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Defective Expression of Transforming Growth Factor ß Receptor Type II Is Associated with CpG Methylated Promoter in Primary Non-Small Cell Lung Cancer

¹ Laboratory of Population and Quantitative Genetics, Institute of Genetics, The State Key Laboratory of Genetic Engineering, Morgan-Tan International Center for Life Sciences, Fudan University, Shanghai, People’s Republic of China; ² Laboratory of Medical Genetics, School of Life Sciences, Suzhou University, Suzhou, People’s Republic of China; ³ School of Biosciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom; ⁴ Department of Surgery, Shanghai Hospital for Pulmonary Diseases, Shanghai, People’s Republic of China; ⁵ Department of Pathology, Shanghai the Second Medical University, Shanghai, People’s Republic of China; and ⁶ School of Life Sciences, Northwest Sci-Tech University of Agriculture and Forestry, Yang Ling, Shaan Xi, People’s Republic of China

Purpose: Reduced expression of the transforming growth factor ß receptor type II (TGFßRII), a key inhibitor of epithelial cell growth and tumor suppressor gene, was reported frequently in many types of tumors including non-small cell lung cancer (NSCLC). This study explored the significance of the TGFßRII gene in NSCLC carcinogenesis.

Experimental Design: With 43 independent pairs of tumor and paracarcinoma tissue samples from patients with primary NSCLC, we carried out PCR-denaturing gradient gel electrophoresis screening for DNA variants over the coding sequence of the TGFßRII gene, immunohistochemical assay of TGFßRII expression, methylation-specific PCR analysis, and semiquantitative reverse transcription-PCR.

Results: The PCR-denaturing gradient gel electrophoresis did not detect variation in the whole coding sequence of the TGFßRII gene, but the immunohistochemistry experiment revealed reduced or lost expression of the gene in 44% (19 of 43) of the tumor samples. The methylation analysis on the 19 pairs detected the frequent occurrence of methylated TGFßRII promoter in tumor tissues, whereas most of the paracarcinoma tissues were free of methylation. The reduced TGFßRII expression was highly significantly associated with the methylation event (P < 10^–4). The reverse transcription-PCR analysis demonstrated a clear agreement between reduced TGFßRII expression and decreased mRNA level of the gene in the tumor tissue samples.

Conclusions: TGFßRII plays an important role as a tumor suppressor in NSCLC carcinogenesis. The defective expression may serve as one of most important molecular mechanisms in explaining progression of the disease. In particular, aberrant 5' CpG methylation of the gene has explained the down-regulation of the gene at a transcriptional level.

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