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.

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.

Figures

PAQR3-centered signaling network. Schematic summary of reported upstream regulators and downstream effectors of PAQR3 in cancer, with emphasis on the PAQR3/Ras/Raf/MEK/ERK axis discussed in the text. Upstream non-coding RNAs (circ_0043280; miR-15b, miR-543, miR-203a-3p) and protein/epigenetic regulators (HER2/ERBB2, DDB2; 5-Aza-2′-deoxycytidine (5-Aza-CdR), ATG7, p6-55) modulate PAQR3 expression/activity. Functionally, PAQR3 attenuates ERK signaling (including reduced ERK phosphorylation reported in multiple tumor models) and influences downstream modules such as NF-κB/p53 and cell-cycle regulators (p21/CDKN1A, p27/CDKN1B, cyclin D1), thereby restraining tumor cell proliferation, cell-cycle progression, migration and invasion, while promoting apoptosis. PAQR3 also intersects with additional pathways implicated in tumor biology, including PI3K/AKT, HIF-1α/p300, EMT, EGFR-linked autophagy, and ferroptosis (context-dependent). Blue blunt-ended lines indicate inhibition; orange arrows indicate activation/promotion. Abbreviations: PAQR3: Progestin and adipoQ receptor family member 3; circ_0043280: Circular RNA circ_0043280; miR: MicroRNA; HER2/ERBB2: Human epidermal growth factor receptor 2; DDB2: Damage-specific DNA binding protein 2; 5-Aza-CdR: 5-Aza-2′-deoxycytidine; ATG7: Autophagy related 7; EGFR: Epidermal growth factor receptor; ERK: Extracellular signal-regulated kinase; NF-κB: Nuclear factor kappa B; p53: Tumor protein p53; CDKN1A/p21: Cyclin-dependent kinase inhibitor 1A; CDKN1B/p27: Cyclin-dependent kinase inhibitor 1B; PI3K: Phosphatidylinositol 3-kinase; AKT: AKT serine/threonine kinase; HIF-1α: Hypoxia-inducible factor-1 alpha; EP300/p300: Histone acetyltransferase p300; EMT: Epithelial–mesenchymal transition.

Tables

Table 1. Expression of PAQR3 in cancer

Type	N	Tissues	Cells	Cancer cells	Normal cell	Ref
Osteosarcoma	60	Down	Down	SOSP-9607, SAOS-2, MG63, U2OS	hFOB	[7]
Thyroid cancer	60	Down	-	-	-	[8]
Glioma	11	Down	Down	U251, U87, LN-18	1800	[9]
Lung cancer	106	Down	-	-	-	[10]
Lung cancer	60	Down	-	-	-	[11]
Lung cancer	20	Down	Down	SK-MES-1, A549, SPCA-1, H1229	BEAS-2B	[12]
Hepatocellular carcinoma	60	Down	Down	HepG2, Hep3B, Bel7402, SMMC-7721	HL-7792	[13]
Hepatocellular carcinoma	194	Down	-	-	-	[14]
Cervical cancer	40	Down	-	-	-	[15]
CRC	54	Down	-	-	-	[16]
CRC	62	Down	-	-	-	[17]
DLBCL	46	Down	Down	SUDHL4, OCI-LY19, U2932, OCI-LY10	HMy2.CIR	[18]
ALL	43	Down	-	-	-	[19]
Breast cancer	60	Down	Down	MDA-MB-231, BT474, SKBR3, MCF7	MCF-10A	[20]
Breast cancer	82	Down	-	-	-	[21]
Breast cancer	46	Down	-	-	-	[22]
ESCA	40	Down	Down	KYSE150, ECA-109, TE-1	HEsEpiCs	[23]
ESCA	80	Down	-	-	-	[24]
ESCA	-	-	Down	EC9706, TE13, ECA109	HEEC	[25]
Gastric cancer	166	Down	Down	HGC27, SGC7901	GES-1	[26]
Gastric cancer	300	Down	-	-	-	[27]
RCC	31	Down	-	-	-	[28]

