Molecular Pathways: P-Rex in Cancer

Pandiella, Atanasio; Montero, Juan Carlos

doi:10.1158/1078-0432.ccr-12-1662

Cited by 24 publications

(33 citation statements)

References 40 publications

(83 reference statements)

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“…Furthermore, ectopic expression of mutant PREX2, which was present in patients with melanomas, accelerated the tumor formation of immortalized human melanocytes in vivo (15). In addition, overexpression of PREX2 has been revealed to be associated with the poor overall survival of patients with breast cancer (22). The present study identified that the expression of PREX2 was upregulated in HCC tissues and cell lines compared with adjacent normal tissues and normal liver cell lines.…”

Section: Discussionsupporting

confidence: 50%

Upregulation of PREX2 promotes the proliferation and migration of hepatocellular carcinoma cells via PTEN-AKT signaling

Lin²,

et al. 2016

Oncology Letters

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Abstract. Phosphatidylinositol-3,4,5-trisphosphate Rac exchanger 2 (PREX2), a regulator of the small guanosine triphosphatase Rac, demonstrates an inhibitory effect on the activity of phosphatase and tensin homolog (PTEN). Previously, PREX2 was implicated in the regulation of cell invasion in hepatocellular carcinoma (HCC). However, the exact role of PREX2 in the regulation of HCC cell proliferation and migration, as well as the underlying mechanisms, remains unclear. In the present study, reverse transcription-quantitative polymerase chain reaction revealed that PREX2 was upregulated in HCC tissue compared with matched adjacent non-tumorous tissue. In addition, the present study demonstrated that the messenger RNA and protein levels of PREX2 increased in human HCC HepG2, LH86, LMH and PLHC-1 cell lines compared with normal human liver THLE-3 cells. Overexpression of PREX2 significantly enhanced the proliferation and migration of HCC cells, and knockdown of PREX2 expression significantly suppressed the proliferation and migration of HCC cells. Additional investigation revealed that overexpression of PREX2 suppressed the activity of PTEN, leading to an enhancement in the activity of protein kinase B (AKT). By contrast, knockdown of PREX2 expression upregulated the activity of PTEN and suppressed the activity of AKT. Overall, the present study suggests that PREX2 promotes the proliferation and migration of HCC cells by inhibiting PTEN-AKT signaling.

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Section: Discussionsupporting

confidence: 50%

Upregulation of PREX2 promotes the proliferation and migration of hepatocellular carcinoma cells via PTEN-AKT signaling

Lin²,

et al. 2016

Oncology Letters

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“…Recently, the overexpression of P-Rex proteins has been linked to poor patient outcome in breast cancer, since it may facilitate metastatic dissemination of prostate cancer cells (16). Whole-genome sequencing identified PREX2 as a significantly mutated gene in melanoma, suggesting that PREX2 may also be involved in the development and progression of melanoma (18).…”

Section: Discussionmentioning

confidence: 99%

“…However, PTEN is frequently mutated or its activity is downregulated in human cancer (13,14). Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger factor 2 (PREX2) is a regulator of the small guanosine triphosphatase Rac, and has recently been reported to act as an inhibitor of PTEN (15,16). PREX2 is able to inhibit the activity of PTEN by directly binding to PTEN through its guanine nucleotide exchange factor domains.…”

Section: Introductionmentioning

confidence: 99%

“…PREX2 is able to inhibit the activity of PTEN by directly binding to PTEN through its guanine nucleotide exchange factor domains. Through inhibition of PTEN activity, PREX2 is capable of activating the downstream PI3K signaling pathway (15,16). Indeed, it has been reported that knockdown of PREX2 inhibits the invasion and clonogenicity of gastric cancer cells via inhibition of PI3K signaling (17).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, silencing of PREX2 could also induce cell cycle arrest at the G1-S phase and promote apoptosis in gastric cancer cells (17). Since the dysregulation of the PI3K signaling pathway has been demonstrated to be involved in multiple types of human cancer, PREX2 may generally act as an oncogene in tumorigenesis (16).…”

