Abstract
The identification of prognostic markers and establishing their value as therapeutic targets improves therapeutic efficacy against human cancers. Ribophorin II (RPN2) has been demonstrated to be a prognostic marker of human cancer, including breast and pancreatic cancers. The present study aimed to evaluate RPN2 expression in gastric cancer and to examine the possible correlation between RPN2 expression and the response of cells to clinical anticancer drugs, which has received little research attention at present. The gastric cancer AGS, TMC-1, SNU-1, TMK-1, SCM-1, MKN-45 and KATO III cell lines were used as a model to elucidate the role of RPN2 in the response of cells to six common chemotherapeutic agents, comprising oxaliplatin, irinotecan, doxorubicin, docetaxel, cisplatin and 5-fluorouricil. The functional role of RPN2 was assessed by silencing RPN2 using small interfering RNA (siRNA), and the cytotoxicity was determined by an MTS assay and analysis of apoptosis. Molecular events were evaluated by western blotting. All the anticancer drugs were found to exert a concentration-dependent decrease on the cell survival rate of each of the cell lines tested, although the RPN2 levels in the various cell lines were not directly correlated with responsiveness to clinical anticancer drugs, based on the calculated IC50 values. siRNA-mediated RPN2 downregulation enhanced cisplatin-induced apoptosis in AGS cells, but did not markedly decrease the cell survival rates of these cells in response to the tested drugs. Furthermore, RPN2 silencing in MKN-45 cells resulted in no additional increase in the cisplatin-induced apoptosis and survival rates. It was also found that RPN2 depletion increased anticancer drug-mediated cytotoxicity in gastric cancer cell lines. However, the predictive value of RPN2 expression in cancer therapy is questionable in gastric cancer models.
Highlights
The human ribophorin II (RPN2) gene has been localized to chromosome 20ql2‐13.1, a region that is frequently deleted in patients with myeloid malignancies [1,2,3,4]
Little is known about the correlation between RPN2 expression and the response of gastric cancer cells to clinical anticancer drugs
RPN2 expression was analyzed in seven gastric cancer cell lines by western blot analysis (Fig. 1B)
Summary
The human ribophorin II (RPN2) gene has been localized to chromosome 20ql2‐13.1, a region that is frequently deleted in patients with myeloid malignancies [1,2,3,4]. In an RNA interference (RNAi)‐based screening study, Honma et al identified RPN2 as a molecular target for therapy [11]. In this animal model of orthotopically implanted, docetaxel‐resistant breast tumors, it was revealed that RPN2 silencing effectively facilitated the accumulation of docetaxel in tumor cells, augmented docetaxel‐induced apoptotic cell death, and suppressed tumor growth. These studies indicated that RPN2 confers drug resistance by N‐glycosylation, which stabilizes the transporter P‐glycoprotein (P‐gp) in the cellular membrane, and by regulating antiapoptotic genes. This study further demonstrated that the RPN2 expression status in patients with breast cancer was associated with the response to docetaxel, proposing RPN2 as a candidate predictive marker for resistance to docetaxel‐based chemotherapy [11,13]
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