Table 2. The role of PAQR3 in cancer cell growth in vitro

Type	Cancer cells	Proliferation	Clone formation	Cycle	Apoptosis	Ref
Osteosarcoma	MG63	Inhibition	-	-	-	[7]
Glioma	U251, U87	Inhibition	-	-	-	[9]
Lung cancer	A549, H1299	Inhibition	Inhibition	Inhibition	Promotion	[11]
Lung cancer	A549, H1299	Inhibition	-	Inhibition	Promotion	[12]
Hepatocellular carcinoma	HepG2	Inhibition	-	-	-	[13]
Hepatocellular carcinoma	Hep-3B	Inhibition	Inhibition	-	-	[14]
Cervical cancer	MS751, HeLa	Inhibition	-	-	-	[15]
Colorectal cancer	SW-480	Inhibition	Inhibition	-	-	[17]
DLBCL	SUDHL4, U2932	Inhibition	-	-	-	[18]
ALL	CEM-C1, Jurkat	Inhibition	-	-	Promotion	[19]
Breast cancer	MCF7, SKBR3, MDA-MB-231, MDA-MB-468, MDA-MB-453	Inhibition	Inhibition	-	-	[21]
Breast cancer	MCF-7	-	Inhibition			[22]
ESCA	ECA-109, TE-1	Inhibition	Inhibition	Inhibition	-	[23]
ESCA	ECA-109	Inhibition				[25]
Gastric cancer	HGC27	Inhibition	Inhibition	-	-	[26]
Gastric cancer	AGS	Inhibition	Inhibition	-	-	[27]
RCC	HUVEC	Inhibition	-	-	-	[28]
Lung cancer	HCC827	Inhibition	Inhibition	-	-	[29]
Prostate cancer	PC3, DU145	Inhibition	Inhibition	-	-	[30]
Gastric cancer	BGC-823, SGC-7901	Inhibition	-	-	-	[31]
Gastric cancer	AGS	Inhibition	Inhibition	-	-	[32]
Colon Cancer	HCT116, HCT115	Inhibition	Inhibition	-	-	[36]

Table 3. The role of PAQR3 in cancer cell metastasis in vitro

Type	Cancer cells	Migration	Invasion	Wound healing	Tube formation	Ref
Osteosarcoma	MG63	Inhibition	Inhibition	-	-	[7]
Glioma	U251, U87	Inhibition	Inhibition	-	-	[9]
Hepatocellular carcinoma	HepG2	-	Inhibition	-	-	[13]
Cervical cancer	MS751, HeLa	Inhibition	Inhibition	Inhibition	-	[15]
Breast cancer	MDA-MB-231	Inhibition	Inhibition	-	-	[20]
Breast cancer	MCF7, SKBR3, MDA-MB-231, MDA-MB-468, MDA-MB-453	Inhibition	-	Inhibition	-	[21]
Breast cancer	MCF-7	-	Inhibition	-	-	[22]
ESCA	ECA-109, TE-1	-	Inhibition	-	-	[23]
ESCA	ECA-109	Inhibition	Inhibition	-	-	[25]
Gastric cancer	HGC27	Inhibition		Inhibition	-	[26]
Gastric cancer	AGS	Inhibition	-	Inhibition	-	[27]
RCC	HUVEC	Inhibition	-	Inhibition	Inhibition	[28]
Prostate cancer	PC3, DU145	Inhibition	-	Inhibition	-	[30]
Gastric cancer	BGC-823, SGC-7901	-	Inhibition	Inhibition	-	[31]
Gastric cancer	AGS	Inhibition	-	Inhibition	-	[32]
Gastric cancer	AGS	Inhibition	-	-	-	[33]
Colon Cancer	HCT116, HCT115	Inhibition	-	-	-	[36]

Table 4. The role of PAQR3 in the tumorigenic potential of cancer cells in nude mice in vivo

Type	Cancer cells	Roles	Ref
Glioma	U251	Inhibition	[9]
Cervical cancer	-	Inhibition	[15]
CRC	SW-480	Inhibition	[17]
DLBCL	U2932	Inhibition	[18]
ESCA	ECA109	Inhibition	[23]
ESCA	ECA109	Inhibition	[25]
Lung cancer	HCC827	Inhibition	[29]
Gastric cancer	AGS	Inhibition	[33]

