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Project description:The reversible and dynamic O-GlcNAcylation regulates vast networks of highly coordinated cellular and nuclear processes. Despite the dysregulation of the sole enzyme O-GlcNAc transferase (OGT), is showed to associated with the progression of hepatocellular carcinoma (HCC), the mechanisms by which OGT controls the cis-regulatory elements in the genome and achieves transcriptional functions remain unclear. Here, we demonstrate that the elevated OGT increases HCC proliferation and metastasis by orchestrating the transcription of numerous malignant regulators in vitro and in vivo. Diverse transcriptional regulators are recruited by OGT in HCC cells with progressive malignancy, which shapes the genome-wide OGT chromatin cis-elements occupation. Further, an unrecognized cooperation between ZNF263 and OGT is crucial for activating downstream transcriptomics. We reveal that the O-GlcNAcylation site Ser662 is responsible for ZNF263 chromatin association at candidate gene promoters and OGT facilitated HCC the malignant phenotypes. Our data establish the importance of aberrant OGT and ZNF263 O-GlcNAcylation in HCC malignant progression, and represents the pursuit of OGT as a target for HCC therapy.
2023-01-09 | GSE222281 | GEO
Project description:The reversible and dynamic O-GlcNAcylation regulates vast networks of highly coordinated cellular and nuclear processes. Despite the dysregulation of the sole enzyme O-GlcNAc transferase (OGT), is showed to associated with the progression of hepatocellular carcinoma (HCC), the mechanisms by which OGT controls the cis-regulatory elements in the genome and achieves transcriptional functions remain unclear. Here, we demonstrate that the elevated OGT increases HCC proliferation and metastasis by orchestrating the transcription of numerous malignant regulators in vitro and in vivo. Diverse transcriptional regulators are recruited by OGT in HCC cells with progressive malignancy, which shapes the genome-wide OGT chromatin cis-elements occupation. Further, an unrecognized cooperation between ZNF263 and OGT is crucial for activating downstream transcriptomics. We reveal that the O-GlcNAcylation site Ser662 is responsible for ZNF263 chromatin association at candidate gene promoters and OGT facilitated HCC the malignant phenotypes. Our data establish the importance of aberrant OGT and ZNF263 O-GlcNAcylation in HCC malignant progression, and represents the pursuit of OGT as a target for HCC therapy.
2023-01-09 | GSE222280 | GEO
Project description:OGT, the only facilitator which attaches the monosaccharide to many oncogenic factors or tumor suppressors, has been suggested to play an influential role in tumorigenesis and metastasis of HCC. OGT interactome analyses indicates that disordered OGT may serve as a hub protein to activate the building of aberrant transcriptional regulatory complexes, supporting that this unique enzyme is an essential regulator in tumor progression. However, the function and related mechanisms by which OGT triggers HCC malignancy are still largely unknown
2023-01-12 | PXD039365 | iProX
Project description:BackgroundThe extravasation capability of hepatocellular carcinoma (HCC) cells plays a vital role in distant metastasis. However, the underlying mechanism of extravasation in HCC lung metastasis remains largely unclear.MethodsThe expression of ARHGEF37 in human HCC specimens and HCC cell lines was examined by quantitative RT-PCR, western blot, and immunohistochemistry (IHC) analyses. The biological roles and mechanisms of ARHGEF37/Cdc42 in promoting lung metastasis were investigated in vitro and in vivo using cell lines, patient samples, xenograft models.ResultsIn the current study, we found that Rho guanine nucleotide exchange factor 37 (ARHGEF37) was upregulated in human HCC samples and was associated with tumor invasiveness, pulmonary metastasis and poor prognosis. Overexpressing ARHGEF37 significantly enhanced the extravasation and metastatic capability of HCC cells via facilitating tumor cell adhesion to endothelial cells and trans-endothelial migration. Mechanistically, ARHGEF37 directly interacted with and activated Cdc42 to promote the invadopodia formation in HCC cells, which consequently disrupted the interaction between endothelial cells and pericytes. Importantly, treatment with ZCL278, a specific inhibitor of Cdc42, dramatically inhibited the attachment of ARHGEF37-overexpressing HCC cells to endothelial cells, and the adherence and extravasation in the lung alveoli, resulting in suppression of lung metastasis in mice.ConclusionOur findings provide a new insight into the underlying mechanisms on the ARHGEF37 overexpression-mediated extravasation and pulmonary metastasis of HCC cells, and provided a potential therapeutic target for the prevention and treatment of HCC pulmonary metastasis.
