Autophagy Plays a Role in the CUL4A-Related Poor Prognosis of Intrahepatic Cholangiocarcinoma

• Published in: Pathology oncology research Vol. 27; p. 602714
• Main Authors: Weng, Shao-Wen, Liu, Ting-Ting, Eng, Hock-Liew, You, Huey-Ling, Huang, Wan-Ting
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media SA 23.02.2021; Frontiers Media S.A
• Subjects: Antibodies; Autophagy; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - mortality; Bile Duct Neoplasms - pathology; Biomarkers, Tumor - metabolism; Cancer; Cholangiocarcinoma; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - mortality; Cholangiocarcinoma - pathology; Cloning; Cullin Proteins - metabolism; Female; Follow-Up Studies; Gene expression; Humans; Male; Medical prognosis; Metabolism; Metastasis; Middle Aged; Prognosis; Prostate; Proteins; Retrospective Studies; Society Journal Archive; Survival analysis; Survival Rate; Tumor Cells, Cultured; Tumorigenesis; United States > US; Switzerland; Japan; CUL4A; LC3II; autophagy; prognosis; intrahepatic cholangiocarcinoma
• ISSN: 1532-2807; 1219-4956; 1532-2807
• DOI: 10.3389/pore.2021.602714

CUL4A regulate the termination of autophagy in a physical process. However, the relationship between CUL4A and autophagy in cancer is unclear. We retrospectively investigated 99 intrahepatic cholangiocarcinoma (iCCA) cases. Whole sections were used for immunohistochemical analysis for p62, and LC3B expression. Q-score was defined as the sum of the labeling intensity and proportion. The cut-off point for immunoreactivity was set. CUL4A was overexpressed in cell lines and autophagy reflux was compared after manipulation. The iCCA cases with CUL4A overexpression had significantly higher prevalence of intact activated autophagy (42.4 vs. 15.2%; p = 0.003), which was significantly associated with advance tumor stage (34.1% vs. 15.4%; p = 0.032), less extensive necrosis (8.3 vs. 49.3%; p < 0.001), and shortened disease-free survival (mean, 19.6 vs. 65.5 months, p = 0.015). In vitro , iCCA cells with CUL4A overexpression significantly increased LC3II level as compared to the cells under basal condition. Although both cell types showed intact autophagy with increased LC3II expression after bafilomycin A1 treatment, the accumulation of LC3II was higher in CUL4A-overexpressing cells. CUL4A overexpression increased the proliferation of cells as compared with control cells. After treatment with bafilomycin A1, proliferation was inhibited in both cell types, but the effects were more prominent in the cells overexpressing CUL4A. CUL4A promotes autophagy, and exhibits significantly higher autophagic flux which affects the proliferation of iCCA cells; these effects correlated with advance tumor stage and poor prognosis. Thus, targeting autophagy may be potentially therapeutic in iCCA.