Table 5. Molecular mechanisms involved in PAQR3 signaling

Type	Downstream pathways	Upstream pathways	Ref
Osteosarcoma	p-ERK	-	[7]
Glioma	PI3K/AKT	-	[9]
Lung cancer	Nf-kB/p53	-	[11]
Lung cancer	PI3K/AKT	-	[12]
Hepatocellular carcinoma	-	miR-543/PAQR3↓	[13]
Cervical cancer	EMT, p-AKT, p-ERK	circ_0043280/miR-203a-3p/PAQR3↑	[15]
CRC	EGF/p-ERK, EGF/β-catenin	-	[17]
DLBCL	LDLR/PI3K/AKT, ferroptosis	-	[18]
ALL	Nrf2/ferroptosis	-	[19]
Breast cancer	-	miR-15b/PAQR3↓	[20]
Breast cancer	-	HER2/PAQR3↓	[21]
Breast cancer	-	5-Aza-CdR/PAQR3↑	[22]
ESCA	P27/p21/CYCLD, p-ERK	5-Aza-CdR/PAQR3↑	[23]
ESCA	EMT, p-AKT	-	[24]
ESCA	EMT, p-ERK	-	[25]
Gastric cancer	TGF-β/Smad/EMT	-	[26]
Gastric cancer	p-AKT, p-ERK, EMT	-	[27]
RCC	VEGF/ERK, HIF-1α/p300	-	[28]
Lung cancer	BECN1/Autophagy, EGFR/Autophagy	ATG7/PAQR3↑	[29]
Prostate cancer	p-AKT, p-ERK, EMT	-	[30]
Gastric cancer	EMT	miR-15b-5p/PAQR3↓	[31]
Gastric cancer	EGF/ERK, AKT, insulin	DDB2/PAQR3↓	[32]
Gastric cancer	Twist1/EMT	-	[33]
Colon cancer	PI3K/AKT	P6-55/PAQR3↑	[36]

Table 6. Clinicopathological features related to PAQR3 in cancer

Type	PAQR3 expression	Prognosis	Clinical characteristics	Ref
Osteosarcoma	Down	-	Metastasis↑	[7]
Thyroid cancer	Down	-	Extrathyroidal-extension	[8]
Lung cancer	Down	OS↓	Pathological stages↑, tissue differentiation↓, metastasis↑	[10]
Lung cancer	Down	-	Tumor size↑, diagnosis	[11]
Hepatocellular carcinoma	Down	OS↓, DFS↓	AFP↑, tumor size↑, tumor grade↓, recurrence↑	[14]
CRC	Down	-	Tissue differentiation↓, lymph node metastasis↑, depth of invasion↑	[16]
CRC	Down	-	Gender, tumor grade↓	[17]
DLBCL	Down	OS↓	-	[18]
Breast cancer	Down	OS↓, DFS↓	Tissue differentiation↓, pathological stage↑, Her2 status	[21]
ESCA	Down	-	Pathological stage↑, lymph node metastasis↑	[23]
ESCA	Down	OS↓, DFS↓	Nationality, tumor size↑, lymph node metastasis↑, recurrence↑	[24]
Gastric cancer	Down	OS↓	Helicobacter pylori, venous invasion↑, invasion depth↑, lymph node metastasis↑, pathological stage↑	[26]
Gastric cancer	Down	DFS↓	Age, Helicobacter pylori, tumor size↑, tumor differentiation↓, venous invasion↑, lymph node metastasis↑, invasion depth↑, pathological stage↑, distant metastasis↑	[27]

Full text

Introduction

Numerous studies have demonstrated that abnormal gene expression is associated with cancer cell growth, metastasis, and poor prognosis in cancer patients [1–6]. Progestin and AdipoQ Receptor 3 (PAQR3) is a gene located on human chromosome 4 that encodes a membrane protein characterized by a unique seven-transmembrane domain architecture. This protein is predominantly localized in the Golgi apparatus and plays a critical role in intracellular signal transduction. It functions by anchoring Raf kinase to the Golgi membrane, thereby exerting a negative regulatory effect on the Ras/Raf/MEK/ERK signaling cascade. PAQR3 influences essential cellular processes, including proliferation and differentiation, highlighting its significance as a key regulator in maintaining normal cellular physiology through Rat sarcoma (Ras)/Rapidly Accelerated Fibrosarcoma (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling [6]. Recent research has confirmed that the downregulation of PAQR3 is linked to various aspects of cancer biology, such as cell proliferation, migration, and invasion across multiple cancer types [7–36]. Despite significant advancements in cancer treatment, the complexity of cancer cell biology, particularly the role of specific genes like PAQR3, continues to present challenges in developing more effective and targeted therapies. This review provides an update and expansion relative to existing synthesizations, including recent findings from 2023–2025 that were not addressed by Guo et al., and encompasses a broader range of literature than the meta-analysis conducted by Zhai et al. [34, 35]. The aim of this review is to summarize the roles, mechanisms, and clinical significance of PAQR3 in cancer, offering new insights and potential therapeutic targets for clinical practitioners and researchers.

