Nogo-B receptor promotes the chemoresistance of human hepatocellular carcinoma via the ubiquitination of p53 protein.
Ontology highlight
ABSTRACT:
SUBMITTER: Dong C
PROVIDER: S-EPMC4891009 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Nogo-B receptor (NgBR) is a type I receptor with a single transmembrane domain and specifically binds to ligand Nogo-B. A previous study demonstrated that NgBR was highly expressed in human breast invasive ductal carcinoma and promoted epithelial-mesenchymal transition in breast tumor cells. Our recent work found that NgBR expression was associated with a poor prognosis in human patients with hepatocellular carcinoma (HCC). Here, we elucidate that the increased expression of NgBR contributes toward the increased cell growth of human HCC cells both in vitro and in vivo. Cell viability and clonogenic survival analysis results demonstrated that knockdown of NgBR inhibits the cell growth in human HCC cells, which correlates with a reduction in the phosphorylation of Akt levels. Furthermore, overexpression of NgBR by the cotransfected pIRES-NgBR plasmid together with NgBR siRNA in human HCC cells can rescue impaired phosphorylation of Akt levels in NgBR knockdown human HCC cells. In addition, cell viability analyses showed that NgBR overexpression can rescue the cell growth inhibition presented in human HCC NgBR knockdown cells. Taken together, our results suggest that NgBR potentially acts as an oncogene in HCC by increasing Akt activity. Thus, NgBR may represent a new potential diagnostic and therapeutic target for the treatment of HCC.
| S-EPMC7328129 | biostudies-literature
Project description:Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies, and the incidence of RCC continues to rise worldwide. Although RCC can be treated with surgery at an early stages, the five-year survival rates have been observed to decline dramatically in patients with advanced disease. Most patients with RCC treated with cytotoxic or targeted drugs will develop resistance at some point during therapy. Thus, it is necessary to identify novel therapeutic targets for RCC. Here, we found that RANBP2-type and C3HC4-type zinc finger-containing 1 (RBCK1) expression was upregulated in human RCC samples. Analysis of multiple public databases revealed the correlation between RBCK1 expression and poor prognosis in RCC patients. Subsequently, we performed RBCK1 depletion experiments in RCC cells that severely affected the in vivo and in vitro proliferation of renal cancer cells. The effects of RBCK1 on cell proliferation could be rescued with p53 expression knockdown in two cell lines expressing wild-type p53. Further experiments demonstrated that RBCK1 could facilitate p53 poly-ubiquitination and degradation by direct interaction with p53. Together, our results show that RBCK1 may serve as a promising target for RCC therapy by restoring p53 functions.
| S-EPMC6420644 | biostudies-literature
Project description:The development of antitumor chemotherapy drugs remains a key goal for oncologists, and natural products provide a vast resource for anti-cancer drug discovery. In the current study, we found that the flavonoid dihydromyricetin (DHM) exhibited antitumor activity against liver cancer cells, including primary cells obtained from hepatocellular carcinoma (HCC) patients. In contrast, DHM was not cytotoxic to immortalized normal liver cells. Furthermore, DHM treatment resulted in the growth inhibition and remission of xenotransplanted tumors in nude mice. Our results further demonstrated that this antitumor activity was caused by the activation of the p53-dependent apoptosis pathway via p53 phosphorylation at serine (15Ser). Moreover, our results showed that DHM plays a dual role in the induction of cell death when administered in combination with cisplatin, a common clinical drug that kills primary hepatoma cells but not normal liver cells.
| S-EPMC3982169 | biostudies-literature
Project description:Coordinated translation initiation is coupled with cell cycle progression and cell growth, whereas excessive ribosome biogenesis and translation initiation often lead to tumor transformation and survival. Hepatocellular carcinoma (HCC) is among the most common and aggressive cancers worldwide and generally displays inherently high resistance to chemotherapeutic drugs. We found that RACK1, the receptor for activated C-kinase 1, was highly expressed in normal liver and frequently upregulated in HCC. Aberrant expression of RACK1 contributed to in vitro chemoresistance as well as in vivo tumor growth of HCC. These effects depended on ribosome localization of RACK1. Ribosomal RACK1 coupled with PKC?II to promote the phosphorylation of eukaryotic initiation factor 4E (eIF4E), which led to preferential translation of the potent factors involved in growth and survival. Inhibition of PKC?II or depletion of eIF4E abolished RACK1-mediated chemotherapy resistance of HCC in vitro. Our results imply that RACK1 may function as an internal factor involved in the growth and survival of HCC and suggest that targeting RACK1 may be an efficacious strategy for HCC treatment.
