KLF7/VPS35 axis contributes to hepatocellular carcinoma progression through CCDC85C-activated β-catenin pathway.
KLF7/VPS35 axis contributes to hepatocellular carcinoma progression through CCDC85C-activated β-catenin pathway.
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KLF7/VPS35轴通过ccdc85c激活的β-catenin途径参与肝细胞癌进展。
DOI：
10.1186/s13578-021-00585-6
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发表时间：
2021-04-15
影响因子：
7.5
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Guo Y;Chai B;Jia J;Yang M;Li Y;Zhang R;Wang S;Xu J
KLF 7的失调参与了各种癌症的发展，但目前还不清楚HCC和KLF 7的异常表达之间是否存在联系。本研究旨在探讨KLF 7在肝癌细胞增殖和迁移中的作用。通过CCK 8、集落生长、transwell、细胞周期分析和凋亡检测等方法，探讨KLF 7、VPS 35和Ccdc 85 c对体外培养的细胞功能的影响。异种移植肿瘤生长用于评估KLF 7的体内作用。采用Chip-qPCR和荧光素酶报告基因检测KLF 7是否以转录方式调控VPS 35。进行Co-IP测定以检测VPS 35与Ccdc 85 c之间的相互作用。采用免疫组化和qRT-PCR方法检测KLF 7、VPS 35和β-catenin在肝癌组织中的表达及临床意义。首先，KLF 7在人肝癌组织中高表达，并与患者的分化程度和转移状态相关。KLF 7过表达促进了肝癌细胞的增殖和侵袭。KLF 7转录激活VPS 35是HCC肿瘤生长和转移所必需的。此外，co-IP研究显示VPS 35可以与HCC细胞中的Ccdc 85 c相互作用。Rescue检测证实VPS 35的过表达和Ccdc 85 c的敲低消除了VPS 35对细胞增殖和侵袭的促进作用。最后，KLF 7/VPS 35轴调节Ccdc 85 c，其参与β-catenin信号通路的激活，使用β-catenin抑制剂GK 974证实。功能研究表明，Ccdc 85 c的下调部分逆转了肝癌细胞的增殖和侵袭能力，这是由VPS 35上调调节。HCC患者中KLF 7、VPS 35和活性β-catenin的表达呈正相关。我们证明KLF 7/VPS 35轴通过激活Ccdc 85 c介导的β-catenin途径促进HCC细胞的进展。靶向该信号轴可能是HCC的潜在治疗策略。
Dysregulation of KLF7 participates in the development of various cancers, but it is unclear whether there is a link between HCC and aberrant expression of KLF7. The aim of this study was to investigate the role of KLF7 in proliferation and migration of hepatocellular carcinoma (HCC) cells. CCK8, colony growth, transwell, cell cycle analysis and apoptosis detection were performed to explore the effect of KLF7, VPS35 and Ccdc85c on cell function in vitro. Xenografted tumor growth was used to assess in vivo role of KLF7. Chip-qPCR and luciferase reporter assays were applied to check whether KLF7 regulated VPS35 at transcriptional manner. Co-IP assay was performed to detect the interaction between VPS35 and Ccdc85c. Immunohistochemical staining and qRT-PCR analysis were performed in human HCC sampels to study the clinical significance of KLF7, VPS35 and β-catenin. Firstly, KLF7 was highly expressed in human HCC samples and correlated with patients’ differentiation and metastasis status. KLF7 overexpression contributed to cell proliferation and invasion of HCC cells in vitro and in vivo. KLF7 transcriptional activation of VPS35 was necessary for HCC tumor growth and metastasis. Further, co-IP studies revealed that VPS35 could interact with Ccdc85c in HCC cells. Rescue assay confirmed that overexpression of VPS35 and knockdown of Ccdc85c abolished the VPS35-medicated promotion effect on cell proliferation and invasion. Finally, KLF7/VPS35 axis regulated Ccdc85c, which involved in activation of β-catenin signaling pathway, confirmed using β-catenin inhibitor, GK974. Functional studies suggested that downregulation of Ccdc85c partly reversed the capacity of cell proliferation and invasion in HCC cells, which was regulated by VPS35 upregulation. Lastly, there was a positive correlation among KLF7, VPS35 and active-β-catenin in human HCC patients. We demonstrated that KLF7/VPS35 axis promoted HCC cell progression by activating Ccdc85c-medicated β-catenin pathway. Targeting this signal axis might be a potential treatment strategy for HCC.
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影响因子：
20.3
作者：
Schuettpelz, Laura G.;Gopalan, Priya K.;Link, Daniel C.
通讯作者：
Link, Daniel C.
影响因子：
3.5
作者：
Du, Chong;Gao, Yang;Guo, Peng
通讯作者：
Guo, Peng
影响因子：
4.3
作者：
Qiu, Wei-Hua;Zhou, Bing-Sen;Yen, Yun
通讯作者：
Yen, Yun
影响因子：
2.3
作者：
Hartke, Justin;Johnson, Matthew;Ghabril, Marwan
通讯作者：
Ghabril, Marwan
DNA和RNA测序鉴定出肝癌中的一个新癌基因VPS35
影响因子：
8
作者：
Zhang, Guiji;Tang, Xia;Ding, Keyue
通讯作者：
Ding, Keyue