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Specific oncogenic activity of the Src-family tyrosine kinase c-Yes in colon carcinoma cells
Florence Sancier1, Aurélie Dumont, Audrey Sirvent
1Institut de Recherches Servier, Croissy-sur-Seine, France.
Abstract:
c-Yes, a member of the Src tyrosine kinase family, is found highly activated in colon carcinoma but its importance relative to c-Src has remained unclear. Here we show that, in HT29 colon carcinoma cells, silencing of c-Yes, but not of c-Src, selectively leads to an increase of cell clustering associated with a localisation of β-catenin at cell membranes and a reduction of expression of β-catenin target genes. c-Yes silencing induced an increase in apoptosis, inhibition of growth in soft-agar and in mouse xenografts, inhibition of cell migration and loss of the capacity to generate liver metastases in mice. Re-introduction of c-Yes, but not c -Src, restores transforming properties of c-Yes depleted cells. Moreover, we found that c-Yes kinase activity is required for its role in β-catenin localisation and growth in soft agar, whereas kinase activity is dispensable for its role in cell migration. We conclude that c-Yes regulates specific oncogenic signalling pathways important for colon cancer progression that is not shared with c-Src.
Insights
c-Yes, a Src tyrosine kinase family member, drives colon cancer progression by regulating cell adhesion and metastasis. Silencing c-Yes inhibits tumor growth and spread, highlighting its distinct role from c-Src in colorectal carcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- c-Yes is a Src tyrosine kinase family member highly activated in colon carcinoma.
- The specific role of c-Yes in colorectal cancer progression relative to c-Src remains unclear.
Purpose of the Study:
- To elucidate the distinct functional role of c-Yes in colon carcinoma progression.
- To investigate the molecular mechanisms underlying c-Yes-mediated oncogenic signaling.
Main Methods:
- Utilized HT29 colon carcinoma cells for gene silencing experiments.
- Assessed cell clustering, β-catenin localization, apoptosis, cell migration, and tumor growth in vivo (xenografts and metastasis models).
- Evaluated the requirement of c-Yes kinase activity for its functions.
Main Results:
- Silencing c-Yes, but not c-Src, increased cell clustering, membrane localization of β-catenin, and reduced target gene expression.
- c-Yes depletion inhibited apoptosis, soft-agar growth, xenograft growth, cell migration, and liver metastasis formation.
- Re-introduction of c-Yes restored transforming properties; kinase activity was essential for β-catenin localization and soft-agar growth but not migration.
Conclusions:
- c-Yes plays a critical, distinct role in colon cancer progression, independent of c-Src.
- c-Yes regulates specific oncogenic signaling pathways crucial for colorectal carcinoma development and metastasis.
- c-Yes kinase activity is selectively required for certain oncogenic functions.
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