The role of PAQR3 in cancer progression – Molecular regulation, signaling pathways, and clinical implications: A review

Progesterone and adiponectin receptor 3 (PAQR3) is a Golgi-localized seven-transmembrane protein that anchors rapidly accelerated fibrosarcoma kinase (Raf) and suppresses rat sarcoma/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Ras/Raf/MEK/ERK) signaling, thereby influencing cellular proliferation, differentiation, and metastasis. This review aims to summarize the expression patterns, regulatory mechanisms, key downstream pathways, and clinical significance of PAQR3 in cancer. We synthesized findings from published clinical and experimental studies, including in vitro assays and nude mouse xenograft models, that evaluate PAQR3 expression, function, and signaling interactions across various tumor types. Overall, PAQR3 is frequently downregulated in many cancers, potentially due to promoter methylation, and low expression levels are associated with adverse clinicopathologic features and reduced survival. Functionally, PAQR3 overexpression inhibits proliferation, colony formation, migration, invasion, and tumor growth, primarily through the inhibition of extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways and modulation of epithelial-mesenchymal transition (EMT). Additionally, PAQR3 is linked to nuclear factor kappa B/tumor protein p53 (NF-κB/p53), epidermal growth factor/beta-catenin (EGF/β-catenin) signaling, autophagy, and nuclear factor erythroid 2-related factor 2/ferroptosis (Nrf2/ferroptosis). These effects are modulated by upstream regulators, including microRNA-543 (miR-543), circular RNA 0043280/microRNA-203a-3p (circ_0043280/miR-203a-3p), microRNA-15b (miR-15b), human epidermal growth factor receptor 2 (HER2), 5-aza-2'-deoxycytidine (5-Aza-CdR), autophagy-related 7 (ATG7), and damage-specific DNA binding protein 2 (DDB2). In conclusion, PAQR3 functions as a tumor suppressor and holds potential as a prognostic biomarker. Targeting PAQR3-related pathways may provide new therapeutic opportunities.