Systemic Multi-Omics Analysis Reveals Amplified P4HA1 Gene Associated With Prognostic and Hypoxic Regulation in Breast Cancer

Abstract

Breast cancer (BC) is a common malignant tumor in females around the world. While multimodality therapies exist, the mortality rate remains high. The hypoxic condition was one of the potent determinants in BC progression. The molecular mechanisms underpinning hypoxia and their association with BC can contribute to a better understanding of tailored therapies. In this study, two hypoxic induced BC transcriptomic cohorts (GSE27813 and GSE47533) were assessed from the GEO database. The P4HA1 gene was identified as a putative candidate and significantly regulated in hypoxic BC cells compared to normal BC cells at different time intervals (6 h, 9 h, 16 h, 32 h, and 48 h). In patients with Luminal (p < 1E-12), triple-negative subclasses (p = 1.35059E-10), Stage 1 (p = 8.8817E-16), lymph node N1 (p = 1.62436E-12), and in the 40–80 age group (p = 1.62447E-12), the expression of P4HA1 was closely associated with the clinical subtypes of BC. Furthermore, at the 10q22.1 chromosomal band, the P4HA1 gene displayed a high copy number elevation and was associated with a poor clinical regimen with overall survival, relapse-free survival, and distant metastases-free survival in BC patients. In addition, using BioGRID, the protein–protein interaction (PPI) network was built and the cellular metabolic processes, and hedgehog pathways are functionally enriched with GO and KEGG terms. This tentative result provides insight into the molecular function of the P4HA1 gene, which is likely to promote hypoxic-mediated carcinogenesis, which may favor early detection of BC and therapeutic stratification.

P4HA1 expression and function in esophageal squamous cell carcinoma

“…P4H hydroxylates proline residues to form 4-hydroxylproline, which is vital for the post-translational modification of collagen. [9][10][11] P4HA1 can regulate collagen synthesis and secretion in fibroblasts, thereby altering the extracellular matrix composition of cells, thus affecting tumor adhesion and migration. [12] In this study, the STRING database was used to analyze the PPI network of P4HA1.…”

The Role of P4HA1 in Multiple Cancer Types and its Potential as a Target in Renal Cell Carcinoma

“…In breast cancer, P4HA1 can regulate HIF-1α expression via regulating α-KG and succinate levels ( Xu, 2019 ), which promotes chemoresistance by regulating the HIF-1–dependent cancer cell stemness ( Xiong et al, 2018 ). Murugesan et al showed that P4HA1 may be used for the early detection and therapeutic stratification of breast cancer ( Murugesan and Premkumar, 2021 ). In OV, miR-122 can suppress cell migration, invasion, EMT, and metastasis by targeting P4HA1 ( Duan et al, 2018 ).…”

P4HA1 Acts as a Potential Target in Renal Cell Carcinoma and Pan-cancer

“…In relevant studies in human cancers, P4HA1 was regarded as an oncogene in several cancers. In breast cancer, P4HA1 can regulate HIF-1α expression via regulating αketoglutarate (α-KG) and succinate levels [23], so as to promote chemoresistance by regulating HIF- show that knockdown of P4HA1 can impaire the invasion of LN18 and T98G cells by regulating the expression pattern of EMT-related genes [11]. In LUAD, P4HA1 is required for cancer cell growth and invasion [10].…”