Angiotensin II Type 1 Receptor Blockade Inhibits Gastric Cancer Metastasis Through Tight Junction Restoration

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 krüppel-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.