Abstract
Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that plays important roles in orchestrating cell signaling. Here, we show that Erbin functions as a tumor suppressor in colorectal cancer. Analysis of Erbin expression in colorectal cancer patient specimens revealed that Erbin was downregulated at both mRNA and protein levels in tumor tissues. Knockdown of Erbin disrupted epithelial cell polarity and increased cell proliferation in 3D culture. In addition, silencing Erbin resulted in increased amplitude and duration of signaling through Akt and RAS/RAF pathways. Erbin loss induced epithelial–mesenchymal transition, which coincided with a significant increase in cell migration and invasion. Erbin interacted with kinase suppressor of Ras 1 (KSR1) and displaced it from the RAF/MEK/ERK complex to prevent signal propagation. Furthermore, genetic deletion of Erbin in Apc knockout mice promoted tumorigenesis and significantly reduced survival. Tumor organoids derived from Erbin/Apc double knockout mice displayed increased tumor initiation potential and activation of Wnt signaling. Results from gene set enrichment analysis revealed that Erbin expression associated positively with the E-cadherin adherens junction pathway and negatively with Wnt signaling in human colorectal cancer. Taken together, our study identifies Erbin as a negative regulator of tumor initiation and progression by suppressing Akt and RAS/RAF signaling in vivo.
| Original language | English |
|---|---|
| Pages (from-to) | 4839-4852 |
| Number of pages | 14 |
| Journal | Cancer Research |
| Volume | 78 |
| Issue number | 17 |
| DOIs | |
| State | Published - Sep 1 2018 |
Bibliographical note
Publisher Copyright:© 2018 American Association for Cancer Research.
Funding
We thank Dr. Emilia Galperin (University of Kentucky) for providing the expression construct of CFP-KSR1. This work was supported by R01CA133429 (T. Gao) and F31 CA196219 (P.D. Stevens). The studies were conducted with support provided by the Biospecimen Procurement and Translational Pathology and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558). J.P, Borg's laboratory is funded by La Ligue Nationale Contre le Cancer (Label Ligue J.P. Borg), Fondation A*MIDEX, and SIRIC (INCa-DGOS-Inserm 6038). We thank Dr. Emilia Galperin (University of Kentucky) for providing the expression construct of CFP-KSR1. This work was supported by R01CA133429 (T. Gao) and F31 CA196219 (P.D. Stevens). The studies were conducted with support provided by the Biospecimen Procurement and Translational Pathol ogy and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558). J.P, Borg' laboratory is funded by La Ligue Nationale Contre le Cancer (Label Ligue J.P. Borg), Fondation AMIDEX, and SIRIC (INCa-DGOS-Inserm 6038).
| Funders | Funder number |
|---|---|
| Fondation A*MIDEX | INCa-DGOS-Inserm 6038 |
| Label Ligue J.P. Borg | |
| National Childhood Cancer Registry – National Cancer Institute | R01CA133429 |
| University of Kentucky | P30CA177558, CA196219 |
| Rhode Island College | 6038 |
| Academy of Marketing | |
| Ligue Contre le Cancer |
ASJC Scopus subject areas
- Oncology
- Cancer Research
