B-cell lymphoma-2-associated transcription factor 1 is overexpressed and contributes to sorafenib resistance in hepatocellular carcinoma.

Abstract

B-cell lymphoma-2-associated transcription factor 1 (BCLAF1) is involved in various biological processes including tumorigenesis, but its function and expression in hepatocellular carcinoma (HCC) is little known, and its clinical value in HCC has not yet been defined. The protein level of BCLAF1 in HCC specimens and paired adjacent normal tissues was examined by immunohistochemical staining. The effects of BCLAF1 on autophagy in HCC cells were detected by confocal microscopy, transmission electron microscopy, and western blot analysis. Cell proliferation and tumorigenicity assays were carried out in vitro and in vivo. Flow cytometry assay was used to determine the apoptosis level of HCC cells. The correlation of BCLAF1 and sorafenib resistance in HCC was analyzed by the Kaplan-Meier survival method. High expression of BCLAF1 was found in HCC tissues compared with adjacent normal tissues, and higher BCLAF1 expression was correlated with higher tumor-node-metastasis stage, worse differentiation, and worse prognosis of HCC patients. BCLAF1 could induce autophagy in HCC cells in response to starvation and BCLAF1-mediated autophagy could enhance cell proliferation and impede cell apoptosis under stress conditions. Animal experiments indicated that BCLAF1 promoted tumorigenicity of HCC cells in vivo. More importantly, high expression of BCLAF1 might contribute to sorafenib resistance in HCC patients. BCLAF1 is a potential oncogene in HCC by inducing autophagy to maintain tumor cell growth in response to stress conditions, and it could serve as a potential biomarker for predicting the prognosis of HCC patients and screening patients who are suitable for sorafenib therapy.