RRC ID 68111
Author Weng SW, Liu TT, Eng HL, You HL, Huang WT.
Title Autophagy Plays a Role in the CUL4A-Related Poor Prognosis of Intrahepatic Cholangiocarcinoma.
Journal Pathol Oncol Res
Abstract 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.
Volume 27
Pages 602714
Published 2021-1-1
DOI 10.3389/pore.2021.602714
PII 602714
PMID 34257560
PMC PMC8262180
MeSH Autophagy* Bile Duct Neoplasms / metabolism Bile Duct Neoplasms / mortality* Bile Duct Neoplasms / pathology Biomarkers, Tumor / metabolism* Cholangiocarcinoma / metabolism Cholangiocarcinoma / mortality* Cholangiocarcinoma / pathology Cullin Proteins / metabolism* Female Follow-Up Studies Humans Male Middle Aged Prognosis Retrospective Studies Survival Rate Tumor Cells, Cultured
Human and Animal Cells SSP-25(RCB1293)