Expression levels of PAQR3 significantly decrease in cancer

The expression levels of PAQR3 are significantly reduced in various cancer tissues and cell lines [7–27]. Specifically, compared to normal tissues, PAQR3 expression is notably lower in tissues from osteosarcoma, thyroid cancer, glioma, lung cancer, hepatocellular carcinoma, cervical cancer, colorectal cancer, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, breast cancer, esophageal cancer, gastric cancer, and renal cell carcinoma (Table 1). This decline in expression is also observed in osteosarcoma, glioma, lung cancer, hepatocellular carcinoma, diffuse large B-cell lymphoma, breast cancer, esophageal cancer, and gastric cancer cells (Table 1). The downregulation of PAQR3 in cancer cells may be attributed to epigenetic modifications. Specifically, DNA methylation of the PAQR3 promoter region has been implicated in certain cancer types, leading to reduced gene transcription and subsequently lower protein expression levels [10, 22]. Preliminary evidence suggests that PAQR3 may act as a tumor suppressor gene in cancer progression.

Overexpression of PAQR3 inhibits cancer cell growth and metastasis

Research has confirmed that inhibiting oncogene expression or promoting tumor suppressor gene expression can suppress cancer growth and metastasis [34–36]. PAQR3 is frequently downregulated in cancer tissues and cells, and its activation can inhibit cancer cell growth (Table 2). Specifically, PAQR3 can suppress the proliferation of osteosarcoma, glioma, lung cancer, hepatocellular carcinoma, cervical cancer, colorectal cancer, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, breast cancer, esophageal cancer, gastric cancer, renal cell carcinoma, colon cancer, and prostate cancer cells [7, 9, 11–15, 17–19, 21, 23, 25–32, 36]. Moreover, PAQR3 overexpression suppresses colony formation in lung cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, esophageal cancer, gastric cancer, colon cancer, and prostate cancer cells [11, 14, 17, 21–23, 26, 27, 29, 30, 32, 36]. Additionally, PAQR3 overexpression can inhibit cell cycle progression in lung cancer and esophageal cancer cells [11, 12, 23]. Furthermore, PAQR3 promotes apoptosis in lung cancer and acute lymphoblastic leukemia cells [11, 12, 19].

Activation of PAQR3 expression can also suppress cancer cell metastasis (Table 3). Specifically, results from Transwell and wound healing assays indicate that PAQR3 overexpression can inhibit the migration of osteosarcoma, glioma, cervical cancer, breast cancer, esophageal cancer, gastric cancer, renal cell carcinoma, colon cancer, and prostate cancer cells [7, 9, 15, 20–23, 25–33, 36]. Additionally, PAQR3 overexpression inhibits the invasion of osteosarcoma, glioma, hepatocellular carcinoma, cervical cancer, breast cancer, esophageal cancer, and gastric cancer cells [7, 9, 13, 15, 22, 23, 25, 31]. Notably, PAQR3 overexpression inhibits the tube formation ability in renal cell carcinoma cells [28]. Based on this information, it can be preliminarily concluded that PAQR3 functions as a tumor suppressor in vitro, and enhancing PAQR3 expression may delay cancer cell growth and metastasis.

Activation of PAQR3 expression in glioma, cervical cancer, colorectal cancer, diffuse large B-cell lymphoma, esophageal cancer, lung cancer, and gastric cancer cells, followed by the establishment of tumorigenic models in athymic nude mice, demonstrated that PAQR3 overexpression significantly inhibits tumor growth and proliferation in these models [9, 15, 17, 18, 23, 25, 29, 33]. This finding suggests that PAQR3 functions as a tumor suppressor in vivo (Table 4), and enhancing PAQR3 expression could represent a viable therapeutic strategy in clinical settings. However, further research is necessary to develop safe and effective methods to specifically upregulate PAQR3 expression in human cancer patients without causing significant side effects.

