Clinical and Functional Significance of C16orf74 in Extrahepatic Cholangiocarcinoma.
Biliary tract cancer (BTC) is an aggressive malignancy associated with a poor prognosis, yet effective molecular therapeutic targets remain scarce. Chromosome 16 open reading frame 74 (C16orf74) has been implicated in tumor progression; however, its specific role in BTC remains unclear. This study aimed to investigate the prognostic significance of C16orf74 in extrahepatic cholangiocarcinoma (eCCA) and to evaluate its potential as a therapeutic target.
We evaluated C16orf74 protein expression in 146 resected eCCA specimens using immunohistochemistry. Functional analyses in BTC cell lines included reverse transcription-polymerase chain reaction, cell proliferation assays, and migration and invasion assays, followed by the evaluation of downstream Akt/mTOR signaling. The in vivo antitumor efficacy of a C16orf74-targeting dimer-blocking (DB) peptide was assessed using a murine xenograft model.
High C16orf74 expression occurred in 45.2% of the tumors and was associated with worse overall survival (5-year survival rate: 27.2% vs. 52.2%). Although this association only trended toward significance following false discovery rate adjustment in the univariate analysis, high C16orf74 expression remained an independent predictor of worse survival in the multivariate analysis. In vitro, the DB peptide inhibited cellular migration and invasion and induced dose-dependent cytotoxicity in C16orf74-high cell lines; these effects were accompanied by decreased Akt phosphorylation. In vivo, DB peptide treatment suppressed tumor growth in the TFK-1 xenograft model.
High C16orf74 expression is associated with a poor prognosis in patients with resected eCCA. Furthermore, targeting C16orf74 with a DB peptide demonstrates substantial antitumor activity. Therefore, C16orf74 represents a promising prognostic biomarker and a potential therapeutic target for eCCA.
We evaluated C16orf74 protein expression in 146 resected eCCA specimens using immunohistochemistry. Functional analyses in BTC cell lines included reverse transcription-polymerase chain reaction, cell proliferation assays, and migration and invasion assays, followed by the evaluation of downstream Akt/mTOR signaling. The in vivo antitumor efficacy of a C16orf74-targeting dimer-blocking (DB) peptide was assessed using a murine xenograft model.
High C16orf74 expression occurred in 45.2% of the tumors and was associated with worse overall survival (5-year survival rate: 27.2% vs. 52.2%). Although this association only trended toward significance following false discovery rate adjustment in the univariate analysis, high C16orf74 expression remained an independent predictor of worse survival in the multivariate analysis. In vitro, the DB peptide inhibited cellular migration and invasion and induced dose-dependent cytotoxicity in C16orf74-high cell lines; these effects were accompanied by decreased Akt phosphorylation. In vivo, DB peptide treatment suppressed tumor growth in the TFK-1 xenograft model.
High C16orf74 expression is associated with a poor prognosis in patients with resected eCCA. Furthermore, targeting C16orf74 with a DB peptide demonstrates substantial antitumor activity. Therefore, C16orf74 represents a promising prognostic biomarker and a potential therapeutic target for eCCA.
Authors
Kimura Kimura, Nakamura Nakamura, Kushibiki Kushibiki, Fujii Fujii, Kuraya Kuraya, Niwa Niwa, Nakanishi Nakanishi, Takeuchi Takeuchi, Sasaki Sasaki, Hatanaka Hatanaka, Hatanaka Hatanaka, Wada Wada, Matsui Matsui, Tanaka Tanaka, Asano Asano, Noji Noji, Tsuchikawa Tsuchikawa, Hirano Hirano
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