Gasdermin D Regulates the Activation of EGFR in Colorectal Cancer

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2024 Dec 31

PMID 39741309

Authors

Ying Li

Jiayao Chen

Huijun Liang

Qindan Du

Jingjie Shen

Xiaoying Wang

Affiliations

Soon will be listed here.

Abstract

Background: Gasdermin D (GSDMD) is a key effector molecule that activates pyroptosis through its N terminal domain (GSDMD-NT). However, the roles of GSDMD in colorectal cancer (CRC) have not been fully explored. The role of the full-length GSDMD (GSDMD-FL) is also not clear. In this study, we observed that GSDMD modulates CRC progression through other mechanisms in addition to activating GSDMD-NT.

Methods: Clinical CRC samples and human-derived CRC cell lines were used in this study. GSDMD expression was evaluated by RT-qPCR, Western blot and immunohistochemical (IHC) analysis. GSDMD knockdown and overexpression stable cell lines were established by Lentiviral transduction. CCK-8 assay, flow cytometry analysis for cell cycle, Transwell assay, and cell scratch assay were performed in vitro to explore the impact of GSDMD on CRC progression. Mouse subcutaneous transplantation tumor models were constructed to assess the role of GSDMD in vivo. Intestinal epithelial cell (IEC)-specific knockout of Gsdmd mice (Gsdmd) was used to evaluate the effect of GSDMD on intestinal adenoma formation in AOM-DSS and Apc mouse models. RNA sequencing was performed to explore the regulatory pathways associated with the role of GSDMD in CRC cells. Co-Immunoprecipitation (CO-IP), Western blot and immunofluorescence (IF) were conducted to investigate the interactions between GSDMD and EGFR. Exogenous addition of Gefitinib was used to evaluate the effect of GSDMD on autophosphorylation of EGFR at the Tyr1068 site.

Results: GSDMD was highly expressed in clinical CRC tissues and human-derived CRC cell lines. GSDMD knockdown inhibited the viability, cell cycle changes, invasion ability and migration ability of CRC cell lines in vitro and vivo, whereas GSDMD overexpression had the opposite effects. Intestinal adenoma development was reduced in Gsdmd mice in both AOM-DSS and Apc mouse models. GSDMD-FL interacted with EGFR and promoted CRC progression by inducing autophosphorylation of EGFR at the Tyr1068 site, subsequently activating ERK1/2. Exogenous Gefitinib abrogated the tumorigenic properties of GSDMD.

Conclusions: GSDMD-FL promotes CRC progression by inducing EGFR autophosphorylation at the Tyr1068 site, subsequently activating the downstream ERK1/2. Inhibition of GSDMD is a potential strategy for the treatment of colorectal cancer.

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