RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma

Zhang, Yixuan; Jiang, Xianyang; Xiao, Qiong; Ye, D.; Yi, Zhengfang; Liu, M.; Bai, Ou; Liu, W.; Xie, Xu; Wang, Zhenzhen; Fang, Jie; Yan, Chen

doi:10.1038/onc.2010.270

Cited by 72 publications

(64 citation statements)

References 39 publications

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“…RKTG has been reported to be closely associated with the progression of different types of malignant cancer cells (14,19). However, the role of RKTG in the proliferation and apoptosis of leukemia cells remains to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…RKTG is a spatial regulator of Raf-1 (11) and acts as an anticancer factor due to its inhibitory activity on Raf/MEK/ERK signaling (12,14,20). RKTG expression in the colorectal cancer samples was significantly reduced compared with adjacent normal tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant upregulation of the Raf/MEK/ERK and PI3K/AKT pathways is frequently observed in leukemia patients, and these changes are closely associated with poor prognosis (24)(25)(26)(27). The inhibitory activity of RKTG on Raf/MEK/ERK signaling has been reported in several tumor cell lines (11,12,14,15,20). Additionally, the activation of the PI3K/AKT signaling pathway induced by Gβlγ2 overexpression in monkey kidney fibroblast cells COS7 has been previously reported to be markedly abrogated by RKTG co-overexpression (28).…”

Section: Discussionmentioning

confidence: 99%

“…Studies have demonstrated that RKTG can act as a tumor suppressor in human malignant melanoma cells (12), renal cell carcinoma (14), colorectal cancer (15), laryngeal squamous cell carcinoma (16) and osteosarcoma (17). Deletion of RKTG markedly increased the incidence of chemical carcinogen-induced tumorigenesis in the mouse skin (14). However, to the best of our knowledge, whether RKTG is implicated in the progress of leukemia remains to be investigated.…”

Section: Introductionmentioning

confidence: 94%

“…The Ras/Raf/MEK/ERK signaling pathway is responsible for the extracellular signal transduction into the nucleus, therefore it has a pivotal role in regulation of fundamental cellular functions, including cell proliferation, apoptosis, metabolism and differentiation (13). Studies have demonstrated that RKTG can act as a tumor suppressor in human malignant melanoma cells (12), renal cell carcinoma (14), colorectal cancer (15), laryngeal squamous cell carcinoma (16) and osteosarcoma (17). Deletion of RKTG markedly increased the incidence of chemical carcinogen-induced tumorigenesis in the mouse skin (14).…”

Section: Introductionmentioning

confidence: 99%

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RKTG overexpression inhibits proliferation and induces apoptosis of human leukemia cells via suppression of the ERK and PI3K/AKT signaling pathways

Deng

Wang

et al. 2017

Oncology Letters

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Abstract. Raf kinase trapping to Golgi (RKTG) is reported to be a tumor suppressor in a number of solid tumors due to its negative modulation of the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathways. However, the role of RKTG in the progression of leukemia remains unknown. In the present study, a human leukemia U937 cell line overexpressing RKTG was established, and the effect of RKTG on proliferation, cell cycle and apoptosis of human leukemia cells was analyzed. The results of the present study demonstrated that exogenous overexpression of RKTG significantly inhibited cell proliferation, which was accompanied by cell cycle arrest. Apoptosis assay and Hoechst staining demonstrated that the percentage of apoptotic cells in RKTG overexpressing cells was markedly increased. Furthermore, western blotting showed that RKTG overexpression significantly increased the level of cleaved caspase 3, B-cell lymphoma 2 (Bcl2)-associated X apoptosis regulator and reduced the level of Bcl-2. In addition, the activation of ERK and phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase 1 signaling pathways in human leukemia cells was also suppressed by RKTG overexpression. In conclusion, the present study demonstrated the tumor-suppressive effect of RKTG on human leukemia cells, which seem to be partially dependent on the suppression of ERK and PI3K/AKT signaling. Overexpression of RKTG may be a potential therapeutic target for the treatment of leukemia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

RKTG overexpression inhibits proliferation and induces apoptosis of human leukemia cells via suppression of the ERK and PI3K/AKT signaling pathways

