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RASSF6 downregulation promotes the epithelial-mesenchymal transition and predicts poor prognosis in colorectal cancer.

ABSTRACT: Distant metastasis is the primary barrier for the successful treatment of patients with colorectal cancer, and thus, searching for new therapeutic targets by further exploring the molecular mechanisms of colorectal cancer metastasis is important. In this study, we investigated the biological and clinical significance of RASSF6 in colorectal cancer as well as the underlying molecular mechanisms. We found that low RASSF6 expression corresponds to a poor prognosis in colorectal cancer patients, and low RASSF6 expression is distinctly associated with tumour progression. Our in vitro analysis revealed that RASSF6 suppresses the proliferation and metastasis of DLD1 cells, and RASSF6 knockdown in HCT116 cells confirmed these observations. Our mechanistic investigation revealed that RASSF6 inhibits the expression of the classical target genes of Wnt signalling, as demonstrated by the reduced expression of TCF1, c-Jun, and c-Myc in RASSF6-overexpressing DLD1 stable cell lines. Furthermore, we show that RASSF6 functions as a negative regulator of the epithelial-mesenchymal transition; the expression levels of the epithelial markers ZO-1 and E-cadherin were increased, while the expression level of the mesenchymal marker Snail was decreased in a RASSF6-overexpressing DLD1 cell line. Additionally, rescue assays revealed that the activation of Wnt signalling by LiCl treatment impaired the inhibitory effect of RASSF6 on the proliferation and metastasis of colorectal cancer cells, which implies that RASSF6 suppresses the tumorigenicity of colorectal cancer cells at least in part through inhibiting Wnt signalling pathway. Collectively, these findings provide new perspectives for the future study of RASSF6 as a therapeutic target for colorectal cancer.

SUBMITTER: Zhou R

PROVIDER: S-EPMC5589649 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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RASSF6 downregulation promotes the epithelial-mesenchymal transition and predicts poor prognosis in colorectal cancer.

Zhou Rui R Qiu Lin L Liu Xiaolong X Ling Lijuan L Li Ninglei N Zhou Kun K Sun Jingbo J Yan Jian J Tan Canliang C Huang Xiaoping X Han Luzhe L Yin Liangchun L Xiao Gang G Liu Lixin L

Oncotarget 20170712 33

Distant metastasis is the primary barrier for the successful treatment of patients with colorectal cancer, and thus, searching for new therapeutic targets by further exploring the molecular mechanisms of colorectal cancer metastasis is important. In this study, we investigated the biological and clinical significance of RASSF6 in colorectal cancer as well as the underlying molecular mechanisms. We found that low RASSF6 expression corresponds to a poor prognosis in colorectal cancer patients, and ...[more]

PMID: 28903410

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Project description:BackgroundAberrant activation of the Wnt/β-catenin signaling pathway is one of the most frequent abnormalities in human cancer, including colorectal cancer (CRC). Previous studies revealed pivotal functions of WNT family members in colorectal cancer, as well as their prognostic values. Nevertheless, the prognostic role and mechanisms underlying WNT7b in colorectal cancer development remains unclear.MethodsIn this study, WNT7b expression was measured by immunohistochemical staining of 100 cases of surgically resected human colorectal cancerous tissues as well as matched adjacent normal tissues constructed as tissue microarrays. In vitro studies, we attempted to substantiate the WNT7b expressional pattern previously found in immunohistochemistry staining. We used the colorectal cancer cell-line HCT116 and normal colorectal cell-line FHC for immunofluorescence staining and nuclear/cytoplasmic separated western blotting. We measured epithelial-mesenchymal transition (EMT) markers and migration capacity of HCT116 in the context of WNT7b knocked-down using short interfering RNA. Finally, clinical and prognostic values of WNT7b activation levels were examined.ResultsWNT7b was expressed in the nucleus in adjacent normal tissues. In CRC tissues, nuclear expression of WNT7b was similar; however, membrane and cytoplasmic expression was strikingly enhanced. Consistently, in vitro analysis confirmed the same expression pattern of WNT7b. Compared with FHC cells, HCT116 cells displayed higher levels of WNT7b membrane and cytoplasmic enrichment, as well as higher migration capacity with a sensitized EMT process. Either partial knockdown of WNT7b or blockade of the Wnt/β-catenin signaling pathway reversed EMT process and inhibited the migration of HCT116 cells. Finally, elevated secretion levels of WNT7b were significantly associated with lymphatic and remote metastasis and predicted worse prognosis in the CRC cohort.ConclusionIn summary, we demonstrated that the activation of WNT7b autocrine probably contributes to CRC metastasis by triggering EMT process through the Wnt/β-catenin signaling pathway. High levels of WNT7b autocrine secretion predicts poor outcome in patients with CRC. This molecule is a promising candidate for clinical CRC treatments.

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RASSF6 downregulation promotes the epithelial-mesenchymal transition and predicts poor prognosis in colorectal cancer.

Publications

RASSF6 downregulation promotes the epithelial-mesenchymal transition and predicts poor prognosis in colorectal cancer.

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