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

## TL;DR

PAQR3 is a tumor suppressor protein that inhibits cancer growth by regulating key signaling pathways and could serve as a potential biomarker for cancer prognosis.

## Contribution

This review systematically summarizes PAQR3's molecular regulation, signaling interactions, and clinical relevance in cancer progression.

## Key findings

- PAQR3 is frequently downregulated in cancers, possibly due to promoter methylation, and low expression correlates with poor survival.
- PAQR3 inhibits tumor growth by suppressing ERK and PI3K/AKT pathways and modulating EMT.
- PAQR3 interacts with multiple upstream regulators and signaling pathways, including NF-κB/p53 and EGF/β-catenin.

## Abstract

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.