Abstract
Epigenetic silencing of tumour suppressors contributes to the development and progression of lung cancer. We recently found that TMEM196 was hypermethylated in lung cancer. This study aimed to clarify its epigenetic regulation, possible roles and clinical significance. TMEM196 methylation correlated with loss of protein expression in chemical-induced rat lung pathologic lesions and human lung cancer tissues and cell lines. 5-aza-2'-deoxycytidine restored TMEM196 expression. Moreover, TMEM196 hypermethylation was detected in 61.2% of primary lung tumours and found to be associated with poor differentiation and pathological stage of lung cancer. Functional studies showed that ectopic re-expression of TMEM196 in lung cancer cells inhibited cell proliferation, clonogenicity, cell motility and tumour formation. However, TMEM196 knockdown increased cell proliferation and inhibited apoptosis and cell-cycle arrest. These effects were associated with upregulation of p21 and Bax, and downregulation of cyclin D1, c-myc, CD44 and β-catenin. Kaplan-Meier survival curves showed that TMEM196 downregulation was significantly associated with shortened survival in lung cancer patients. Multivariate analysis showed that patients with TMEM196 expression had a better overall survival. Our results revealed for the first time that TMEM196 acts as a novel functional tumour suppressor inactivated by DNA methylation and is an independent prognostic factor of lung cancer.
Highlights
Lung cancer remains the most common cancer and first leading cause of cancer-related deaths worldwide [1]
The frequency of transmembrane protein 196 (TMEM196) methylation correlated with the pathological severity of lung carcinogenesis, with a gradual increase in methylation frequency from 14.8% (4/27) in squamous metaplasia, 29.7% (11/37) in dysplasia, 40.0% (12/30) in carcinoma in situ (CIS), and 52.0% (13/25) in infiltrating carcinoma samples (Supplementary Table S2)
We found that TMEM196 was hypermethylated in human primary lung cancer tissues and cell lines but not in corresponding normal tissues
Summary
Lung cancer remains the most common cancer and first leading cause of cancer-related deaths worldwide [1]. Better understanding of the key molecular changes in normal cells that lead to precancerous lesions and malignant tumour cells will further the development of potential treatment for this disease. The molecular mechanisms of lung carcinogenesis remain unclear, DNA methylation is the third most common mechanism of tumour suppressor gene inactivation and tumourigenesis, following the loss of heterozygosity and acquisition of mutations, and plays an important role in cancer development [6, 7]. The characterisation of novel functional genes associated with CpG island methylation may help provide insights into the mechanisms for the inactivation of the tumour suppressive pathways involved in lung carcinogenesis and help identify better potential targets for the diagnosis and treatment of lung cancer
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