SHARPIN通过p53/SLC7A11/GPX4信号通路促进胆管癌细胞增殖并抑制铁死亡,Cancer Science

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SHARPIN通过p53/SLC7A11/GPX4信号通路促进胆管癌细胞增殖并抑制铁死亡
Cancer Science ( IF 4.5 ) Pub Date : 2022-08-15 , DOI: 10.1111/cas.15531
Chong Zeng ₁ , Jie Lin ₂ , Ketao Zhang ₂ , Huohui Ou ₂ , Ke Shen ₃ , Qingbo Liu ₂ , Zibo Wei ₁ , Xinhuai Dong ₁ , Xiaokang Zeng ₁ , Liming Zeng ₁ , Weidong Wang ₂ , Jie Yao ₁

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SHARPIN 是一种与多种肿瘤类型的生长和增殖有关的肿瘤相关基因。SHARPIN 在胆管癌 (CCA) 中的作用目前尚不清楚。在这里，我们研究了 SHARPIN 在 CCA 中的作用和功能，并揭示了其相关的分子机制。使用免疫组织化学、定量 PCR 和蛋白质印迹分析在患者胆管癌组织中分析 SHARPIN 的表达。SHARPIN的表达被siRNA沉默或慢病毒过表达载体抑制/过表达，并通过CCK-8测定和流式细胞术确定对细胞增殖的影响。用 MitoTracker 测量活性氧的积累，JC-1 染色显示由于沉默或过表达导致线粒体分裂/融合和线粒体膜电位变化。通过蛋白质印迹分析铁死亡标记溶质载体家族 7 成员 11 (SLC7A11)、谷胱甘肽过氧化物酶 4 (GPX4) 和抗氧化酶超氧化物歧化酶 1 (SOD-1) 和 SOD-2。结果表明，SHARPIN在CCA组织中的表达增加，这与细胞增殖有关。SHARPIN 沉默导致活性氧积累、线粒体裂变减少和线粒体膜电位降低。SHARPIN 的沉默抑制了 p53 的泛素化和降解，并下调了 SLC7A11、GPX4、SOD-1 和 SOD-2 的水平，所有这些都导致了导致铁死亡的过度氧化应激。SHARPIN 的过度表达将逆转上述过程。收集的数据表明，在 CCA 中，通过 p53/SLC7A11/GPX4 信号通路的 SHARPIN 介导的细胞铁死亡被抑制。靶向 SHARPIN 可能是治疗 CCA 的一种有前途的方法。

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SHARPIN promotes cell proliferation of cholangiocarcinoma and inhibits ferroptosis via p53/SLC7A11/GPX4 signaling

SHARPIN is a tumor-associated gene involved in the growth and proliferation of many tumor types. A function of SHARPIN in cholangiocarcinoma (CCA) is so far unclear. Here, we studied the role and function of SHARPIN in CCA and revealed its relevant molecular mechanism. The expression of SHARPIN was analyzed in cholangiocarcinoma tissues from patients using immunohistochemistry, quantitative PCR, and western blot analysis. Expression of SHARPIN was suppressed/overexpressed by siRNA silencing or lentiviral overexpression vector, and the effect on cell proliferation was determined by the CCK-8 assay and flow cytometry. Accumulation of reactive oxygen species was measured with MitoTracker, and JC-1 staining showed mitochondrial fission/fusion and mitochondrial membrane potential changes as a result of the silencing or overexpression. The ferroptosis marker solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and the antioxidant enzymes superoxide dismutase 1 (SOD-1) and SOD-2 were analyzed by western blot. The results showed that SHARPIN expression was increased in CCA tissue, and this was involved in cell proliferation. SHARPIN silencing resulted in accumulated reactive oxygen species, reduced mitochondrial fission, and a reduced mitochondrial membrane potential. Silencing of SHARPIN inhibited the ubiquitination and degradation of p53, and downregulated levels of SLC7A11, GPX4, SOD-1, and SOD-2, all of which contributed to excessive oxidative stress that leads to ferroptosis. Overexpression of SHARPIN would reverse the above process. The collected data suggest that in CCA, SHARPIN-mediated cell ferroptosis via the p53/SLC7A11/GPX4 signaling pathway is inhibited. Targeting SHARPIN might be a promising approach for the treatment of CCA.

更新日期：2022-08-15

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