Claudin-1/4 as directly target gene of HIF-1α can feedback regulating HIF-1α by PI3K-AKT-mTOR and impact the proliferation of esophageal squamous cell though Rho GTPase and p-JNK pathway
Claudin-1/4 as directly target gene of HIF-1α can feedback regulating HIF-1α by PI3K-AKT-mTOR and impact the proliferation of esophageal squamous cell though Rho GTPase and p-JNK pathway
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DOI：
10.1038/s41417-021-00328-2
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发表时间：
2021-07-19
影响因子：
6.4
通讯作者：
Xu, Wei
中科院分区：
文献类型：
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作者：
Liu, Hong;Zhang, Zhancheng;Xu, Wei
免疫组化芯片包括80例食管鳞状细胞癌（ESCC）患者，发现CLDN 1和CLDN 4的表达在癌组织中显着高于癌旁组织。此外，CLDN 4显著影响癌症患者的总体存活率。当两个ESCC细胞系（TE 1，KYSE 410）暴露于缺氧（0.1%O-2）时，CLDN 1/4显示影响食管癌的发生和发展。与对照组相比，低氧条件下培养的癌细胞CLDN 1和CLDN 4在mRNA和蛋白水平上的表达均发生明显变化。通过基因干预和芯片技术，我们发现HIF-1 alpha可以直接调控癌细胞中CLDN 1和CLDN 4的表达。缺氧可通过调节PI 3 K-Akt-mTOR途径影响癌细胞的增殖和凋亡。分子分析进一步揭示了CLDN 1和CLDN 4可以参与调节过程，并对癌细胞中HIF-1 α的表达具有反馈调节作用。体外细胞实验和裸鼠体内实验进一步揭示了CLDN 4在癌细胞中表达的变化可以通过调节Rho GTP和p-JNK通路影响癌细胞的增殖。CLDN 4是否可以作为食管鳞癌治疗的靶点还有待进一步研究。
Immunohistochemical microarray comprising 80 patients with esophageal squamous cell carcinoma (ESCC) and discovered that the expression of CLDN1 and CLDN4 were significantly higher in cancer tissues compared to para-cancerous tissues. Furthermore, CLDN4 significantly affected the overall survival of cancer patients. When two ESCC cell lines (TE1, KYSE410) were exposed to hypoxia (0.1% O-2), CLDN1/4 was shown to influence the occurrence and development of esophageal cancer. Compared with the control culture group, the cancer cells cultured under hypoxic conditions exhibited obvious changes in CLDN1 and CLDN4 expression at both the mRNA and protein levels. Through genetic intervention and Chip, we found that HIF-1 alpha could directly regulate the expression of CLDN1 and CLDN4 in cancer cells. Hypoxia can affect the proliferation and apoptosis of cancer cells by regulating the PI3K-Akt-mTOR pathway. Molecular analysis further revealed that CLDN1 and CLDN4 can participate in the regulation process and had a feedback regulatory effect on HIF-1 alpha expression in cancer cells. In vitro cellular experiments and vivo experiments in nude mice further revealed that changes in CLDN4 expression in cancer cells could affect the proliferation of cancer cells via regulation of Rho GTP and p-JNK pathway. Whether CLDN4 can be target for the treatment of ESCC needs further research.