Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Pathol Oncol Res. 2021 Feb 23;27:602714. doi: 10.3389/pore.2021.602714. eCollection 2021.
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%; = 0.003), which was significantly associated with advance tumor stage (34.1% vs. 15.4%; = 0.032), less extensive necrosis (8.3 vs. 49.3%; < 0.001), and shortened disease-free survival (mean, 19.6 vs. 65.5 months, = 0.015). , 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.
CUL4A 通过一种物理过程调节自噬的终止。然而，CUL4A 与癌症中的自噬之间的关系尚不清楚。我们回顾性调查了 99 例肝内胆管癌（iCCA）病例。对所有切片进行 p62 和 LC3B 表达的免疫组化分析。Q 评分定义为标记强度和比例的总和。设定免疫反应性的截止点。CUL4A 在细胞系中过表达，并在操作后比较自噬回流。CUL4A 过表达的 iCCA 病例具有更高的完整激活自噬的患病率（42.4%比 15.2%； = 0.003），这与肿瘤进展（34.1%比 15.4%； = 0.032）、较少的广泛坏死（8.3%比 49.3%； < 0.001）和更短的无病生存期（平均 19.6 比 65.5 个月， = 0.015）显著相关。与对照细胞相比，CUL4A 过表达的 iCCA 细胞的 LC3II 水平显著增加。尽管两种细胞类型在用巴弗洛霉素 A1 处理后均显示出完整的自噬和增加的 LC3II 表达，但在 CUL4A 过表达的细胞中 LC3II 的积累更高。与对照细胞相比，CUL4A 过表达增加了细胞的增殖。在用巴弗洛霉素 A1 处理后，两种细胞类型的增殖均受到抑制，但在过表达 CUL4A 的细胞中抑制作用更为明显。CUL4A 促进自噬，并表现出明显更高的自噬通量，这影响 iCCA 细胞的增殖；这些影响与肿瘤进展和预后不良相关。因此，靶向自噬可能在 iCCA 中具有潜在的治疗作用。
