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FSTL1 interacts with VIM and promotes colorectal cancer metastasis via activating the focal adhesion signalling pathway.

ABSTRACT: Follistatin-like protein 1 (FSTL1) has been reported to have both tumour-promoting and tumour-suppressive characters. However, the role of FSTL1 in colorectal cancer (CRC) remains unclear. Here we showed that FSTL1 expression was significantly up-regulated in CRC tissues compared with the paired normal tissues. In addition, the higher FSTL1 expression was associated with the infiltrating depth, lymph node metastasis and poor prognosis of CRC. Enhanced expression of FSTL1 distinctly increased cell migration and invasion in vitro, as well as promoting liver metastasis of CRC in vivo. Conversely, knockdown of FSTL1 expression significantly repressed invasion and metastasis of CRC. Mechanically, transcription factor Smad3 was involved in FSTL1 protein expression inducing by TGF?1-Smad2/3 signalling. Furthermore, this effect of FSTL1 in promoting CRC progression was actualised via activating focal adhesions signalling pathway and regulating cytoskeleton rearrangement. We identified VIM, as an interactive protein of FSTL1, participated in FSTL1-mediated aggressive phenotype. We showed the role of FSTL1 in CRC and explored its transcription regulation and downstream signalling molecular mechanisms. In conclusion, our findings suggested that FSTL1 promoted CRC progression and metastasis, making it a novel target for diagnosis and prognostic evaluation of CRC.

SUBMITTER: Gu C

PROVIDER: S-EPMC5974179 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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FSTL1 interacts with VIM and promotes colorectal cancer metastasis via activating the focal adhesion signalling pathway.

Gu Chuansha C Wang Xiaoyan X Long Ting T Wang Xia X Zhong Yan Y Ma Yidan Y Hu Zhiyan Z Li Zuguo Z

Cell death & disease 20180529 6

Follistatin-like protein 1 (FSTL1) has been reported to have both tumour-promoting and tumour-suppressive characters. However, the role of FSTL1 in colorectal cancer (CRC) remains unclear. Here we showed that FSTL1 expression was significantly up-regulated in CRC tissues compared with the paired normal tissues. In addition, the higher FSTL1 expression was associated with the infiltrating depth, lymph node metastasis and poor prognosis of CRC. Enhanced expression of FSTL1 distinctly increased cel ...[more]

PMID: 29844309

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Project description:BackgroundMetastasis is the leading cause of death among patients with colorectal cancer (CRC). Therefore, it is important to explore the molecular mechanisms of metastasis to develop effective therapeutic targets for CRC. In the present study, ribosomal protein L21 (RPL21) was considered as being involved in promoting CRC metastasis, yet the underlying mechanism requires further investigation.MethodsImmunohistochemistry, western blotting, and quantitative reverse transcription polymerase chain reaction were performed to measure the expression of RPL21 and lysosome-associated membrane protein 3 (LAMP3) in CRC tissues and cells. Wound healing, transwell migration, and invasion assays were performed to study the migration and invasion of cultured CRC cells. An orthotopic CRC mouse model was developed to investigate the metastatic ability of CRC. Transcriptome sequencing was conducted to identify the genes related to RPL21. The dual-luciferase reporter gene assay was performed to determine the transcriptional activity of transcription factor EB (TFEB). The GST/His pull-down assay was performed to investigate the specific binding sites of RPL21 and LAMP3. The cell adhesion assay was performed to determine the adhesion ability of CRC cells. Immunofluorescence staining was performed to observe focal adhesions (FAs).ResultsRPL21 was highly expressed in CRC, contributing to tumor invasiveness and poor patient prognosis. Functionally, RPL21 promoted the migration and invasion of CRC cells in vitro and tumor metastasis in vivo. Moreover, LAMP3 was identified as being highly related to RPL21 and was essential in promoting the migration and invasion of CRC cells. Mechanistically, RPL21 activated the transcriptional function of TFEB to upregulate LAMP3 expression. RPL21 directly bound to the aa 341-416 domain of LAMP3 via its aa 1-40 and aa 111-160 segments. The combination of RPL21 and LAMP3 enhanced the stability of the RPL21 protein by suppressing the degradation of the ubiquitin-proteasome system. Furthermore, RPL21 and LAMP3 promoted the formation of immature FAs by activating the FAK/paxillin/ERK signaling pathway.ConclusionsRPL21 promoted invasion and metastasis by regulating FA formation in a LAMP3-dependent manner during CRC progression. The interaction between RPL21 and LAMP3 may function as a potential therapeutic target against CRC.

Project description:BackgroundFocal adhesion plays an essential role in tumour invasiveness and metastasis. Hippo component YAP has been widely reported to be involved in many aspects of tumour biology. However, its role in focal adhesion regulation in breast cancer remains unexplored.MethodsTissue microarray was used to evaluate YAP expression in clinical breast cancer specimens by immunohistochemical staining. Cell migration and invasion abilities were measured by Transwell assay. A cell adhesion assay was used to measure the ability of cell adhesion to gelatin. The focal adhesion was visualized through immunofluorescence. Phosphorylated FAK and other proteins were detected by Western blot analysis. Gene expression profiling was used to screen differently expressed genes, and gene ontology enrichment was performed using DAVID software. The gene mRNA levels were measured by quantitative real-time PCR. The activity of the THBS1-promoter was evaluated by dual luciferase assay. Chromatin immunoprecipitation (ChIP) was used to verify whether YAP could bind to the THBS1-promoter region. The prediction of potential protein-interaction was performed with the String program. The ChIP sequence data of TEAD was obtained from the ENCODE database and analysed via the ChIP-seek tool. The gene expression dataset (GSE30480) of purified tumour cells from primary breast tumour tissues and metastatic lymph nodes was used in the gene set enrichment analysis. Prognostic analysis of the TCGA dataset was performed by the SurvExpress program. Gene expression correlation of the TCGA dataset was analysed via R2: Genomics Analysis and Visualization Platform.ResultsOur study provides evidence that YAP acts as a promoter of focal adhesion and tumour invasiveness via regulating FAK phosphorylation in breast cancer. Further experiments reveal that YAP could induce FAK phosphorylation through a TEAD-dependent manner. Using gene expression profiling and bioinformatics analysis, we identify the FAK upstream gene, thrombospondin 1, as a direct transcriptional target of YAP-TEAD. Silencing THBS1 could reverse the YAP-induced FAK activation and focal adhesion.ConclusionOur results unveil a new signal axis, YAP/THBS1/FAK, in the modulation of cell adhesion and invasiveness, and provides new insights into the crosstalk between Hippo signalling and focal adhesion.

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FSTL1 interacts with VIM and promotes colorectal cancer metastasis via activating the focal adhesion signalling pathway.

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FSTL1 interacts with VIM and promotes colorectal cancer metastasis via activating the focal adhesion signalling pathway.

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