Multi-omics analyses identify mannose phosphate isomerase-centered hypoxia-induced angiogenesis signature in colorectal cancer.

BACKGROUND: Hypoxia and angiogenesis are crucial hallmarks of cancer that play key roles in the development and progression of colorectal cancer (CRC). However, the transcriptional mechanism underlying hypoxia induced angiogenesis (HIA) remain elusive. This study aimed to explore the regulatory networks, molecular mechanisms, and prognostic value of HIA-related genes. METHODS: We collected multi-omics data, including chromatin immunoprecipitation sequencing (ChIP-seq), bulk RNA-seq, single cell RNA-seq, spatial transcriptomics, and microarray data from CRC patients and cell lines. Computational methods, including single sample gene set enrichment analysis (ssGSEA), signature-related gene analysis (SRGA), consensus clustering, and others, were utilized to explore the correlation between hypoxia and angiogenesis, identify the HIA-related genes, and establish the risk scoring system based on HIA-related genes. The role of mannose phosphate isomerase (MPI) was validated using quantitative real-time PCR (RT-qPCR), Co-immunoprecipitation (Co-IP), western blot, colony formation, tube formation assay, and subcutaneous xenograft tumor models in vitro and in vivo. RESULTS: We identified 12 HIA-related genes that are transcriptionally activated by hypoxia-inducible factors (HIFs) and functionally implicated in angiogenesis in CRC. Based on the differentially expressed genes among HIA-related CRC subtypes, we constructed a prognostic scoring system termed HIAscore. Patients with high HIAscore was correlated with poor survival, aggressive phenotype, and immunosuppressive tumor microenvironment. Spatial analysis revealed sequestration regions between epithelial cells with higher HIAscore and T/I/NK cells, hindering their infiltration. Particularly, MPI was found to interact with lactate dehydrogenase A (LDHA), and promote proliferation and angiogenesis of CRC through phosphorylation and activation of Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) signaling pathways. CONCLUSIONS: This study depicts the transcriptional landscape linking hypoxia and angiogenesis in CRC, and identifies MPI as a novel regulator of this process.