Epigenetic deregulations of Wnt/β-catenin and transforming growth factor beta-Smad pathways in esophageal cancer: Outcome of DNA methylation

• Published in: Journal of cancer research and therapeutics 2019-01, Vol.15 (1), p.192-203
• Main Authors: Singh, Virendra, Singh, Avninder, Sharma, Ira, Singh, Laishram, Sharma, Jagannath, Borthakar, Bibhuti, Rai, Avdhesh, Kataki, Amal, Kapur, Sujala, Saxena, Sunita
• Format: Article
• Language: English
• Subjects: beta Catenin - metabolism; Cell adhesion & migration; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Colorectal cancer; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - genetics; Down-Regulation; Enzymes; Epigenesis, Genetic - genetics; Epigenetics; Esophageal cancer; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - pathology; Esophagus - pathology; Family medical history; Gene expression; Gene Expression Regulation, Neoplastic; Genomes; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Habits; Humans; Investigations; Male; Neoplasm Grading; Population; Promoter Regions, Genetic - genetics; Proteins; Signal Transduction - genetics; Smad Proteins - metabolism; Telomerase; Tissue Array Analysis; Tobacco; Transforming Growth Factor beta - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Wnt Proteins - metabolism
• ISSN: 0973-1482; 1998-4138
• DOI: 10.4103/jcrt.JCRT_634_17

Background: Promoter methylation of tumor suppressor genes (TSGs) is a well-reported portent in carcinogenesis; hence, it is worthy to investigate this in high-risk Northeast population of India. The study was designed to investigate methylation status of 94 TSGs in esophageal squamous cell carcinoma (ESCC). Further, the effect of OPCML promoter methylation on gene expression was analyzed by immunohistochemistry. Moreover, in silico protein-protein interactions were examined among 8 TSGs identified in the present study and 23 epigenetically regulated genes reported previously by our group in ESCC. Materials and Methods: Methylation profiling was carried out by polymerase chain reaction array and OPCML protein expression was examined by tissue microarray-based immunohistochemistry. Results: OPCML, NEUROG1, TERT, and WT1 genes were found hypermethylated and SCGB3A1, CDH1, THBS1, and VEGFA were hypomethylated in Grade 2 tumor. No significant change in OPCML expression was observed among control, Grade 1, and Grade 2 tumor. Conclusively, hypermethylation of the studied OPCML promoter in Grade 2 tumor produced no effect on expression. Unexpectedly, OPCML expression was downregulated in Grade 3 tumor in comparison to other groups signifying that downregulation of OPCML expression may lead to higher grade of tumor formation at the time of diagnosis of ESCC in patients. Significant interactions at protein level were found as VEGFA:PTK2, CTNNB1:CDH1, CTNNB1:VEGFA, CTNNB1:NEUROG1, CTNND2:CDH1, and CTNNB1:TERT. These interactions are pertinent to Wnt/β-catenin and TGF-β-Smad pathways. Conclusions: Deranged OPCML expression may lead to high-grade ESCC as well as epigenetically regulated genes, that is, CDH1, CTNNB1, CTNND2, THBS1, PTK2, WT1, OPCML, TGFB1, and SMAD4 may alter the Wnt/β-catenin and TGF-β-Smad pathways in ESCC. Further study of these genes could be useful to understand the molecular pathology of ESCC with respect to epithelial-mesenchymal transition (EMT) mediated by Wnt/β-catenin and TGF-β signaling pathways.