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Human MSCs promotes colorectal cancer epithelial-mesenchymal transition and progression via CCL5/?-catenin/Slug pathway.

ABSTRACT: Mesenchymal stem cells (MSCs) extensively interact with cancer cells and other stroma cells in the tumor microenvironment. However, the role of MSCs in colorectal cancer (CRC) progression and metastasis is controversial. This study was designed to identify the role of inflammation-activated-MSCs in CRC development. Our results show that tumor necrosis factor (TNF)-?-preactivated-hMSCs significantly promote the progression of colon cancer cells by enhancing cell proliferation, epithelial-mesenchymal transition, migration, and invasion. TNF-?-primed-hMSCs secrete high level of CCL5, which interacts with its receptor CCR1 expressed in colon cancer cells. Interestingly, the stimulation of colon cancer cell progression by TNF-?-primed hMSCs is associated with the upregulation of ?-catenin signaling pathway. Blocking ?-catenin pathway significantly decreases the TNF-?-primed-conditioned medium or CCL5-mediated cancer cell progression by decreasing the enhancement of Slug, suggesting that the CCL5/?-catenin/Slug pathway plays a critical role in hMSC-mediated cancer progression. Furthermore, in vivo model in nude mice confirms the ability of hMSCs to promote the proliferation and progression of colon cancer cells, and the upregulation of CCl5/?-catenin/Slug pathway. Taken together, the present study has demonstrated a novel pathway involving CCl5/CCR1/?-catenin/Slug, via which hMSCs promotes CRC development.

SUBMITTER: Chen K

PROVIDER: S-EPMC5520690 | biostudies-other | 2017 May

REPOSITORIES: biostudies-other

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Human MSCs promotes colorectal cancer epithelial-mesenchymal transition and progression via CCL5/β-catenin/Slug pathway.

Chen Ke K Liu Qianqian Q Tsang Lai Ling LL Ye Qiao Q Chan Hsiao Chang HC Sun Yunwei Y Jiang Xiaohua X

Cell death & disease 20170525 5

Mesenchymal stem cells (MSCs) extensively interact with cancer cells and other stroma cells in the tumor microenvironment. However, the role of MSCs in colorectal cancer (CRC) progression and metastasis is controversial. This study was designed to identify the role of inflammation-activated-MSCs in CRC development. Our results show that tumor necrosis factor (TNF)-α-preactivated-hMSCs significantly promote the progression of colon cancer cells by enhancing cell proliferation, epithelial-mesenchy ...[more]

PMID: 28542126

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Project description:Rationale: The role of SLUG in epithelial-mesenchymal transition during tumor progression has been thoroughly studied, but its precise regulation remains poorly explored. Methods: The affinity purification, mass spectrometry and CO-IP were performed to identify the interaction between SLUG and ubiquitin-specific protease 5 (USP5). Cycloheximide chase assays and deubiquitination assays confirmed that the effect of USP5 on the deubiquitin of SLUG. The dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the direct transcriptional regulation of E-cadherin by SLUG effected by USP5. EMT related markers was detected by western blotting and immunofluorescence. Molecular docking, SPR sensor (biacore) and co-location were detected to prove Formononetin targets USP5. Bioinformatics analysis was used to study the relation of USP5 and SLUG to malignancy degree of HCC. Cell migration, invasion in HCC cells and xenografts model in nude mouse were conducted to detect the promotion of USP5 and the inhibition of Formononetin on EMT. Results: USP5 interacts with and stabilizes SLUG to regulate its abundance through USP5 deubiquitination activities in epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC). USP5 is highly expressed and positively correlated with SLUG expression in HCC with high malignancy. Knockdown of USP5 inhibits SLUG deubiquitination and inhibits HCC cells proliferation, metastasis, and invasion, while overexpression of USP5 promotes SLUG stability and EMT in vitro and in vivo. Through virtual screening, we found that Formononetin exhibits excellent binding to USP5. Moreover, Formononetin inhibits deubiquitinating activities of USP5 to SLUG and consequently impedes the EMT and malignant progression of HCC. Conclusion: Our findings reveal that USP5 serve as a potential target for tumor intervention and provide a preliminary antitumor therapy for inhibit EMT by targeting USP5 or its interaction with SLUG in HCC.

Dataset Information

Human MSCs promotes colorectal cancer epithelial-mesenchymal transition and progression via CCL5/?-catenin/Slug pathway.

Publications

Human MSCs promotes colorectal cancer epithelial-mesenchymal transition and progression via CCL5/β-catenin/Slug pathway.

Similar Datasets

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