title: Identification of transmembrane protein 98 as a novel chemoresistance-conferring gene in hepatocellular carcinoma.
abstract: Chemoresistance is one of the major obstacles in systemic chemotherapy and targeted therapy for patients with advanced hepatocellular carcinoma. To identify novel chemoresistance-associated targets in hepatocellular carcinoma, chemoresistant hepatocellular carcinoma cell lines were established. By comparing the global gene expression profiles between chemoresistant and chemosensitive cell lines, eight novel chemoresistance-associated genes were identified to be significantly associated with the commonly augmented chemoresistance of hepatocellular carcinoma cells. One upregulated candidate named transmembrane protein 98 (TMEM98) was found to be overexpressed in 80 of 118 (67.80%) of patients with hepatocellular carcinoma. TMEM98 mRNA in tumor tissues was significantly higher than nontumor tissues of patients with hepatocellular carcinoma (P < 0.0001). Upregulation of TMEM98 was significantly correlated with advanced tumor stage (P = 0.048), high incidence of early tumor recurrence (P = 0.005), poor overall survival (P = 0.029), and poor disease-free survival (P = 0.011) of patients with hepatocellular carcinoma after hepatectomy. Importantly, upregulation of TMEM98 mRNA in patients with hepatocellular carcinoma who received transarterial chemoembolization (TACE) treatment was significantly higher than in patients without TACE treatment (P = 0.046). Moreover, patients with poor response to TACE treatment had higher degree of TMEM98 upregulation than the responsive patients. In vitro and in vivo studies showed that suppression of TMEM98 in chemoresistant hepatocellular carcinoma cells restored their chemosensitivity, while forced overexpression of TMEM98 enhanced their chemoresistance. The mechanism of TMEM98 in conferring chemoresistance of hepatocellular carcinoma might be possibly through activation of the AKT pathway and deactivation of p53. In conclusion, we identified a panel of novel common chemoresistance-associated genes and demonstrated that TMEM98 is a chemoresistance-conferring gene in hepatocellular carcinoma.
authors.affiliation: Authors' Affiliations: Department of Surgery; Center for Cancer Research; and State Key Laboratory for Liver Research, the University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Kevin Tak-Pan
authors.initials: KT
authors.lastname: Ng
authors.forename: Chung Mau
authors.initials: CM
authors.lastname: Lo
authors.forename: Dong Yong
authors.initials: DY
authors.lastname: Guo
authors.forename: Xiang
authors.initials: X
authors.lastname: Qi
authors.forename: Chang Xian
authors.initials: CX
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Geng
authors.forename: Xiao Bing
authors.initials: XB
authors.lastname: Liu
authors.forename: Chang Chun
authors.initials: CC
authors.lastname: Ling
authors.forename: Yuen Yuen
authors.initials: YY
authors.lastname: Ma
authors.forename: Wai Ho
authors.initials: WH
authors.lastname: Yeung
authors.forename: Yan
authors.initials: Y
authors.lastname: Shao
authors.forename: Ronnie Tung-Ping
authors.initials: RT
authors.lastname: Poon
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012307:Risk Factors; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; C000592526:TMEM98 protein, human; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt