Angiotensin II- Angiotensin II Receptor Type 1 Signaling Facilitates Gastric Cancer Metastasis via Kruppel-like Factor 4 Suppression and Tight Junction Breakdown

Cell-Cell adhesion maintained by tight junctions (TJs) is essential for epithelial integrity; loss of TJs correlates with poor prognosis, metastasis, and adverse clinical outcome in gastric cancer (GC). Restoring TJ integrity is therefore considered a promising therapeutic strategy in GC. The study identifies the stomach renin angiotensin system (stRAS) as a crucial regulator of TJ function in GC. Using integrative analysis of GC patient tissues, human GC cell lines, and orthotopic GC xenografts models, here we show that angiotensin II (ATII), the principal effector peptide of stRAS, drives TJ disassembly through an autocrine loop involving angiotensin receptor type 1 (AT1R) expressed on gastric cancer cells. Both ATII and AT1R are overexpressed in GC, where they suppress the expression of key TJ proteins. By analyzing global RNA-seq data and performing CRISPR/Cas9 gene deletion, chromatin immunoprecipitation, and functional assays, we mechanistically reveal that ATII, which is predominantly produced by cancer cells within the tumor microenvironment (TME), inhibits the expression of kruppel-like factor 4 (KLF4), a transcription factor crucial for the transcription of key TJ genes (CLDN1, 3, 4, and TJP1), leading to reduced synthesis of TJ proteins via AT1R expressed on cancer cells. Notably, the study demonstrates the effectiveness of pharmacological inhibition of AT1R with clinically established AT1R antagonists in preventing GC growth and metastasis by restoring TJ stability in vivo. These findings delineate a previously unrecognized role for ATII in governing TJ disassembly in GC and highlight the ATII/AT1R axis as a promising therapeutic target. GRAPHICAL ABSTRACT(Image created using BioRender) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/698396v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@172a3a7org.highwire.dtl.DTLVardef@15654c4org.highwire.dtl.DTLVardef@d73daeorg.highwire.dtl.DTLVardef@1128495_HPS_FORMAT_FIGEXP M_FIG C_FIG