Over-expression of AURKA, SKA3 and DSN1 contributes to colorectal adenoma to carcinoma progression.

// Tzu-Po Chuang 1, 2, 10 , Jaw-Yuan Wang 3, 4, 5 , Shu-Wen Jao 6 , Chang-Chieh Wu 6 , Jiann-Hwa Chen 7 , Koung-Hung Hsiao 8 , Chung-Yen Lin 9 , Shu-Hwa Chen 9 , Sheng-Yao Su 9 , Ying-Ju Chen 10 , Yuan-Tsong Chen 10 , Deng-Chyang Wu 11, 12, 13 , Ling-Hui Li 10 1 Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan 2 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan 3 Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 4 Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan 6 Department of Surgery, Division of Colon and Rectal Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 7 Department of Internal Medicine, Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan 8 Department of Colorectal Surgery, Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan 9 Institute of Information Science, Academia Sinica, Taipei, Taiwan 10 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 11 Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan 12 Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan 13 Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan Correspondence to: Ling-Hui Li, email: lli@ibms.sinica.edu.tw Deng-Chyang Wu, email: dechwu@yahoo.com Keywords: colon cancer progression, malignant transformation, AURKA, SKA3, DSN1 Received: January 11, 2016      Accepted: May 28, 2016      Published: June 13, 2016 ABSTRACT Development of colorectal cancer (CRC) involves sequential transformation of normal mucosal tissues into benign adenomas and then adenomas into malignant tumors. The identification of genes crucial for malignant transformation in colorectal adenomas (CRAs) has been based primarily on cross-sectional observations. In this study, we identified relevant genes using autologous samples. By performing genome-wide SNP genotyping and RNA sequencing analysis of adenocarcinomas, adenomatous polyps, and non-neoplastic colon tissues (referred as tri-part samples) from individual patients, we identified 68 genes with differential copy number alterations and progressively dysregulated expression. Aurora A, SKA3, and DSN1 protein levels were sequentially up-regulated in the samples, and this overexpression was associated with chromosome instability (CIN). Knockdown of SKA3 in CRC cells dramatically reduced cell growth rates and increased apoptosis. Depletion of SKA3 or DSN1 induced G2/M arrest and decreased migration, invasion, and anchorage-independent growth. AURKA and DSN1 are thus critical for chromosome 20q amplification-associated malignant transformation in CRA. Moreover, SKA3 at chromosome 13q was identified as a novel gene involved in promoting malignant transformation. Evaluating the expression of these genes may help identify patients with progressive adenomas, helping to improve treatment.