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Rictor promotes cell migration and actin polymerization through regulating ABLIM1 phosphorylation in Hepatocellular Carcinoma

ABSTRACT: As one of the most ominous malignancies, hepatocellular carcinoma (HCC) is frequently diagnosed at an advanced stage, owing to its aggressive invasion and metastatic spread. Emerging evidence has demonstrated that Rictor, as a unique component of the mTORC2, plays a role in cell migration, as it is dysregulated in various cancers, including HCC. However, the underlying molecular mechanism has not been well-characterized. Here, evaluation on a tissue-array panel and bioinformatics analysis revealed that Rictor is highly expressed in HCC tissues. Moreover, increased Rictor expression predicts poor survival of HCC patients. Rictor knockdown significantly suppressed cell migration and actin polymerization, thereby leading to decreased nuclear accumulation of MKL1 and subsequent inactivation of SRF/MKL1-dependent gene transcription, i.e. Arp3 and c-Fos. Mechanistically, we identified ABLIM1 as a previously unknown phosphorylation target of Rictor. Rictor interacts with ABLIM1 and regulates its serine phosphorylation in HCC cells. We generated ABLIM1 knockout cell lines of HCC, in which dominant negative mutations of Ser 214 and Ser 431 residues inhibited the ABLIM1-mediated actin polymerization and the MKL1 signaling pathway. Overall, ABLIM1 phosphorylation induced by Rictor plays an important role in controlling actin polymerization in HCC cells.

SUBMITTER: Dong X

PROVIDER: S-EPMC7545703 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:ObjectivesRecent evidence suggests that Sort1 promotes carcinogenesis and tumor progression in multiple types of cancers. This study investigates the role of Sort1 in hepatocellular carcinoma (HCC).MethodsThe differentially expressed gene was screened through GEO and TCGA databases. The Sort1 gene was identified and its expression was then verified by TCGA and HCCDB (a database of hepatocellular carcinoma expression atlas) databases. The Human Protein Atlas database was used to assess the gene expression in tissues. The TCGA and KM-plotter databases were used to study the relationship between Sort1 and HCC. The correlation between Sort1 and immune cells was evaluated through the TIMER database. GO and KEGG enrichment analysis was used to investigate the possible mechanism. The role of Sort1 in cell proliferation and invasion of HCC was further explored through in vitro experiments.ResultThe differentially expressed molecule obtained from database screening was Sort1. Its expression was higher in cancer tissues than in paracancerous ones, and it was mainly located in the cytoplasm. The TCGA, KM-plotter databases, and our study data showed that low expression of Sort1 in HCC patients had better overall survival (OS), progression-free survival (PFI), and disease-specific survival (DSS). Further analysis indicated a significant correlation between Sort1 expression and immune cell infiltration. The gene set enrichment analysis (GSEA) analysis showed that Sort1 affected the biological events of HCC by participating in the WNT, TGF-BETA, JAK, STAT, and CALCIUM signaling pathways. In vitro, cytological experiments demonstrated reduced expression of PCNA, Ki-67, Vimentin, N-cadherin, and MMP-9 mRNA after knocking down Sort1, although E-cadherin expression was promoted. Overall, these processes reduced the ability of proliferation and invasion of HCC cells.ConclusionDownregulation of Sort1 can prolong the OS, PFI, and DSS of HCC patients. Furthermore, due to its link with immune cell infiltration, the Sort1 gene represents a potentially novel predictive biomarker of HCC. The growth of HCC can be significantly inhibited by interfering with Sort1; therefore, these results provide a potential target for developing anticancer strategies for HCC.

Project description:BackgroundForkhead box M1 (FOXM1) is a proliferation-associated transcription factor of the forkhead box proteins superfamily, which includes four isoforms FOXM1a, b, c, and d. FOXM1 has been implicated in hepatocellular carcinoma (HCC) progression, but the underlying molecular mechanism remains elusive. In this study, we aim to clarify the molecular basis for FOXM1-mediated HCC progression.MethodsBioinformatic analysis was used to explore the differentially expressed genes predicting HCC proliferation. The expression of FOXM1 and kinesin family member (KIF)4A was confirmed by western blotting and immunohistochemistry in HCC tissues. Kaplan-Meier survival analysis was conducted to analyze the clinical impact of FOXM1 and KIF4A on HCC. The effect of FOXM1 on the regulation of KIF4A expression was studied in cell biology experiments. The interaction between KIF4A and FOXM1 was analyzed by chromatin immunoprecipitation and luciferase experiments. A series of experiments was performed to explore the functions of FOXM1/KIF4A in HCC progression, such as cell proliferation, cell growth, cell viability, and cell cycle. A xenograft mouse model was used to explore the regulatory effect of FOXM1-KIF4A axis on HCC tumor growth.ResultsFOXM1 and KIF4A were overexpressed in human primary HCC tissues compared to that in matched adjacent normal liver tissue and are significant risk factors for HCC recurrence and shorter survival. We found that KIF4A was dominantly regulated by FOXM1c among the four isoforms, and further identified KIF4A as a direct downstream target of FOXM1c. Inhibiting FOXM1 decreased KIF4A expression in HCC cells, whereas its overexpression had the opposite effect. FOXM1-induced HCC cell proliferation was dependent on elevated KIF4A expression as KIF4A knockdown abolished FOXM1-induced proliferation of HCC cells both in vitro and in vivo.ConclusionThe FOXM1-KIF4A axis mediates human HCC progression and is a potential therapeutic target for HCC treatment.

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Rictor promotes cell migration and actin polymerization through regulating ABLIM1 phosphorylation in Hepatocellular Carcinoma

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