Loss of ARHGDIA expression is associated with poor prognosis in HCC and promotes invasion and metastasis of HCC cells

Liang, Lei; Li, Qian; Huang, Li; Li, Da Wei; Wang, Yu Wei; Li, Xin Xiang; Cai, San Jun

doi:10.3892/ijo.2014.2451

Cited by 21 publications

(11 citation statements)

References 29 publications

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“…These findings are in line with the previous report that EZH2 regulates actin polymerization in prostate cancer [34]. Loss of RhoGDIγ expression is associated with poor prognosis and promotes metastasis and invasion in hepatocellular carcinoma [35]. Our results indicate that EZH2 is a key arbiter mediating cell motility through RhoGDIγ.…”

Section: Discussionsupporting

confidence: 93%

Verification of EZH2 as a druggable target in metastatic uveal melanoma

et al. 2020

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Background: Hepatic metastasis develops in~50% of uveal melanoma (UM) patients with no effective treatments. Although GNAQ/GNA11 mutations are believed to confer pathogenesis of UM, the underlying mechanism of liver metastasis remains poorly understood. Given that profound epigenetic evolution may occur in the long journey of circulating tumor cells (CTCs) to distant organs, we hypothesized that EZH2 endowed tumor cells with enhanced malignant features (e.g., stemness and motility) during hepatic metastasis in UM. We aimed to test this hypothesis and explore whether EZH2 was a therapeutic target for hepatic metastatic UM patients. Methods: Expression of EZH2 in UM was detected by qRT-PCR, Western blotting and immunohistochemistry staining. Proliferation, apoptosis, cancer stem-like cells (CSCs) properties, migration and invasion were evaluated under circumstances of treatment with either EZH2 shRNA or EZH2 inhibitor GSK126. Antitumor activity and frequency of CSCs were determined by xenografted and PDX models with NOD/SCID mice. Hepatic metastasis was evaluated with NOG mice. Results: We found that EZH2 overexpressed in UM promoted the growth of UM; EZH2 increased the percentage and self-renewal of CSCs by miR-29c-DVL2-β-catenin signaling; EZH2 facilitates migration and invasion of UM cells via RhoGDIγ-Rac1 axis. Targeting EZH2 either by genetics or small molecule inhibitor GSK126 decreased CSCs and motility and abrogated the liver metastasis of UM. Conclusions: These findings validate EZH2 as a druggable target in metastatic UM patients, and may shed light on the understanding and interfering the complicated metastatic process.

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Section: Discussionsupporting

confidence: 93%

Verification of EZH2 as a druggable target in metastatic uveal melanoma

et al. 2020

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“…In addition to the NF-kappa-B pathway, the JNK pathway is also a specific pathway in tumor initiation and progression, including PC [ 47 , 48 ]. A specific regulator of Rho protein exchange reactions which is crucial for JNK pathway, ARHGDIA (see row 2 of Table 1 , with betweenness 94 and permutation FDR 0.012), was also identified using our method and functions in several types of tumors [ 49 , 50 ]. In addition, this apoptosis inhibitory protein has been confirmed to control Rho protein homeostasis and participate in the initiation and progression of PC through the apoptosis associated GDP/GTP exchange reaction via RhoA-Rho pathway [ 51 ].…”

Section: Resultsmentioning

confidence: 99%

Mining for Candidate Genes Related to Pancreatic Cancer Using Protein-Protein Interactions and a Shortest Path Approach

Yuan

Zhang

Wan

et al. 2015

BioMed Research International

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Pancreatic cancer (PC) is a highly malignant tumor derived from pancreas tissue and is one of the leading causes of death from cancer. Its molecular mechanism has been partially revealed by validating its oncogenes and tumor suppressor genes; however, the available data remain insufficient for medical workers to design effective treatments. Large-scale identification of PC-related genes can promote studies on PC. In this study, we propose a computational method for mining new candidate PC-related genes. A large network was constructed using protein-protein interaction information, and a shortest path approach was applied to mine new candidate genes based on validated PC-related genes. In addition, a permutation test was adopted to further select key candidate genes. Finally, for all discovered candidate genes, the likelihood that the genes are novel PC-related genes is discussed based on their currently known functions.

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“…Despite having no binding to DNA directly, HBx can deregulate cellular gene expression by interacting with transcription regulators in the nucleus [2–4, 22]. Previous reports showed that full-length HBx can transcriptionally suppress a subset of important tumor-related genes through enhancing the promoters binding to transcription suppressors like E2F1, SMAD4, YY1 and MAZ [23–25].…”

Section: Discussionmentioning

confidence: 99%

Carboxyl-terminal truncated HBx contributes to invasion and metastasis via deregulating metastasis suppressors in hepatocellular carcinoma

Liao

et al. 2016

Oncotarget

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Hepatitis B virus (HBV) X protein (HBx), a trans-regulator, is frequently expressed in truncated form without carboxyl-terminus in hepatocellular carcinoma (HCC), but its functional mechanisms are not fully defined. In this report, we investigated frequency of this natural HBx mutant in HCCs and its functional significance. In 102 HBV-infected patients with HCC, C-terminal truncation of HBx, in contrast to full-length HBx, were more prevalent in tumors (70.6%) rather than adjacent non-tumorous tissues (29.4%) (p = 0.0032). Furthermore, two naturally-occurring HBx variants (HBxΔ31), which have 31 amino acids (aa) deleted (codons 123-125/124-126) at C-terminus were identified in tumors and found that the presence of HBxΔ31 significantly correlated with intrahepatic metastasis. We also show that over-expression of HBxΔ31 enhanced hepatoma cell invasion in vitro and metastasis in vivo compared to full-length HBx. Interestingly, HBxΔ31 exerts this function via down-regulating Maspin, RhoGDIα and CAPZB, a set of putative metastasis-suppressors in HCC, in part, by enhancing the binding of transcriptional repressor, myc-associated zinc finger protein (MAZ) to the promoters through physical association with MAZ. Notably, these HBxΔ31-repressed proteins were also significantly lower expression in a subset of HCC tissues with C-terminal HBx truncation than the adjacent non-tumorous tissues, highlighting the clinical significance of this novel HBxΔ31-driven metastatic molecular cascade. Our data suggest that C-terminal truncation of HBx, particularly breakpoints at 124aa, plays a role in enhancing hepatoma cell invasion and metastasis by deregulating a set of metastasis-suppressors partially through MAZ, thus uncovering a novel mechanism for the progression of HBV-associated hepatocarcinogenesis.

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Loss of ARHGDIA expression is associated with poor prognosis in HCC and promotes invasion and metastasis of HCC cells

Cited by 21 publications

References 29 publications

Verification of EZH2 as a druggable target in metastatic uveal melanoma

Verification of EZH2 as a druggable target in metastatic uveal melanoma

Mining for Candidate Genes Related to Pancreatic Cancer Using Protein-Protein Interactions and a Shortest Path Approach

Carboxyl-terminal truncated HBx contributes to invasion and metastasis via deregulating metastasis suppressors in hepatocellular carcinoma

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