| S-EPMC9308268 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is a common digestive tumor with high fatality worldwide. Previous studies have shown that Reticulocalbin-2 (RCN2) was a crucial factor for HCC proliferation, but invasion and migration mechanism of RCN2 contributing to HCC is poorly investigated. In this study, we estimated the RCN2 expression in both patient tissues and cell lines by polymerase chain reaction (PCR) and western blotting (WB), as well as the clinical information of HCC patients from public databases. Biological function induced by RCN2 in vitro and vivo was also researched through multiple functional experiments. Upstream and downstream signal of RCN2 was identified by bioinformatics. We found that up-regulated RCN2 was related to poorer prognosis in HCC patients and attached significance to HCC proliferation, invasion and migration. Luciferase reporter assay and chromatin immunoprecipitation validated that YY1 as the upstream transcription factor of RCN2, facilitating the expression of RCN2. Gene set enrichment analysis indicated that HCC progression induced by RCN2 might be related to MYC signaling. Furthermore, we demonstrated RCN2 reduced proteasomal degradation of MYC and lead to HCC progression. The effects of overexpressed RCN2 in HCC were attenuated by MYC silencing. In conclusion, our study highlighted the vital role of RCN2 in tumor progression and the potential benefit for the treatment of HCC.
| S-EPMC8167676 | biostudies-literature
Project description:The increasing incidence of hepatocellular carcinoma (HCC) is of great concern globally, but the molecular pathogenesis of these tumors remains unclear. Sorafenib is a first-line drug for the treatment of advanced HCC. However, the efficacy of sorafenib in improving patient survival is limited, and most patients inevitably develop resistance to this drug. Recent studies have demonstrated that the activation of the IRE1α-XBP1s pathway might play a protective role in the response to sorafenib and contribute to malignancy in HCC. Here, we found that RCN1, an endoplasmic reticulum resident protein, is significantly upregulated in sorafenib-resistant HCC cells and promotes tumor progression. Our analysis showed that RCN1 may be an independent predictor of tumor recurrence and overall survival. Mechanistically, RCN1 promotes the dissociation of GRP78 from IRE1α in sorafenib-resistant cells by interacting with GRP78 through its EFh1/2 domain. Subsequently, the IRE1α-XBP1s pathway, a branch of the unfolded protein response, is sustainably activated. Interestingly, IRE1α-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in HCC. These results suggest that RCN1-targeted therapy might be a feasible strategy for the treatment of HCC.
| S-EPMC8523720 | biostudies-literature
Project description:We previously identified the important role of RIN1 expression in the prognosis of clear cell renal cell carcinoma (ccRCC). The role of RIN1 in ccRCC malignancy and underlying molecular mechanisms remain unclear. Here we report that ccRCC cells and tissues expressed more RIN1 than normal controls. Gain-of-function and loss-of-function studies demonstrated that RIN1 enhanced ccRCC cell growth, migration and invasion abilities in vitro and promoted tumor growth and metastasis in vivo. Mechanistic studies revealed that RIN1 has an activating effect on EGFR signaling in ccRCC. In addition, we unveil Rab25, a critical GTPase in ccRCC malignancy, as a functional RIN1 interacting partner. Knockdown of Rab25 eliminated the augmentation of carcinoma cell proliferation, migration and invasion by ectopic RIN1. We also confirmed that RIN1 and Rab25 expression correlates with the overall-survival of ccRCC patients from TCGA. These findings suggest that RIN1 plays an important oncogenic role in ccRCC malignancy by activation of EGFR signaling through interacting with Rab25, and RIN1 could be employed as an effective therapeutic target for ccRCC.
