Over-expression of AURKA, SKA3 and DSN1 contributes to colorectal adenoma to carcinoma progression
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Tzu-Po Chuang1,2,10, Jaw-Yuan Wang3,4,5, Shu-Wen Jao6, Chang-Chieh Wu6, Jiann-Hwa Chen7, Koung-Hung Hsiao8, Chung-Yen Lin9, Shu-Hwa Chen9, Sheng-Yao Su9, Ying-Ju Chen10, Yuan-Tsong Chen10, Deng-Chyang Wu11,12,13, Ling-Hui Li10
1Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan
2Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan
3Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
4Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
5Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan
6Department of Surgery, Division of Colon and Rectal Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
7Department of Internal Medicine, Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
8Department of Colorectal Surgery, Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
9Institute of Information Science, Academia Sinica, Taipei, Taiwan
10Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
11Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
12Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
13Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
Ling-Hui Li, email: [email protected]
Deng-Chyang Wu, email: [email protected]
Keywords: colon cancer progression, malignant transformation, AURKA, SKA3, DSN1
Received: January 11, 2016 Accepted: May 28, 2016 Published: June 13, 2016
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.
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