Section: Introductionmentioning

confidence: 99%

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PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway

et al. 2016

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Abstract. Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger factor 2 (PREX2) is a novel regulator of the small guanosine triphosphatase Rac, and has been observed to be implicated in human cancer by inhibiting the activity of phosphatase and tensin homolog (PTEN), thus upregulating the activity of the phosphoinositide 3-kinase (PI3K) signaling pathway. However, the exact role of PREX2 in pancreatic cancer has not been reported to date. In the present study, the expression levels of PREX2 were observed to be frequently increased in pancreatic cancer specimens compared with those in their matched adjacent normal tissues. In addition, PREX2 expression was also frequently upregulated in several pancreatic cancer cell lines, including AsPC-1, BxPC-3, PANC-1 and CFAPC-1, compared with that in the normal pancreatic epithelial cell line HPC-Y5. Overexpression of PREX2 significantly promoted the proliferation, invasion and migration of pancreatic cancer PANC-1 cells, while small interfering RNA-induced knockdown of PREX2 expression significantly inhibited the proliferation, invasion and migration of these cells. Investigation of the molecular mechanism revealed that the overexpression of PREX2 upregulated the phosphorylation levels of PTEN, indicating that the activity of PTEN was reduced, which further increased the phosphorylation levels of AKT, which indicated that the activity of the PI3K signaling pathway was upregulated. By contrast, knockdown of PREX2 upregulated the activity of PTEN and inhibited the activity of the PI3K signaling pathway. In conclusion, the present study demonstrated that PREX2 regulates the proliferation, invasion and migration of pancreatic cancer cells, probably at least via modulation of the activity of PTEN and the PI3K signaling pathway.

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Genetic mutations in smoking‐associated prostate cancer

et al. 2023

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ObjectivesTobacco smoking is known to cause cancers potentially predisposed by genetic risks. We compared the frequency of gene mutations using a next generation sequencing database of smokers and nonsmokers with prostate cancer (PCa) to identify subsets of patients with potential genetic risks.Materials and MethodsData from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE) registry was analyzed. The GENIE registry contains clinically annotated sequenced tumor samples. We included 1832 men with PCa in our cohort, categorized as smokers and nonsmokers, and compared the frequency of mutations (point mutations, copy number variations, and structural variants) of 47 genes with more than 5% mutation rate between the two categories and correlated with overall survival using logistic regression analysis.ResultsOverall, 1007 (55%) patients were nonsmokers, and 825 (45%) were smokers. The mutation frequency was significantly higher in smokers compared to nonsmokers, 47.6% and 41.3%, respectively (p = 0.02). The median tumor mutational burden was also significantly higher in the samples from smokers (3.59 mut/MB) compared to nonsmokers (1.87 mut/MB) (p < 0.001). Patients with a smoking history had a significantly higher frequency of PREX2, PTEN, AGO2, KMT2C, and a lower frequency of adenomatous polyposis coli (APC) and KMT2A mutations than compared to nonsmokers. The overall mortality rate (28.5% vs. 22.8%) was significantly higher among smokers (p = 0.006). On a multivariate logistic regression analysis, the presence of metastatic disease at the time of diagnosis (OR: 2.26, 95% CI: 1.78−2.89, p < 0.001), smoking history (OR: 1.32, 95% CI: 1.05−1.65, p = 0.02), and higher frequency of PTEN somatic gene mutation (OR: 1.89, 95% CI: 1.46−2.45, p < 0.001) were independent predictors of increased overall mortality among patients with PCa. Patients with PTEN mutation had poorer overall survival compared to men without PTEN mutations: 96.00 (95% CI: 65.36−113.98) and 120.00 (95% CI: 115.05−160.00) months, respectively (p < 0.001) irrespective of smoking history although the G129R PTEN mutation was characteristically detected in smokers.ConclusionsPCa patients with a tobacco smoking history demonstrated a significantly higher frequency of somatic genetic mutations. Whereas mutations of PREX2, KMT2C, AGO2, and PTEN genes were higher in smokers, the APC and KMT2A mutations were higher in nonsmokers. The PTEN somatic gene mutation was associated with increased overall mortality among patients with PCa irrespective of smoking history. We found that G129R PTEN mutation known to reduce the PTEN phosphatase activity and K267Rfs*9 a frameshift deletion mutation in the C2 domain of PTEN associated with membrane binding exclusively detected in smokers and nonsmokers, respectively. These findings may be used to further our understanding of PCa associated with smoking.

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Molecular Pathways: P-Rex in Cancer

Cited by 24 publications

References 40 publications

Upregulation of PREX2 promotes the proliferation and migration of hepatocellular carcinoma cells via PTEN-AKT signaling

Upregulation of PREX2 promotes the proliferation and migration of hepatocellular carcinoma cells via PTEN-AKT signaling

PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway

Genetic mutations in smoking‐associated prostate cancer

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