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SSH3 facilitates colorectal cancer cell invasion and metastasis by affecting signaling cascades involving LIMK1/Rac1.

ABSTRACT: Slingshot phosphatase 3 (SSH3) is a member of the SSH phosphatase family that regulates actin filament dynamics. However, its role in cancer metastasis is relatively unclear compared to that of SSH1. Here, we showed that SSH3 was upregulated in colorectal cancer (CRC). Of note, SSH3 was upregulated in the tumor thrombus and lymph node metastasis compared with that in paired primary CRC tissues. High SSH3 expression was associated with the aggressive phenotype of CRC and may be an independent prognostic factor for the poor survival of patients with CRC. SSH3 significantly enhanced the invasion and metastasis of CRC cells in vitro and in vivo. Moreover, SSH3 regulated the remodeling of actin, which is involved in the cytoskeleton signaling pathway, through its interaction with LIMK1/Rac1 and subsequently promoted CRC cell invasion and metastasis. Our data elucidate an important role for SSH3 in the progression of CRC, and SSH3 may be considered a potential therapeutic target for CRC.

SUBMITTER: Hu YH

PROVIDER: S-EPMC6556607 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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SSH3 facilitates colorectal cancer cell invasion and metastasis by affecting signaling cascades involving LIMK1/Rac1.

Hu Yu-Han YH Lu Yan-Xia YX Zhang Zhe-Ying ZY Zhang Jian-Ming JM Zhang Wen-Juan WJ Zheng Lin L Lin Wei-Hao WH Zhang Wei W Li Xue-Nong XN

American journal of cancer research 20190501 5

Slingshot phosphatase 3 (SSH3) is a member of the SSH phosphatase family that regulates actin filament dynamics. However, its role in cancer metastasis is relatively unclear compared to that of SSH1. Here, we showed that SSH3 was upregulated in colorectal cancer (CRC). Of note, SSH3 was upregulated in the tumor thrombus and lymph node metastasis compared with that in paired primary CRC tissues. High SSH3 expression was associated with the aggressive phenotype of CRC and may be an independent pro ...[more]

PMID: 31218112

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Project description:BackgroundColorectal cancer (CRC) is one of the most common digestive malignant tumors, and DMTN is a transcriptionally differentially expressed gene that was identified using CRC mRNA sequencing data from The Cancer Genome Atlas (TCGA). Our preliminary work suggested that the expression of DMTN was downregulated in CRC, and the Rac1 signaling pathway was significantly enriched in CRC tissues with low DMTN expression. However, the specific functions and underlying molecular mechanisms of DMTN in the progression of CRC and the upstream factors regulating the downregulation of the gene remain unclear.MethodsDMTN expression was analyzed in CRC tissues, and the relationship between DMTN expression and the clinicopathological parameters was analyzed. In vitro and in vivo experimental models were used to detect the effects of DMTN dysregulation on invasion and metastasis of CRC cells. GSEA assay was performed to explore the mechanism of DMTN in invasion and metastasis of CRC. Westernblot, Co-IP and GST-Pull-Down assay were used to detect the interaction between DMTN and ARHGEF2, as well as the activation of the RAC1 signaling. Bisulfite genomic sequence (BSP) assay was used to test the degree of methylation of DMTN gene promoter in CRC tissues.ResultsWe found that the expression of DMTN was significantly decreased in CRC tissues, and the downregulation of DMTN was associated with advanced progression and poor survival and was regarded as an independent predictive factor of CRC patient prognosis. The overexpression of DMTN inhibited, while the knockdown of DMTN promoted, invasion and metastasis in CRC cells. Moreover, hypermethylation and the deletion of DMTN relieved binding to the ARHGEF2 protein, activated the Rac1 signaling pathway, regulated actin cytoskeletal rearrangements, and promoted the invasion and metastasis of CRC cells.ConclusionOur study demonstrated that the downregulation of DMTN promoted the metastasis of colorectal cancer cells by regulating the actin cytoskeleton through RAC1 signaling activation, potentially providing a new therapeutic target to enable cancer precision medicine for CRC patients.

Project description:Aberrant expression of microRNAs (miRNAs/miRs) is associated with the initiation and progression of colorectal cancer (CRC), but how they regulate colorectal tumorigenesis is still unknown. The present study was designed to investigate the expression profile of miRNAs in human CRC tissues, and to reveal the molecular mechanism of miRNA‑142‑3p in suppressing colon cancer cell proliferation. The expression of miRNA was examined using an Exiqon miRNA array. Bioinformatics was used to predict the target genes of differentially expressed miRNAs and to analyze their biological function in CRC. The effect of miR‑142‑3p in colon cancer cells was evaluated in vitro using cell proliferation, colony formation and Transwell assays. Dual‑luciferase reporter gene assays were performed to investigate the association between miR‑142‑3p and Rac family small GTPase 1 (RAC1). The effect of miR‑142‑3p regulation on colon cancer proliferation was assessed through western blotting and quantitative polymerase chain reaction analysis. Compared with their expression in adjacent non‑cancer mucosal tissues, 76 miRNAs were upregulated and 102 miRNAs were downregulated in CRC. One of the most significantly and differentially regulated miRNAs was miR‑142‑3p, which was downregulated in 81.0% (51/63) of primary CRC tissues. After transfection of miR‑142‑3p mimics into colon cancer cells, proliferation and colony formation were decreased, and migration and invasion were markedly suppressed. RAC1 was a possible target of miR‑142‑3p, which was confirmed by dual‑luciferase reporter assay. Transfection of miR‑142‑3p mimics decreased the levels of RAC1 and suppressed epithelial‑to‑mesenchymal transition in colon cancer cells. The phosphorylation of extraceullar signal‑regulated kinase (ERK) was decreased significantly by the inhibition of RAC1 or transfection of miR‑142‑3p mimics in colon cancer cells. In conclusion, aberrant miRNAs are implicated in CRC. Decreased expression of miR‑142‑3p may be associated with CRC tumorigenesis via Rac1‑ERK signaling.

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SSH3 facilitates colorectal cancer cell invasion and metastasis by affecting signaling cascades involving LIMK1/Rac1.

Publications

SSH3 facilitates colorectal cancer cell invasion and metastasis by affecting signaling cascades involving LIMK1/Rac1.

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