PAQR3 involves the signaling mechanisms

Upstream regulation of PAQR3 in cancer

PAQR3 may be inhibited by upstream circular RNA/microRNAs (miRNAs), thereby affecting the function of the target genes of PAQR3 [13, 15, 20, 31]. For instance, Yu et al. reported that miR-543 is overexpressed in hepatocellular carcinoma tissues, while PAQR3 is downregulated, establishing a negative correlation and a targeted regulatory relationship between the two. miR-543 can promote the proliferation and invasion of hepatocellular carcinoma cells by specifically targeting and suppressing PAQR3 expression [13]. Zhang et al. noted a significant decrease in circ_0043280 levels in cervical cancer; circ_0043280 can competitively bind to miR-203a-3p, thereby promoting PAQR3 expression and suppressing the growth and metastasis of cervical cancer [15]. Qi et al. demonstrated a targeted regulatory relationship between miR-15b and PAQR3, where miR-15b inhibits PAQR3 expression, promoting progression in breast and gastric cancers [20, 31]. Additionally, PAQR3 may be regulated by factors such as Human epidermal growth factor receptor 2 (HER2), 5-Aza-2′-deoxycytidine (5-Aza-CdR), Autophagy related 7 (ATG7), P6-55, and Damage-specific DNA binding protein 2 (DDB2) [19, 21–23, 29, 32, 36]. For example, Li et al. reported that PAQR3 can inhibit the proliferation, colony formation, and migration of breast cancer cells. Trastuzumab, which inhibits HER2 expression, can promote PAQR3 expression, thereby enhancing its inhibitory effects on breast cancer [21]. Chen et al. demonstrated that treatment with 5-Aza-CdR significantly stimulates PAQR3 expression in breast and esophageal cancer cells, thereby enhancing PAQR3’s efficacy against cancer cells [22, 23].

Downstream effects of PAQR3 in cancer

The PAQR3/Ras/Raf/MEK/ERK signaling axis

ERK, a member of the Mitogen-Activated Protein Kinase (MAPK) family, plays a pivotal role in the signaling network governing cell growth, development, and division [37]. PAQR3 has been shown to inhibit the growth and metastasis of various cancers, including osteosarcoma, cervical cancer, esophageal cancer, gastric cancer, renal cell carcinoma, colorectal cancer, and prostate cancer, by suppressing ERK signaling [7, 15, 17, 23, 25, 27, 28, 30, 32], as illustrated in Table 5 and Figure 1. For example, Ma et al. demonstrated that overexpression of PAQR3 suppresses the phosphorylation of ERK (p-ERK), thereby inhibiting the proliferation and invasion of osteosarcoma cells. Notably, the MEK inhibitor U0126 completely negates the effects of PAQR3 silencing on osteosarcoma cell proliferation and invasion [7]. Bai et al. reported that PAQR3 overexpression reduces p-ERK protein levels in esophageal cancer cells and enhances the expression of downstream ERK proteins, such as Cyclin-dependent kinase inhibitor 1B (CDKN1B) and Cyclin-dependent kinase inhibitor 1A (CDKN1A), while inhibiting cyclin D1, Cyclin-dependent kinase 4 (CDK4), and Cyclin-dependent kinase 2 (CDK2), thus suppressing esophageal cancer growth [23, 25]. Additionally, PAQR3 overexpression can inhibit downstream signaling of Nuclear Factor Kappa B (NF-κB) and Protein 53 (p53) via ERK, consequently delaying the growth of lung cancer cells [11].

PAQR3-centered signaling network. Schematic summary of reported upstream regulators and downstream effectors of PAQR3 in cancer, with emphasis on the PAQR3/Ras/Raf/MEK/ERK axis discussed in the text. Upstream non-coding RNAs (circ_0043280; miR-15b, miR-543, miR-203a-3p) and protein/epigenetic regulators (HER2/ERBB2, DDB2; 5-Aza-2′-deoxycytidine (5-Aza-CdR), ATG7, p6-55) modulate PAQR3 expression/activity. Functionally, PAQR3 attenuates ERK signaling (including reduced ERK phosphorylation reported in multiple tumor models) and influences downstream modules such as NF-κB/p53 and cell-cycle regulators (p21/CDKN1A, p27/CDKN1B, cyclin D1), thereby restraining tumor cell proliferation, cell-cycle progression, migration and invasion, while promoting apoptosis. PAQR3 also intersects with additional pathways implicated in tumor biology, including PI3K/AKT, HIF-1α/p300, EMT, EGFR-linked autophagy, and ferroptosis (context-dependent). Blue blunt-ended lines indicate inhibition; orange arrows indicate activation/promotion. Abbreviations: PAQR3: Progestin and adipoQ receptor family member 3; circ_0043280: Circular RNA circ_0043280; miR: MicroRNA; HER2/ERBB2: Human epidermal growth factor receptor 2; DDB2: Damage-specific DNA binding protein 2; 5-Aza-CdR: 5-Aza-2′-deoxycytidine; ATG7: Autophagy related 7; EGFR: Epidermal growth factor receptor; ERK: Extracellular signal-regulated kinase; NF-κB: Nuclear factor kappa B; p53: Tumor protein p53; CDKN1A/p21: Cyclin-dependent kinase inhibitor 1A; CDKN1B/p27: Cyclin-dependent kinase inhibitor 1B; PI3K: Phosphatidylinositol 3-kinase; AKT: AKT serine/threonine kinase; HIF-1α: Hypoxia-inducible factor-1 alpha; EP300/p300: Histone acetyltransferase p300; EMT: Epithelial–mesenchymal transition.

