Hypoxia Promotes Malignant Progression of Colorectal Cancer by Inducing POSTN+ Cancer‐Associated Fibroblast Formation

ABSTRACT Colorectal cancer (CRC) is one of the most common malignancies. Hypoxia can promote the occurrence and development of CRC. However, how hypoxia regulates the CRC immune microenvironment needs to be further explored. The bulk RNA sequencing data and clinicopathological information of CRC patients were enrolled from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. The single‐cell RNA sequencing (scRNA‐seq) datasets of CRC were collected from and analyzed from the GEO database and the ArrayExpress database. The score of the hypoxia gene set was estimated using the “ssGSEA” algorithm in the “GSVA” R package. The functional characteristics of CAF subtypes were studied by bioinformatics analysis and in vitro experiments, and a prognostic model was constructed based on machine learning correlation. Hypoxia is associated with poor prognosis in CRC patients. Periostin (POSTN) + Fib is a cancer‐associated fibroblast (CAF) closely associated with hypoxia, and high infiltration of POSTN + Fib is associated with adverse outcomes in overall survival (OS) and relapse‐free survival (RFS) in CRC patients. Hypoxia can induce POSTN expression and secretion in CAFs. Hypoxia‐induced increase of POSTN expression in CAFs can significantly promote the migration and proliferation of CRC cells. Hypoxia‐induced increase of POSTN expression in CAFs can significantly promote the proliferation and migration of CRC cells. The POSTN + Fib Hypoxia‐Related Risk Model (PFHRM) can predict the survival and immunotherapy response of CRC patients. Our study identified a POSTN + Fib cell subpopulation closely associated with hypoxia, which promotes the malignant progression of CRC. The development of PFHRM provides a theoretical basis for improving patient survival and prognosis.