title: Expression and function analysis of mitotic checkpoint genes identifies TTK as a potential therapeutic target for human hepatocellular carcinoma.
abstract: The mitotic spindle checkpoint (SAC) genes have been considered targets of anticancer therapies. Here, we sought to identify the attractive mitotic spindle checkpoint genes appropriate for human hepatocellular carcinoma (HCC) therapies. Through expression profile analysis of 137 selected mitotic spindle checkpoint genes in the publicly available microarray datasets, we showed that 13 genes were dramatically up-regulated in HCC tissues compared to normal livers and adjacent non-tumor tissues. A role of the 13 genes in proliferation was evaluated by knocking them down via small interfering RNA (siRNA) in HCC cells. As a result, several mitotic spindle checkpoint genes were required for maintaining the proliferation of HCC cells, demonstrated by cell viability assay and soft agar colony formation assay. Then we established sorafenib-resistant sublines of HCC cell lines Huh7 and HepG2. Intriguingly, increased TTK expression was significantly associated with acquired sorafenib-resistance in Huh7, HepG2 cells. More importantly, TTK was observably up-regulated in 46 (86.8%) of 53 HCC specimens. A series of in vitro and in vivo functional experiment assays showed that TTK overexpression promoted cell proliferation, anchor-dependent colony formation and resistance to sorafenib of HCC cells; TTK knockdown restrained cell growth, soft agar colony formation and resistance to sorafenib of HCC cells. Collectively, TTK plays an important role in proliferation and sorafenib resistance and could act as a potential therapeutic target for human hepatocellular carcinoma.
authors.affiliation: Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, First People's Hospital, Hangzhou, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Liang
authors.affiliation: Central Hospital of Taizhou City, Taizhou, Zhejiang, China.
authors.forename: Yue-Chu
authors.initials: YC
authors.lastname: Dai
authors.affiliation: Central Hospital of Taizhou City, Taizhou, Zhejiang, China.
authors.forename: Zhao-Yun
authors.initials: ZY
authors.lastname: Li
authors.affiliation: Taizhou Hospital, Wenzhou Medical University Linhai, Zhejiang, China.
authors.forename: Mei-Fu
authors.initials: MF
authors.lastname: Gan
authors.affiliation: Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, First People's Hospital, Hangzhou, China.
authors.forename: Shi-Rong
authors.initials: SR
authors.lastname: Zhang
authors.affiliation: Central Hospital of Taizhou City, Taizhou, Zhejiang, China.
authors.lastname: Yin-Pan
authors.affiliation: Central Hospital of Taizhou City, Taizhou, Zhejiang, China.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Lu
authors.affiliation: Central Hospital of Taizhou City, Taizhou, Zhejiang, China.
authors.forename: Xue-Quan
authors.initials: XQ
authors.lastname: Cao
authors.affiliation: Central Hospital of Taizhou City, Taizhou, Zhejiang, China.
authors.forename: Bei-jia
authors.initials: BJ
authors.lastname: Zheng
authors.affiliation: Central Hospital of Taizhou City, Taizhou, Zhejiang, China.
authors.forename: Ling-Fen
authors.initials: LF
authors.lastname: Bao
authors.affiliation: Central Hospital of Taizhou City, Taizhou, Zhejiang, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Wang
authors.affiliation: Central Hospital of Taizhou City, Taizhou, Zhejiang, China.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Zhang
authors.affiliation: Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, First People's Hospital, Hangzhou, China.
authors.forename: Sheng-Lin
authors.initials: SL
authors.lastname: Ma
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D018816:Genes, cdc; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D000077157:Sorafenib
chemical_list: D018797:Cell Cycle Proteins; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human