Multi-omics based consensus subtypes, development of prognostic signature, and identification of INHBB as a potential therapeutic target in colorectal cancer

Abstract

This study aims to refine molecular subtypes via multi-omics data, develop a prognostic signature, and identify novel biomarkers in colorectal cancer (CRC). On the basis of the multi-omics data, the MOVICS R package was used to divide patients with CRC into three consensus subtypes (CSs). Among the 3 CSs, CS1 had higher immune scores, immune checkpoint expression, infiltration of immune cells, and sensitivity to chemotherapy drugs. Specific markers of CS1 were identified, and 101 combinations of machine learning methods were applied for calculating the consensus machine learning-based score (CMLS) and constructing the CMLS signature for predicting patient survival. CMLS showed high efficiency in predicting the outcome of patients across multiple CRC datasets, and the results demonstrated that CMLS was an independent prognostic factor in CRC. The high- and low-CMLS groups presented distinct immune landscapes. CMLS was linked to malignant cancer features, suggesting its potential as a predictor of malignant progression in diverse cancers. Among the genes used to calculate CMLS, the role of inhibin subunit beta B (INHBB) in CRC remains unexplored. Expression analysis of INHBB across different cancer types revealed its upregulation in CRC, which was further validated by western blot and immunohistochemistry (IHC) experiments. INHBB silencing significantly inhibited tumor cell proliferation and migration, decreased phosphorylated AKT and N-cadherin levels, and increased E-cadherin expression. INHBB potentially suppresses CRC development and progression by suppressing the AKT signaling pathway and the EMT process.