PAQR3

Official Full Name

progestin and adipoQ receptor family member 3

Organism

Homo sapiens

GeneID

152559

Background

This gene encodes a seven-transmembrane protein localized in the Golgi apparatus in mammalian cells. The encoded protein belongs to the progestin and adipoQ receptor (PAQR) family. This protein functions as a tumor suppressor by inhibiting the Raf/MEK/ERK signaling cascade. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

Synonyms

RKTG;

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Detailed Information

Recent research Progress

PAQR3, also known as RKTG, is a seven-transmembrane protein that is used to capture Rag kinase into the Golgi. It is a type III membrane protein specifically localized in the Golgi apparatus in mammalian cells. PAQR3 has been found to be a negative regulator of Raf-1 by sequestering Raf-1 in the Golgi apparatus and then blocking the Ras-Raf-MEK-ERK signaling pathway. PAQR3 has a negative role in regulating angiogenesis in endothelial cells. PAQR3 interacts with p53 function in cancer formation and epithelial-mesenchymal transition (EMT). PAQR3 also inhibits AKT activation by two mechanisms, by inhibiting the signaling of the G protein βγ subunit and by spatially regulating the p110a subunit to inhibit PI3K. PAQR3 has been reported to exhibit anticancer activity in a variety of malignancies.

PAQR3 and breast cancer

Recent studies have found that PAQR3 expression is down-regulated in breast cancer tissues, and that down-regulation of PAQR3 expression is significantly associated with aberrant methylation of gene promoters. Methylation-specific PCR showed that hypermethylation of the PAQR3 gene was observed in 71.8% of breast cancers, whereas only 28.2% was found in the corresponding non-tumor tissues. Furthermore, the methylation status of the PAQR3 promoter is associated with lymph node metastasis. In addition, overexpression of PAQR3 inhibits invasion and growth of breast cancer cells. In addition, PAQR3 expression was restored in MCF-7 cells after treatment with the demethylating agent 5-aza-2'-deoxycytidine, and demethylation induced invasion and proliferation inhibition of MCF-7 cells. Overall, the results suggested that aberrant methylation of PAQR3 is the basis for down-regulation in breast cancer, and that epigenetic silencing of PAQR3 gene expression by promoter hypermethylation may play an important role in breast cancer.

PAQR3 and glioma

Glioma is the most common primary malignant brain tumor in the central nervous system. In human glioma tissues and cell lines, the expression of PAQR3 was significantly reduced. Overexpression of PAQR3 inhibits proliferation of glioma cells in vitro and attenuates tumor xenograft growth in vivo. Furthermore, PAQR3 overexpression inhibits migration and invasion of glioma cells and prevents the EMT process. Mechanistic studies showed that PAQR3 overexpression significantly down-regulated the levels of phosphorylated PI3K and Akt in U251 cells. Taken together, these results indicate that PAQR3 inhibits proliferation, migration and invasion of glioma cells, at least in part, through inactivation of the PI3K/Akt signaling pathway. Therefore, PAQR3 may be a therapeutic target for the treatment of glioma.

PAQR3 and prostate cancer

Recently, the study found that PAQR3 can inhibit the growth and migration of human prostate cancer cells in vitro and in vivo. Overexpression of PAQR3 inhibited proliferation of PC3 and DU145 cells by MTT and colony formation assays. Consistently, knocking down PAQR3 would enhance the proliferation of these cells. In wound healing and transwell analysis, overexpression of PAQR3 reduced migration of PC3 and DU145 cells, while inhibition of PAQR3 increased migration. In the tumor xenograft model, overexpression of PAQR3 inhibited tumor growth in PC3 cells in vivo, while inhibition of PAQR3 promoted tumor growth. PAQR3 is also capable of inhibiting serum-induced AKT and ERK phosphorylation in PC3 and DU145 cells. In addition, PAQR3 inhibits the expression of epithelial-mesenchymal transition (EMT) markers in PC3 cells. Taken together, these data indicate that PAQR3 has tumor suppressor activity in human prostate cancer cells and may be a potential therapeutic target for prostate cancer.

PAQR3 and gastric cancer

PAQR3 actively participates in the degradation of Twist1 and thereby regulates the metastasis of EMT and gastric cancer cells. Overexpression of PAQR3 reduced the protein level but not the mRNA level of Twist1. PAQR3 altered the protein stability and polyubiquitination of Twist1. PAQR3 forms a complex with Twist1 and BTRC, an E3 ubiquitin ligase. PAQR3 enhances the interaction between Twist1 and BTRC. When PAQR3 and BTRC are overexpressed, Twist1 mobilizes from the nucleus to the proteasome structure in the cytoplasm, which is required for PAQR3 to induce Twist1 degradation. The Twist1 cassette domain of the Twist1 protein is required for the interaction of Twist1 with PAQR3 and BTRC, which is essential for PAQR3-mediated degradation of Twist1. The inhibitory effect of PAQR3 on gastric cancer cell migration and EMT phenotype requires BTRC and Twist1. Importantly, Twist1 is essential for the inhibition of PAQR3 on gastric cancer cell metastasis in vivo. Taken together, these findings not only indicate that Twist1 mediates the regulation of PAQR3 on EMT and metastasis, but also suggest that targeting Twist1 is a promising strategy to control tumor metastasis by down-regulating PAQR3.

In addition, PAQR3 was underexpressed in colorectal cancer samples, and the expression level of PAQR3 was negatively correlated with tumor grade. The expression level of PAQR3 was significantly down-regulated in clinical clear cell renal cell carcinoma samples, and negatively correlated with the expression level of VEGF. In addition, some data strongly suggest that down-regulation of PAQR3 promotes tumor metastasis and proliferation by inducing ERK phosphorylation in osteosarcoma. In summary, current research indicates that PAQR3 plays an important role in the pathogenesis and development of various cancers.

References:

Huang Wenqiang, et al. PAQR3 suppresses the proliferation, migration and tumorigenicity of human prostate cancer cells. Oncotarget, 2017, 8(33): 53948-53958
Thamara Hewavitharana, et al. PAQR3 regulates Golgi vesicle fission and transport via the Gβγ–PKD signaling pathway. Cellular Signalling, 2015, 27: 2444-2451
Chen Jinpeng, et al. The role of PAQR3 gene promoter hypermethylation in breast cancer and prognosis. Oncology Reports, 2016, 36: 1612-1618
Guo Weiwei, et al. PAQR3 enhances Twist1 degradation to suppress epithelial–mesenchymal transition and metastasis of gastric cancer cells. Carcinogenesis, 2016, 37(4): 397-407
Li Riheng, et al. PAQR3 gene expression and its methylation level in colorectal cancer tissues. Oncology Letters, 2016, 12:1773-1778

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