Activation of WNT7b autocrine eases metastasis of colorectal cancer via epithelial to mesenchymal transition and predicts poor prognosis
Open Access
- 19 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in BMC Cancer
- Vol. 21 (1), 1-11
- https://doi.org/10.1186/s12885-021-07898-2
Abstract
Aberrant 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. In 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. WNT7b 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. In 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.Keywords
Funding Information
- Suqian Sci&Tech Program (K201907, S201905)
This publication has 30 references indexed in Scilit:
- Colorectal cancerThe Lancet, 2019
- High WNT6 expression indicates unfavorable survival outcome for patients with colorectal liver metastasis after liver resectionJournal of Cancer, 2019
- Up-regulation of Wnt7b rather than Wnt1, Wnt7a, and Wnt9a indicates poor prognosis in breast cancer2018
- Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/β-catenin pathway during brain angiogenesiseLife, 2015
- Comparison of gene expression of the oncogenic Wnt/β-catenin signaling pathway components in the mouse and human epididymisAsian Journal of Andrology, 2015
- Gpr124 Controls CNS Angiogenesis and Blood-Brain Barrier Integrity by Promoting Ligand-Specific Canonical Wnt SignalingDevelopmental Cell, 2014
- TGF-β in Epithelial to Mesenchymal Transition and Metastasis of Liver CarcinomaCurrent Pharmaceutical Design, 2012
- Wnt/β-Catenin Signaling and DiseaseCell, 2012
- Wnt/β-Catenin Signaling: Components, Mechanisms, and DiseasesDevelopmental Cell, 2009
- Efficacy of Wnt-1 monoclonal antibody in sarcoma cellsBMC Cancer, 2005