The PAQR3/phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling axis

The PI3K/AKT pathway is a well-established signaling cascade that promotes cell survival and insulin secretion [38, 39]. Research has elucidated a significant relationship between PAQR3 and the PI3K/AKT signaling pathway [9, 12, 15, 18, 24, 27, 30, 36]. For instance, Li et al. found that PAQR3 overexpression inhibits PI3K/AKT signaling by reducing PI3K phosphorylation (p-PI3K) and AKT phosphorylation (p-AKT) without significantly affecting the overall protein levels of PI3K and AKT, thus inhibiting the growth of lung cancer cells A549 and H1299 [12]. In diffuse large B-cell lymphoma U2932 cells, PAQR3 may impede cell progression through the Low-Density Lipoprotein Receptor (LDLR)/PI3K/AKT signaling pathway by modulating the expression levels of LDLR, p-AKT, and p-PI3K [19]. Moreover, studies indicate that PAQR3 expression is associated with insulin signaling mechanisms [32]. PAQR3 inhibits insulin-stimulated phosphorylation of p-AKT and Glycogen Synthase Kinase 3 Beta (GSK3β), thereby influencing the growth and metastasis of gastric cancer [32].

The PAQR3/Epithelial-mesenchymal transition (EMT) signaling axis

The EMT process is critically linked to cancer metastasis [40]. PAQR3 contributes to the metastasis of cervical cancer, esophageal cancer, gastric cancer, and prostate cancer through the EMT process [15, 24, 25, 27, 30, 31, 33]. For instance, Huang et al. reported that PAQR3 overexpression suppresses vimentin expression during EMT while promoting E-cadherin and Zonula Occludens-1 (ZO-1) expression, thereby inhibiting migration of prostate cancer cells PC3 and DU145 [30]. Bai et al. noted that PAQR3 overexpression enhances E-cadherin expression while inhibiting N-cadherin expression, consequently reducing migration of esophageal cancer cells [24, 25]. Wu et al. demonstrated that PAQR3 inhibits the expression levels of snail, vimentin, Transforming Growth Factor Beta 1 (TGF-β1), Phosphorylated SMAD Family Member 2 (p-SMAD2), and Phosphorylated SMAD Family Member 3 (p-SMAD3) within the TGF-β/SMAD/EMT signaling pathway, thereby promoting E-cadherin expression and inhibiting gastric cancer progression [26].

Other downstream signaling mechanisms

Dysregulation of PAQR3 may also impact ferroptosis through interactions with nuclear factor erythroid 2-related factor 2 (Nrf2), Epidermal Growth Factor (EGF)/β-catenin signaling, and autophagy, thereby influencing cancer progression [17–19, 26, 28, 29, 36]. For example, Wang et al. reported that PAQR3 inhibits nuclear accumulation of β-catenin in colorectal cancer SW-480 cells, thus delaying tumorigenic potential [17]. Additionally, it may promote ferroptosis in diffuse large B-cell lymphoma and acute lymphoblastic leukemia [18, 19]. Specifically, Song et al. observed that PAQR3 overexpression suppresses glutathione (GSH) levels in diffuse large B-cell lymphoma cells while promoting Malondialdehyde (MDA), Reactive Oxygen Species (ROS), and Fe2+ levels [18]. Jin and Tong found that PAQR3 overexpression enhances MDA, Dichlorofluorescein (DCF), and Fe2+ levels in acute lymphoblastic leukemia cells [19]. Furthermore, PAQR3 can inhibit the Hypoxia-Inducible Factor 1a (HIF-1α)/E1A Binding Protein p300 (p300), Beclin 1 (BECN1)/autophagy, and Epidermal Growth Factor Receptor (EGFR)/autophagy pathways to suppress progression in lung cancer and renal cell carcinoma [28, 29].

