Abstract
ObjectiveDysregulation 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.MethodsCCK8, 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.ResultsFirstly, 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.ConclusionWe 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.
Highlights
Hepatocellular carcinoma ranks as the most frequently occurring type of malignancy with poor survival and high mortality, which constitutes 7% of all the cancers worldwide [1, 2]
KLF7 is overexpressed in human hepatocellular carcinoma (HCC) patients Firstly, we explored the expression of KLF7 in human HCC patients
We showed that KLF7 was strongly expressed in cancer tissues, in which the cell nucleus was stained with KLF7 antibody
Summary
Hepatocellular carcinoma ranks as the most frequently occurring type of malignancy with poor survival and high mortality, which constitutes 7% of all the cancers worldwide [1, 2]. KLFs play important roles in regulating gene expression via binding to the GC rich elements of targeted gene promoters [6]. KLF5 contributes to cell migration of bladder cancer cells by up-regulating FYN expression [8]. There are growing evidence revealing that KLF7 is aberrantly expressed in a variety of human solid tumors and plays pivotal roles in proliferation, migration, invasion and EMT, poor prognosis of cancer cell lines [10, 11]. It is unclear whether there is a link between HCC and aberrant expression of KLF7
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