Metastasis-suppressing NID2 , an epigenetically-silenced gene, in the pathogenesis of nasopharyngeal carcinoma and esophageal squamous cell carcinoma

// Annie Wai Yeeng Chai 1 , Arthur Kwok Leung Cheung 1 , Wei Dai 1 , Josephine Mun Yee Ko 1 , Joseph Chok Yan Ip 1 , Kwok Wah Chan 2, 3 , Dora Lai-Wan Kwong 1, 4 , Wai Tong Ng 4, 5 , Anne Wing Mui Lee 1, 4 , Roger Kai Cheong Ngan 4, 6 , Chun Chung Yau 4, 7 , Stewart Yuk Tung 4, 8 , Victor Ho Fun Lee 1, 4 , Alfred King-Yin Lam 9 , Suja Pillai 9 , Simon Law 2, 10 , Maria Li Lung 1, 2, 4 1 Department of Clinical Oncology, The University of Hong Kong, Hong Kong (SAR), People’s Republic of China 2 Center for Cancer Research, The University of Hong Kong, Hong Kong (SAR), People’s Republic of China 3 Department of Pathology, The University of Hong Kong, Hong Kong (SAR), People’s Republic of China 4 Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong (SAR), People’s Republic of China 5 Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong (SAR), People’s Republic of China 6 Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong (SAR), People’s Republic of China 7 Department of Oncology, Princess Margaret Hospital, Hong Kong (SAR), People’s Republic of China 8 Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong (SAR), People’s Republic of China 9 Department of Cancer Molecular Pathology, Griffith Medical School and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia 10 Department of Surgery, The University of Hong Kong, Hong Kong (SAR), People’s Republic of China Correspondence to: Maria Li Lung, email: mlilung@hku.hk Keywords: Nidogen-2 (NID2), promoter hypermethylation, metastasis, nasopharyngeal carcinoma (NPC), esophageal squamous cell carcinoma (ESCC) Received: June 21, 2016      Accepted: October 19, 2016      Published: October 25, 2016 ABSTRACT Nidogen-2 (NID2) is a key component of the basement membrane that stabilizes the extracellular matrix (ECM) network. The aim of the study is to analyze the functional roles of NID2 in the pathogenesis of nasopharyngeal carcinoma (NPC) and esophageal squamous cell carcinoma (ESCC). We performed genome-wide methylation profiling of NPC and ESCC and validated our findings using the methylation-sensitive high-resolution melting (MS-HRM) assay. Results showed that promoter methylation of NID2 was significantly higher in NPC and ESCC samples than in their adjacent non-cancer counterparts. Consistently, down-regulation of NID2 was observed in the clinical samples and cell lines of both NPC and ESCC. Re-expression of NID2 suppresses clonogenic survival and migration abilities of transduced NPC and ESCC cells. We showed that NID2 significantly inhibits liver metastasis. Mechanistic studies of signaling pathways also confirm that NID2 suppresses the EGFR/Akt and integrin/FAK/PLCγ metastasis-related pathways. This study provides novel insights into the crucial tumor metastasis suppression roles of NID2 in cancers.