CLINICOPATHOLOGIC CHARACTERIZATION OF SORAFENIB-INDUCED ENDOPLASMIC RETICULUM STRESS IN HUMAN LIVER CANCER CELLS
CLINICOPATHOLOGIC CHARACTERIZATION OF SORAFENIB-INDUCED ENDOPLASMIC RETICULUM STRESS IN HUMAN LIVER CANCER CELLS
复制标题
索拉非尼诱导的人肝癌细胞内质网应激的临床病理学特征
DOI：
10.26402/jpp.2018.4.08
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发表时间：
2018-08-01
影响因子：
2.2
通讯作者：
Yang, B.
中科院分区：
文献类型：
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作者：
Liu, M.;Zhou, R.;Yang, B.
索拉非尼（Sorafenib，Sor）是晚期肝细胞癌（HCC）的标准治疗药物。然而，Sor发挥药理作用的详细分子机制仍不清楚。在这项研究中，血清样本，分期肝癌组织从索尔治疗晚期肝癌患者收获一组生化检测和免疫测定。与对照组相比，经Sor治疗的HCC患者血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、甲胎蛋白（AFP）、成纤维细胞生长因子21（FGF 21）水平降低，而白细胞介素10（IL-10）水平升高。同样，在经Sor治疗的HCC患者中，检查了血清中甘油三酯（TG）、总胆固醇（T-CHOL）、干扰素γ（IFN-γ）和肿瘤坏死因子α（TNF-α）水平的降低。与未处理的癌切片相比，Sor处理的HCC细胞显示增殖细胞核抗原（PCNA）的增殖标记物和细胞角蛋白19（CK 19）的转移生物标记物的阳性细胞减少。此外，在Sor处理的HCC肝脏中观察到内质网（ER）应激标志物激活转录因子6（ATF 6）、真核起始因子2 α激酶（eIF 2 α）、葡萄糖调节蛋白（GRP-78）、X盒结合蛋白1（XBP 1）的免疫荧光标记细胞升高。Western blot结果显示，经Sor处理的肝癌细胞中ATF 6、eIF 2 α、GRP 78、XBP 1的表达均上调。简言之，我们目前的临床病理学研究结果表明，Sor诱导的ER应激可能是治疗晚期HCC的机制。此外，诱导细胞内ER应激作为治疗晚期HCC的有希望的策略。
Sorafenib (Sor) is clinical standard therapy for advanced hepatocellular carcinoma (HCC). However, detailed molecular mechanism behind Sor-exerted pharmacological effect remains unknown. In this study, sera samples, staged hepatic cancer tissues from Sor-treated patients with advanced HCC were harvested for a group of biochemical tests and immunoassays. Compared to non-treated control, blood contents of alanine transaminase (ALT), aspartate transaminase (AST), alpha-fetoprotein (AFP), fibroblast growth factor 21 (FGF21) were decreased in Sor-treated HCC patients, while the level of interleukin 10 (IL-10) were increased. As well, reduced triglyceride (TG), total cholesterol (T-CHOL), interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) levels in sera were checked in Sor-treated HCC patients. In comparison with non-treated cancer sections, Sor-treated HCC cells showed decreased positive cells of proliferative marker for proliferating cell nuclear antigen (PCNA) and metastasized biomarker for cytokeratin 19 (CK19). In addition, elevated immunofluorescence-labeled cells of endoplasmic reticulum (ER)-stress markers of activating transcription factor 6 (ATF6), eukaryotic initiation factor 2 alpha kinase (eIF2 alpha), glucose-regulated protein (GRP-78), X-box binding protein 1 (XBP1) were observed in Sor-treated HCC livers. Further, validated data from Western blot assay exhibited that hepatocellular expressions of ATF6, eIF2 alpha, GRP78, XBP1 in Sor-treated HCC liver cells were up-regulated. Briefly, our present clinicopathologic findings indicate that Sor-induced ER stress may be responsible for therapeutic mechanism against advanced HCC. In addition, induction of intracellular ER stress functions as a promising strategy for treating advanced HCC.