Role of Clusterin/NF-κB in the secretion of senescence-associated secretory phenotype in Cr(VI)-induced premature senescent L-02 hepatocytes
Role of Clusterin/NF-κB in the secretion of senescence-associated secretory phenotype in Cr(VI)-induced premature senescent L-02 hepatocytes
复制标题
Clusterin/NF-kappa B 在 Cr(VI) 诱导的过早衰老 L-02 肝细胞衰老相关分泌表型分泌中的作用
DOI：
10.1016/j.ecoenv.2021.112343
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发表时间：
2021-05-18
影响因子：
6.8
通讯作者：
Xiao, Fang
中科院分区：
文献类型：
--
作者：
Liang, Yuehui;Liang, Ningjuan;Xiao, Fang
六价铬[Cr(VI)]及其化合物造成了严重的环境污染和健康损害。衰老细胞可以通过分泌一些因子主动改变周围环境，这种因子被称为衰老相关分泌表型（SASP）。我们前期的工作已证实Cr(VI)诱导的过早衰老肝细胞表达高水平的Clusterin (CLU)并分泌白细胞介素6 (IL-6)和IL-8。 CLU参与肿瘤发生发展和耐药性的调节，但CLU是否调节SASP成分并参与Cr(VI)诱导的恶性转化尚不清楚。在本研究中，我们证明 Cr(VI) 诱导衰老 L-02 肝细胞分泌 SASP 的肿瘤促进成分，如 IL-6、IL-8 和粒细胞巨噬细胞集落刺激因子 (GM-CSF)，而 SASP 的抗肿瘤成分，如趋化因子（c-x-c 基序）配体-1 (CXCL-1) 和单核细胞趋化蛋白-1 (MCP-1) 的水平没有改变。 CLU shRNA 干扰显着降低了衰老细胞培养基中 IL-6、IL-8 和 GM-CSF 的水平，表明 CLU 可能调节 SASP。 NF-kappa B 抑制剂 PDTC 显着减轻 Cr(VI) 诱导的 IL-6、IL-8 和 GM-CSF 增加，证实 NF-kappa B 可以调节 SASP 的促肿瘤成分。 CLU shRNA干扰加剧了PDTC对SASP分泌的抑制作用，表明CLU通过NF-kappa B信号调节Cr(VI)诱导的衰老肝细胞中SASP的分泌。我们推测Cr(VI)诱导的肝细胞过早衰老所分泌的SASP与Cr(VI)的致癌作用密切相关。因此，阐明SASP的上游调控机制具有重要意义。除了进一步阐明Cr(VI)相关的致癌机制外，我们还可以寻找治疗Cr(VI)相关癌症的新靶点。
Hexavalent chromium [Cr(VI)] and its compounds have caused serious environmental pollution and health damage. Senescent cells can actively change the surrounding environment by secreting some factors, which are called senescence associated secretory phenotype (SASP). Our previous work has confirmed that premature senescent hepatocytes induced by Cr(VI) expressed high level of Clusterin (CLU) and secrete interleukin-6 (IL-6) and IL-8. CLU is involved in the regulation of tumor development and drug resistance, but whether CLU regulates SASP components and participates in Cr(VI)-induced malignant transformation is unclear. In this study we demonstrated that Cr(VI) induced the secretion of tumor promoting components of SASP such as IL-6, IL-8, and granulocyte-macrophage colony stimulating factor (GM-CSF) in senescent L-02 hepatocytes, while the levels of the anti-tumor components of SASP such as chemokine (c-x-c motif) ligand-1 (CXCL-1) and monocyte chemoattractant protein-1 (MCP-1) were not altered. CLU shRNA interference significantly reduced the levels of IL-6, IL-8, and GM-CSF in the culture medium of senescent cells, suggesting CLU may regulate SASP. The NF-kappa B inhibitor PDTC significantly alleviated Cr(VI)-induced increase of IL-6, IL-8, and GM-CSF, confirming that NF-kappa B can regulate the tumor promoting components of SASP. CLU shRNA interference aggravated the inhibitory effect of PDTC on SASP secretion, indicating that CLU regulated the secretion of SASP in Cr(VI)-induced senescent hepatocytes through the NF-kappa B signaling. We speculated that SASP secreted by Cr(VI)-induced premature senescent hepatocytes was tightly related to the carcinogenic effect of Cr(VI). Therefore, elucidation of upstream regulatory mechanism of SASP is of great significance. In addition to further clarifying the carcinogenic mechanisms associated with Cr(VI), we could also seek out new targets for treatment of Cr(VI)-related cancer.