Ki-67 expression was analyzed using immunohistochemistry. The promoter region of HOXA11 was highly methylated in six lung cancer cell lines, but not in normal bronchial epithelial cells. The loss of expression was restored by treatment of the cells with a demethylating agent, 5-aza-2’-deoxycytidine (5-Aza-dC). Transient transfection of HOXA11 into H23 lung cancer cells resulted in the inhibition of cell migration and proliferation. HOXA11 hypermethylation was found in 218 (69%) of 317 primary NSCLCs. HOXA11 hypermethylation was found at a higher prevalence in squamous cell carcinoma than in adenocarcinoma (74% vs. 63%, respectively). HOXA11 hypermethylation was associated with Ki-67 proliferation index ( P = 0.03) and pT stage ( P = 0.002), but not with patient survival. Patients with pT2 and pT3 stages were 1.85 times (95% confidence interval [CI] = 1.04-3.29; P = 0.04) and 5.47 times (95% CI = 1.18-25.50; P = 0.01), respectively, more likely to show HOXA11 hypermethylation than those with pT1 stage, after adjusting for age, sex, and histology. In conclusion, the present study suggests that HOXA11 hypermethylation may contribute to the progression of NSCLC by promoting cell proliferation or migration.