Decreased PAQR3 expression as a biomarker for poor prognosis in cancer patients

Table 6 presents indicators related to the prognosis and pathological features associated with PAQR3 overexpression in cancer patients. Notably, overexpression is linked to favorable characteristics concerning metastasis, pathological stage, tumor size, and diagnosis [7, 8, 10, 11, 14, 16–18, 21, 23, 24, 26, 27]. Specifically, decreased PAQR3 expression levels correlate significantly with shorter overall survival (OS) in patients with lung cancer, hepatocellular carcinoma, diffuse large B-cell lymphoma, breast cancer, esophageal cancer, and gastric cancer [10, 14, 18, 21, 24, 26]. Furthermore, reduced PAQR3 levels are associated with shorter disease-free survival (DFS) in patients with hepatocellular carcinoma, breast cancer, esophageal cancer, and gastric cancer [14, 21, 24, 27]. Additionally, diminished PAQR3 expression correlates significantly with pathological staging, subtype, tissue differentiation, metastasis, tumor size, and diagnosis in lung cancer patients [10, 11]. It is also linked to factors such as Helicobacter pylori, venous invasion, invasion depth, lymph node metastasis, pathological stage, age, tumor size, tumor differentiation, and distant metastasis in gastric cancer patients [26, 27]. The relationship between PAQR3 expression and patient prognosis may be confounded by other factors, including co-existing genetic mutations, the patient’s immune status, and concurrent medication use. Future studies should consider these variables to accurately assess the prognostic value of PAQR3.

Conclusion

Research has established that PAQR3 functions as a tumor suppressor gene in cancer, and activation of PAQR3 expression may enhance patient prognosis. This is linked to various signaling mechanisms, including PI3K/AKT, EMT, ferroptosis, and Ras/Raf/MEK/ERK pathways, and is regulated by miR-543, miR-203a-3p, miR-15b, HER2, and 5-Aza-CdR, thereby influencing cancer cell growth and metastasis (Table 5). The anti-tumor mechanisms of PAQR3 exhibit significant heterogeneity. In certain cancer types, such as diffuse large B-cell lymphoma, PAQR3 enhances ferroptosis through the PI3K/AKT pathway [18]. In contrast, in other cancers, such as gastric cancer, it may operate via different pathways. These differences may be attributed to cancer-specific expression patterns, tissue-specific microenvironments, mutation backgrounds, and upstream regulatory factors. Furthermore, while epigenetic drugs like 5-Aza-CdR can demethylate and activate PAQR3 expression, their clinical application faces challenges, including strong toxicity and the development of drug resistance, underscoring the urgent need for more precise epigenetic intervention strategies.

Despite the progress, studies on PAQR3 remain in preliminary stages. Future research should focus on the upstream and downstream mechanisms of PAQR3 to deepen the understanding of its pathogenesis and ultimately impede disease progression. Additionally, anti-cancer treatments targeting PAQR3 encounter various challenges. First, the heterogeneity of the underlying mechanisms necessitates the design of specific treatment strategies tailored to different cancer types, alongside precise regulation of the PAQR3 pathway in conjunction with tumor molecular typing and microenvironment characteristics. Second, the development of drugs targeting PAQR3 must address critical issues, including low delivery efficiency and poor stability. Moreover, the PAQR3 pathway interacts with multiple signaling networks, raising concerns about potential off-target effects from targeted therapies. Enhancing treatment safety through highly selective delivery systems (e.g., nanocarriers or conditionally activated gene editing tools) is essential. Ultimately, the combined targeting of upstream regulatory factors (e.g., HER2 inhibitors) or downstream effector pathways (e.g., ferroptosis inducers) may represent a crucial approach to improve efficacy and overcome drug resistance. Future research could utilize patient-derived organoids to more accurately replicate the in vivo tumor microenvironment and investigate the roles of PAQR3. Overall, this review summarizes the mechanisms and clinical significance of PAQR3, providing a novel theoretical foundation and direction for cancer treatment.