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

Ki Hyung Kim; Seung Joon Lee; Juil Kim; Yuseok Moon

doi:10.1016/j.isci.2020.101076

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

iScience. 2020 May 22;23(5):101076. doi: 10.1016/j.isci.2020.101076. Epub 2020 Apr 18.

Authors

Ki Hyung Kim¹, Seung Joon Lee², Juil Kim², Yuseok Moon³

Affiliations

¹ Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University, Yangsan 50612, Korea; Department of Obstetrics and Gynecology, Pusan National University College of Medicine, Busan 49241, Korea; Biomedical Research Institute, Pusan National University Hospital, Busan, 49241, Korea.
² Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University, Yangsan 50612, Korea.
³ Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University, Yangsan 50612, Korea; Biomedical Research Institute, Pusan National University Hospital, Busan, 49241, Korea. Electronic address: moon@pnu.edu.

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.

Keywords: Biological Sciences; Cancer; Cell Biology; Functional Aspects of Cell Biology.