| S-EPMC5543468 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor outcomes. The main causes of HCC-related deaths are recurrence and metastasis. Long noncoding RNAs (lncRNAs) are recently identified as critical regulators in cancers. However, the lncRNAs involved in HCC recurrence and metastasis are poorly understood. In this study, via analyzing The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset, we identified a novel lncRNA LINC01134, which is highly expressed in HCC tissues and correlated with microvascular invasion, macrovascular invasion, recurrence, and poor overall survival of HCC patients. Functional experiments revealed that ectopic expression of LINC01134 promotes HCC cell migration and invasion in vitro and HCC liver metastasis and lung metastasis in vivo. Knockdown of LINC01134 represses HCC cell migration and invasion in vitro and HCC liver metastasis and lung metastasis in vivo. Mechanistically, we found that LINC01134 directly binds the promoter of AKT1S1 and activates AKT1S1 expression. Via activating AKT1S1, LINC01134 further activates NF-?B signaling. The expression of LINC01134 is significantly positively correlated with that of AKT1S1 in HCC tissues. In line with LINC01134, AKT1S1 is also highly expressed in HCC tissues and correlated with poor survival of HCC patients. Functional rescue experiments showed that repressing AKT1S1 or NF-?B signaling abrogates the roles of LINC01134 in HCC. Taken together, these findings recognized LINC01134 as a novel oncogenic lncRNA, which indicates vascular invasion, recurrence, and poor overall survival of HCC patients. LINC01134 promotes HCC metastasis via activating AKT1S1 expression and subsequently activating NF-?B signaling. This study suggested LINC01134 as a potential prognostic biomarker and therapeutic target for HCC.
| S-EPMC7325970 | biostudies-literature
Project description:Protein arginine methyltransferases (PRMT) catalyze protein arginine methylation and play an important role in many biological processes. Aberrant PRMT expression in tumor cells has been documented in several common cancer types; however, its precise contribution to hepatocellular carcinoma (HCC) cell invasion and metastasis is not fully understood. In this study, we identified a new oncogene, PRMT9, whose overexpression strongly promotes HCC invasion and metastasis. PRMT9 expression was detected more frequently in HCC tissues than in adjacent noncancerous tissues. PRMT9 overexpression was significantly correlated with hepatitis B virus antigen (HBsAg) status, vascular invasion, poor tumor differentiation and advanced TNM stage. Patients with higher PRMT9 expression had a shorter survival time and higher recurrence rate. PRMT9 expression was an independent and significant risk factor for survival after curative resection. Functional studies demonstrated that PRMT9 increased HCC cell invasion and lung metastasis. Knocking down PRMT9 with short hairpin RNA (shRNA) inhibited HCC cell invasion. Further investigations found that PRMT9 increased cell migration and invasion through epithelial-mesenchymal transition (EMT) by regulating Snail expression via activation of the PI3K/Akt/GSK-3?/Snail signaling pathway. In clinical HCC samples, PRMT9 expression was positively associated with Snail expression and was negatively associated with E-cadherin expression. In conclusion, our study demonstrated that PRMT9 is an oncogene that plays an important role in HCC invasion and metastasis through EMT by regulating Snail expression via activation of the PI3K/Akt/GSK-3?/Snail signaling pathway. Thus, PRMT9 may serve as a candidate prognostic biomarker and a potential therapeutic target.
| S-EPMC5980302 | biostudies-literature
Project description:Liver cancer was reported to be the sixth most frequently diagnosed cancer, and hepatocellular carcinoma (HCC) accounts for 75%-85% of primary liver cancer. Nevertheless, the concrete molecular mechanisms of HCC progression remain obscure, which is essential to elucidate. The expression profile of RAD54B in HCC was measured using qPCR and western blotting. Moreover, the levels of RAD54B in paraffin-embedded samples were evaluated using immunohistochemistry (IHC). The effect of RAD54B on HCC progression was testified by in vitro experiments, and in vivo orthotopic xenograft tumor experiments. The mechanisms of RAD54B promoting HCC progression were investigated through molecular and function experiments. Herein, RAD54B are dramatically upregulated in HCC tissues and cell lines both on mRNA and protein levels, and RAD54B can servers as an independent prognostic parameter of 5-year overall survival and 5-year disease-free survival for patients with HCC. Moreover, up-regulation of RAD54B dramatically increases the capacity for in vitro cell viability and motility, and in vivo intrahepatic metastasis of HCC cells. Mechanistically, RAD54B promotes the HCC progression through modulating the wnt/β-catenin signaling. Notably, blocking the wnt/β-catenin signaling axis can counteract the activating effects of RAD54B on motility of HCC cells. Besides, further analysis illustrates that DNA amplification is one of the mechanisms leading to mRNA overexpression of RAD54B in HCC. Our findings indicate that RAD54B might be a promising potential prognostic marker and a candidate therapeutic target to therapy HCC.
| S-EPMC8167290 | biostudies-literature