title: Over-expression of AURKA, SKA3 and DSN1 contributes to colorectal adenoma to carcinoma progression.
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.
authors.affiliation: Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.|Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Tzu-Po
authors.initials: TP
authors.lastname: Chuang
authors.affiliation: Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jaw-Yuan
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Department of Surgery, Division of Colon and Rectal Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Jao
authors.affiliation: Department of Surgery, Division of Colon and Rectal Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chang-Chieh
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan.
authors.forename: Jiann-Hwa
authors.initials: JH
authors.lastname: Chen
authors.affiliation: Department of Colorectal Surgery, Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan.
authors.forename: Koung-Hung
authors.initials: KH
authors.lastname: Hsiao
authors.affiliation: Institute of Information Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Chung-Yen
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Institute of Information Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Shu-Hwa
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Institute of Information Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Sheng-Yao
authors.initials: SY
authors.lastname: Su
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.|Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Deng-Chyang
authors.initials: DC
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Ling-Hui
authors.initials: LH
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000236:Adenoma / Q000235:genetics / Q000473:pathology*; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D064096:Aurora Kinase A / Q000096:biosynthesis; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000096:biosynthesis; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D008875:Middle Aged; D012372:ROC Curve; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C532764:DSN1 protein, human; D008869:Microtubule-Associated Proteins; C541140:Ska3 protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A
keywords: AURKA; DSN1; SKA3; colon cancer progression; malignant transformation