Identification of transmembrane protein 98 as a novel chemoresistance-conferring gene in hepatocellular carcinoma

Chemoresistance is one of the major obstacles in systemic chemotherapy and targeted therapy for patients with advanced hepatocellular carcinoma (HCC). To identify novel chemoresistance-associated targets in HCC, chemoresistant HCC 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 HCC cells. One up-regulated candidates named transmembrane protein 98 (TMEM98) was found to be overexpressed in 80 of 118 (67.80%) of HCC patients. TMEM98 mRNAs in tumor tissues was significantly higher than non-tumor tissues of HCC patients (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 HCC patients after hepatectomy. Importantly, upregulation of TMEM98 mRNA in HCC patients 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 HCC cells restored their chemosensitivity while forced overexpression of TMEM98 enhanced their chemoresistance. The mechanism of TMEM98 in conferring chemoresistance of HCC might be possibly through activation of AKT pathway and deactivation of p53. In conclusion, we identified a panel of novel common chemoresistance-associated genes and demonstrated that TMEM98 is chemoresistance-conferring gene in HCC.

http://mct.aacrjournals.org/content/early/2014/03/06/1535-7163.MCT-13-0806.abstract

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