Dynamic Malignant Wave of Ribosome-Insulted Gut Niche via the Wnt-CTGF/CCN2 Circuit.

Abstract

Stress-driven ribosome dysfunction triggers an eIF2α-mediated integrated stress response to maintain cellular homeostasis. Among four key eIF2α kinases, protein kinase R (PKR) expression positively associates with poor prognoses for colorectal cancer (CRC) patients. We identified PKR-linked Wnt signaling networks that facilitate early inflammatory niche and epithelial-mesenchymal transitions of tumor tissues in response to ribosomal insults. However, the downstream Wnt signaling target fibrogenic connective tissue growth factor (CTGF/CCN2) regulates the nuclear translocation of β-catenin in a negative feedback manner. Moreover, dwindling expression of the Wnt/β-catenin pathway-regulator CTGF triggers noncanonical Wnt pathway-mediated exacerbation of intestinal cancer progression such as an increase in cancer stemness and acquisition of chemoresistance in the presence of ribosomal insults. The Wnt-CTGF-circuit-associated landscape of oncogenic signaling events was verified with clinical genomic profiling. This ribosome-associated wave of crosstalk between stress and oncogenes provides valuable insight into potential molecular interventions against intestinal malignancies.

• Authors: Ki Hyung Kim, Seung Joon Lee, Juil Kim, Yuseok Moon
• Journal: iScience (iScience) Vol. 23 Issue 5 Pg. 101076 (May 22 2020) ISSN: 2589-0042 [Electronic] United States
• PMID: 32361596 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.