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

He, Shan; Lin, Juan; Yu, Shao-Ping; Sun, Shenghua

doi:10.3892/ol.2016.4164

Cited by 18 publications

(19 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PREX2 has been reported to be upregulated in HCC and to play roles in the regulation of HCC cell proliferation and in CXCL9‐induced HCC migration and invasion . In agreement with these reports, we demonstrated that PREX2 accumulation resulting from either GNMT or HectH9 depletion led to AKT activation and enhanced proliferation.…”

Section: Discussionsupporting

confidence: 91%

See 1 more Smart Citation

Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma

Yen

Chen

et al. 2017

Int. J. Cancer

View full text Add to dashboard Cite

The pathogenesis of hepatocellular carcinoma (HCC) involves many molecular pathways. Glycine N-methyltransferase (GNMT) is downregulated in almost all HCC and its gene knockout mice developed HCC with high penetrance. We identified PREX2, a novel PTEN inhibitor, as a GNMT-interacting protein. Such interaction enhanced degradation of PREX2 through an E3 ligase HectH9-mediated proteasomal ubiquitination pathway. Depletion of GNMT or HectH9 resulted in AKT activation in a PREX2 dependent manner and enhanced cell proliferation. An elevated PREX2 protein expression accompanied by activation of AKT was observed in the liver of Gnmt knockout mice. PREX2 protein expression was upregulated in 54.9% of human HCC samples, while its mRNA level was comparable in tumor and tumor-adjacent tissue, suggesting a post-translational alteration of PREX2 expression. Higher level of PREX2 in the tumor tissues was associated with poorer survival. These results reveal a novel mechanism in which GNMT participates in AKT signaling and HCC tumorigenesis by promoting HectH9-mediated PREX2 degradation.

show abstract

Section: Discussionsupporting

confidence: 91%

“…The dissimilarity between the finding in our study and previous reports could be attributed to the sample size used in different studies (139 pairs in our study vs . 45 pairs in Lan's report and 15 pairs in He's report) . In addition, viral infection could also contribute to these discrepancies.…”

Section: Discussionmentioning

confidence: 87%

Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma

Yen

Chen

et al. 2017

Int. J. Cancer

View full text Add to dashboard Cite

show abstract

“…The sequences of P-Rex2a and P-Rex2b are homologous with those of P-Rex1. 31 , 32 Despite various studies pointing out the oncogenicity of guanine nucleotide exchange factors (GEFs) in multiple cancer types, especially melanoma, breast cancer, glioblastoma, and prostate cancer, the present work unveiled a specific new function of P-Rex1 in the pathogenesis of liver cancer. P-Rex1 knockdown attenuated liver cancer cell proliferation, migration, and xenograft tumor growth by mediating the activation of the HGF signaling pathway.…”

Section: Discussionmentioning

confidence: 76%

<p>Identification of P-Rex1 in the Regulation of Liver Cancer Cell Proliferation and Migration via HGF/c-Met/Akt Pathway</p>

Qiu¹,

Chang²,

Liu³

et al. 2020

OTT

View full text Add to dashboard Cite

Background: Rho-GTPases and their activators, guanine nucleotide exchange factors (GEFs), are increasingly being recognized as essential mediators of oncogenic signaling. Although it is known that P-Rex1, a member of the Dbl family of GEFs for the Rac small GTPase, contributes to the migration of cancer cells, its exact role in liver cancer and the underlying mechanisms remain unclear. Materials and Methods: Public datasets from the Gene Expression Omnibus database (GEO) and clinical liver cancer samples were analyzed to explore the expression of P-Rex1. P-Rex1 knockdown and overexpression cell lines were established using a recombinant lentiviral transfection system. BrdU and colony formation assays were performed to determine cell viability. Migratory capacity was analyzed using a transwell migration assay and an in vitro wound-healing assay. Nude mice bearing subcutaneous xenograft tumors were established to determine the effects of P-Rex1 on tumorigenesis in vivo. The role of P-Rex1 in hepatocarcinogenesis was determined through Western blot and coimmunoprecipitation. Results: Induced expression of endogenous P-Rex1 was identified in liver cancer tumors when compared with adjacent nonmalignant tissues from clinical data. In response to HGF treatment, P-Rex1-knockdown cells displayed reduced proliferation and migration in vitro as well as reduced xenograft tumor growth in vivo. Overexpression of P-Rex1 promoted liver cancer cell proliferation and migration. P-Rex1 primarily acts as a downstream effector of GPCR signaling. This study demonstrated that downregulation of P-Rex1 led to a significant decrease in the phosphorylation of Akt and Erk1/2 by reducing the phosphorylation of the tyrosine kinase receptor c-Met. Furthermore, a physical association between P-Rex1 and c-Met was observed after HGF treatment, suggesting that P-Rex1 may be involved in the HGF/c-Met signaling pathway. Conclusion: These results support the role of P-Rex1 as a novel player in liver cancer, which suggest that targeting P-Rex1 may provide a potential strategy for liver cancer treatment.

show abstract

“…These results implied that increased expression of these mutated genes might cause the loss of function on tumor suppression, and contribute to the development of HCC. Other identified genes, including CTNNB1, PREX2, and TERT, facilitate the survival or invasion of HCC cells. In the study, we found that these three genes were upregulated in HCC.…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of highly mutated genes in hepatitis B virus‐related hepatic carcinoma

Kong

Yang

et al. 2020

Cancer Medicine

View full text Add to dashboard Cite

Gene mutation is responsible for the development of hepatocellular carcinoma (HCC) with hepatitis B virus (HBV) infection; however, the characteristics and associated biological functions of highly mutated genes, in which the mutation frequencies are at least 5% in HCC patients with HBV infection, are not clearly evaluated. In the study, we analyzed the information regarding somatic mutation obtained by whole‐exome sequencing in 280 HBV‐related HCC tissues from public databases and published studies. Via integrative analysis, 78 genes, including TP53, TTN, MUC16, CTNNB1, and PCLO were summarized as highly mutated genes, and some of these mutated genes were further identified as cancer driver genes. Besides, we discovered that the highly mutated genes were enriched with various biological functions and pathways. The expression of many of highly mutated genes was found to be significantly altered in HBV‐related HCC, and several highly mutated genes were related to a variety of clinical factors and associated with the poor survival of the disease. Taken together, these results could enrich our understanding of highly mutated genes and their relationships with HBV‐related HCC. Some of the identified highly mutated genes might be used as novel biomarkers of disease prognosis, or as molecular targets for the treatment of HCC with HBV infection.

show abstract

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

Cited by 18 publications

References 23 publications

Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma

Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma

<p>Identification of P-Rex1 in the Regulation of Liver Cancer Cell Proliferation and Migration via HGF/c-Met/Akt Pathway</p>

Integrative analysis of highly mutated genes in hepatitis B virus‐related hepatic carcinoma

Contact Info

Product

Resources

About