Integrin α9 gene promoter is hypermethylated and downregulated in nasopharyngeal carcinoma

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// Imran Nawaz 1, 2 * , Li-Fu Hu 1, # , Zi-Ming Du 1, 3 * , Khalid Moumad 4, 5 , Ilya Ignatyev 1 * , Tatiana V. Pavlova 1 , Vladimir Kashuba 1 , Malin Almgren 6, 7 , Eugene R. Zabarovsky 1, 8 † , Ingemar Ernberg 1, # 1 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden 2 Department of Microbiology, Faculty of Life Sciences, University of Balochistan, Quetta, Pakistan 3 State Key Laboratory of Oncology in South China, and Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China 4 Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Oncovirology Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco 6 Department Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden 7 Centre for Molecular Medicine, Stockholm, Sweden 8 Department of Clinical & Experimental Medicine, Division of Cell Biology, Linköping University, Linköping, Sweden * These authors have contributed equally to this work # These senior authors have contributed equally to this work † Deceased 2013 Correspondence to: Ingemar Ernberg, e-mail: ingemar.ernberg@ki.se Li-Fu Hu, e-mail: lifu.hu@ki.se Keywords: nasopharyngeal carcinoma, ITGA9, DNA methylation, notI microarrays, epigenetics Received: March 15, 2015 Accepted: August 27, 2015 Published: September 08, 2015 ABSTRACT Epigenetic silencing of tumor suppressor genes (TSGs) by promoter methylation can be an early event in the multi-step process of carcinogenesis. Human chromosome 3 contains clusters of TSGs involved in many cancer types including nasopharyngeal carcinoma (NPC), the most common cancer in Southern China. Among ten candidate TSGs identified in chromosome 3 using NotI microarray, ITGA9 and WNT7A could be validated. 5′-aza-2′ deoxycytidine treatment restored the expression of ITGA9 and WNT7A in two NPC cell lines. Immunostaining showed strong expression of these genes in the membrane and cytoplasm of adjacent control nasopharyngeal epithelium cells, while they were weakly expressed in NPC tumor cells. The ITGA9 promoter showed marked differentially methylation between tumor and control tissue, whereas no differentially methylation could be detected for the WNT7A promoter. The expression level of ITGA9 in NPC tumors was downregulated 4.9-fold, compared to the expression in control. ITGA9 methylation was detected by methylation specific PCR (MSP) in 56% of EBV positive NPC-cases with 100% specificity. Taken together, this suggests that ITGA9 might be a TSG in NPC that is involved in tumor cell biology. The possibility of using ITGA9 methylation as a marker for early detection of NPC should further be explored.