Sun Lemeng, Feng Liangshu, Cui Jiuwei
Stem Cell and Cancer Center, The First Bethune Hospital, Jilin University, Changchun, Jilin, 130021, People's Republic of China.
Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, Jilin, China.
Diagn Pathol. 2018 Sep 15;13(1):72. doi: 10.1186/s13000-018-0749-1.
BACKGROUND: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death in Asia; however, the molecular mechanism in its tumorigenesis remains unclear. Abnormal expression of claudins (CLDNs), a family of tight junction (TJ) proteins, plays an important role in the metastatic phenotype of epithelial-derived tumors by affecting tight junction structure, function and related cellular signaling pathways. In a previous study, we used a tissue chip assay to identify CLDN17 as an upregulated gene in HCC. Here we aimed to use molecular biology technology to explore the effect of CLDN17 on the malignant phenotype of HCC and the underlying molecular mechanism, with the objective of identifying a new target for HCC treatment and the control of HCC metastasis. METHOD: The expression levels of CLDN17 in HCC tissues and histologically non-neoplastic hepatic tissues were explored by immunohistochemistry. Stable transfection of the hepatocyte line HL7702 with CLDN17 was detected by real-time polymerase chain reaction (PCR), western blotting and immunofluorescence. The impact of CLDN17 on the malignant phenotype of HL7702 cells in vitro was assessed by a Cell Counting Kit-8 (CCK8) assay, a Transwell assay and a wound-healing experiment. Western blotting was utilized to detect the activation state of Tyrosine kinase 2 (Tyk2) / signal transducer and activator of transcription3 (Stat3) pathway. A Tyk2 RNA interference (RNAi) was utilized to determine the impact of the Tyk2/Stat3 signaling pathway on the malignant phenotype of hepatocytes. RESULTS: In this work, our research group first found that CLDN17 was highly expressed in HCC tissues and was associated with poor prognosis. In addition, we demonstrated that CLDN17 affected the Stat3 signaling pathway via Tyk2 and ultimately enhanced the migration ability of hepatocytes. CONCLUSION: In conclusion, we confirmed that the upregulated expression of CLDN17 significantly enhances the migration ability of hepatocytes in vitro and we found that the activation of the Stat3 pathway by Tyk2 may an important mechanism by which CLDN17 promotes aggressiveness in hepatocytes.
背景：肝细胞癌（HCC）是亚洲癌症死亡的第二大主要原因；然而，其肿瘤发生的分子机制仍不清楚。紧密连接（TJ）蛋白家族claudins（CLDNs）的异常表达，通过影响紧密连接结构、功能及相关细胞信号通路，在上皮源性肿瘤的转移表型中发挥重要作用。在先前的一项研究中，我们使用组织芯片分析确定CLDN17为肝癌中一个上调基因。在此，我们旨在利用分子生物学技术探讨CLDN17对肝癌恶性表型的影响及其潜在分子机制，以期确定肝癌治疗和控制肝癌转移的新靶点。 方法：通过免疫组化检测CLDN17在肝癌组织和组织学上无肿瘤的肝组织中的表达水平。通过实时聚合酶链反应（PCR）、蛋白质印迹法和免疫荧光检测肝细胞系HL7702中CLDN17的稳定转染情况。通过细胞计数试剂盒-8（CCK8）检测、Transwell检测和伤口愈合实验评估CLDN17对HL7702细胞体外恶性表型的影响。利用蛋白质印迹法检测酪氨酸激酶2（Tyk2）/信号转导及转录激活因子3（Stat3）通路的激活状态。利用Tyk2 RNA干扰（RNAi）确定Tyk2/Stat3信号通路对肝细胞恶性表型的影响。 结果：在本研究中，我们的研究小组首次发现CLDN17在肝癌组织中高表达且与预后不良相关。此外，我们证明CLDN17通过Tyk2影响Stat3信号通路，最终增强肝细胞的迁移能力。 结论：总之，我们证实CLDN17的上调表达显著增强了体外肝细胞的迁移能力，并且发现Tyk2激活Stat3通路可能是CLDN17促进肝细胞侵袭性的重要机制。
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