Deng

Wang

et al. 2017

Oncology Letters

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Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1

Zhao

Wang

et al. 2018

Hepatology

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Peroxisome proliferator‐activated receptor α (PPARα) is a key transcriptional factor that regulates hepatic lipid catabolism by stimulating fatty acid oxidation and ketogenesis in an adaptive response to nutrient starvation. However, how PPARα is regulated by posttranslational modification is poorly understood. In this study, we identified that progestin and adipoQ receptor 3 (PAQR3) promotes PPARα ubiquitination through the E3 ubiquitin ligase HUWE1, thereby negatively modulating PPARα functions both in vitro and in vivo. Adenovirus‐mediated Paqr3 knockdown and liver‐specific deletion of the Paqr3 gene reduced hepatic triglyceride levels while increasing fatty acid oxidation and ketogenesis upon fasting. PAQR3 deficiency enhanced the fasting‐induced expression of PPARα target genes, including those involved in fatty acid oxidation and fibroblast growth factor 21, a key molecule that mediates the metabolism‐modulating effects of PPARα. PAQR3 directly interacted with PPARα and increased the polyubiquitination and proteasome‐mediated degradation of PPARα. Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARα polyubiquitination. Additionally, PAQR3 enhanced the interaction between HUWE1 and PPARα. Conclusion: Ubiquitination modification through the coordinated action of PAQR3 with HUWE1 plays a crucial role in regulating the activity of PPARα in response to starvation. (Hepatology 2018;68:289‐303).

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Golgi scaffold protein PAQR3 as a candidate suppressor of gastric cardia adenocarcinoma via regulating TGF‐β/Smad pathway

Ling

et al. 2022

Clinical Laboratory Analysis

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Objectives To investigate the function of PAQR3 in gastric cardia adenocarcinoma (GCA) and understand the possible mechanism of PAQR3 in regulating epithelial–mesenchymal transition (EMT). Methods We detected PAQR3 protein in 146 GCA tissues and paired normal adjacent tissues (PNTs) specimens using immunohistochemical analysis, and explored its clinical significance. The expression levels of PAQR3 protein in 20 GCA tissues, their paired PNTs, HGC27, SGC7901, and GES‐1 cells were analyzed by Western blot. Wild‐type PAQR3 was overexpressed in HGC27 cells. The effects of PAQR3 overexpression on the function of HGC27 cells and its underlying mechanisms were then analyzed through a series of cell and molecular biology experiments. Results PAQR3 was significantly down‐regulated in GCA tissues when compared with paired PNTs ( p < 0.0001). The expression level of PAQR3 in GCA tissues was significantly negatively correlated with Helicobacter pylori infection ( p = 0.000), venous invasion ( p = 0.000), invasion depth ( p = 0.000), lymph node metastasis ( p = 0.022), tumor stage ( p = 0.000), and patient survival ( p = 0.009). Downregulation of PAQR3 was highly correlated with increased EMT signature and activated TGF‐β/Smad pathway in GCA tissues. Overexpression of PAQR3 in HGC27 cells negatively regulates its cellular functions, such as cell proliferation and migration, and suppresses EMT. Mechanistically, overexpression of PAQR3 significantly down‐regulates the protein expression levels of TGF‐1, p‐Smad2, and p‐Smad3 in HGC27 cells. Conclusion PAQR3 was significantly down‐regulated in GCA tissues, HGC27, and SGC7901 cells. PAQR3 significantly inhibits the proliferation, migration, and invasion of HGC27 cells. Mechanistically, PAQR3 can inhibit the EMT process in HGC27 cells by regulating TGF‐β/Smad signaling pathway.

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RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma

Cited by 72 publications

References 39 publications

RKTG overexpression inhibits proliferation and induces apoptosis of human leukemia cells via suppression of the ERK and PI3K/AKT signaling pathways

RKTG overexpression inhibits proliferation and induces apoptosis of human leukemia cells via suppression of the ERK and PI3K/AKT signaling pathways

Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1

Golgi scaffold protein PAQR3 as a candidate suppressor of gastric cardia adenocarcinoma via regulating TGF‐β/Smad pathway

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