| S-EPMC3386807 | biostudies-other
Project description:Ubiquitination displays a crucial role in various biological functions, such as protein degradation, signal transduction, and cellular homeostasis. Accumulating evidence has indicated that ubiquitination is essential in cancer progression. Ubiquitin-conjugating enzyme E2S (UBE2S) is a member of ubiquitin-conjugating enzyme family of the ubiquitin system and its role in hepatocellular cancer (HCC) is largely unknown. We investigated the role of UBE2S in HCC and found UBE2S upregulation is relevant with large tumor size, recurrence, and advanced TNM stage, serving as an independent risk factor of overall survival (OS) and disease-free survival (DFS) for HCC patients. We conducted in vitro experiments and found that in HCC cells, UBE2S overexpression increases the resistance to 5-FU and oxaliplatin, while UBE2S knockdown achieves an opposite effect. UBE2S is transcriptionally activated by the binding of FOXM1 to UBE2S promoter, which induces its upregulation and reduces PTEN protein level by promoting PTEN ubiquitination at Lys60 and Lys327 and facilitating AKT phosphorylation. The promotional effect of FOXM1-UBE2S axis on HCC cell chemoresistance is attenuated by allosteric AKT inhibitor, MK2206. In conclusion, our results reveal that UBE2S is a prognostic biomarker for HCC patients, and the FOXM1-UBE2S-PTEN-p-AKT signaling axis might be a promising target for the treatment of HCC.
| S-EPMC8595659 | biostudies-literature
Project description:Tumor angiogenesis is one of the hallmarks of cancer as well as an attractive target for cancer therapy. Characterization of novel pathways that act in parallel with the VEGF/VEGFR axis to promote tumor angiogenesis may provide insights into novel anti-angiogenic therapeutic targets. We found that the expression level of Nogo-B is positively correlated with tumor vessel density in hepatocellular carcinoma (HCC). While Nogo-B depletion inhibited tumor angiogenesis, Nogo-B overexpression promoted tumor angiogenesis in a tumor xenograft subcutaneous model of the human HCC cell line. Mechanically, Nogo-B regulates tumor angiogenesis based on its association with integrin αv β3 and activation of focal adhesion kinase. Moreover, Nogo-B antibody successfully abolished the function of Nogo-B in tumor angiogenesis in vitro and in vivo. Collectively, our results strongly suggest that Nogo-B is an important tumor angiogenic factor and blocking Nogo-B selectively inhibits tumor angiogenesis.
| S-EPMC6275258 | biostudies-literature
Project description:Amplification or over-expression of an activated Cdc42-associated kinase 1 (ACK1) gene is common in breast, lung and ovarian cancers. However, little is known about the role of ACK1 in gastric tumorigenesis. Here, we found that DNA copy numbers of the ACK1 gene and its mRNA expression levels were significantly increased in gastric cancer (GC) compared to normal gastric tissues. Additionally, silencing ACK1 inhibited GC cell proliferation and colony formation, induced G2/M arrest and cellular apoptosis in vitro, and suppressed tumor growth in vivo. Gene Ontology annotation revealed that 147 differential proteins regulated by ACK1 knockdown were closely related with cellular survival. A cell cycle regulator, ecdysoneless homolog (ECD), was found to be significantly down-regulated by ACK1 knockdown. Silencing of ECD inhibited colony formation and induced G2/M arrest and cell apoptosis, which is similar to the effects of ACK1 knockdown. Silencing of ECD did not further enhance the effects of ACK1 knockdown on G2/M arrest and apoptosis, while silencing of ECD blocked the enhancement of colony formation by ACK1 over-expression. Over-expression of ACK or ECD promoted the ubiquitination of tumor suppressor p53 protein and decreased p53 levels, while silencing of ACK1 or ECD decreased the p53 ubiquitination level and increased p53 levels. Silencing of ECD attenuated the ubiquitination enhancement of p53 induced by ACK1 over-expression. Collectively, we demonstrate that amplification of ACK1 promotes gastric tumorigenesis by inducing an ECD-dependent ubiquitination degradation of p53.
| S-EPMC5355047 | biostudies-literature
Project description:BackgroundCancer cells often have characteristic changes in metabolism. Besides Warburg effect, abnormal lipid metabolism is also considered as one of the most typical metabolic symbols of cancer. Thus, understanding the mechanisms of cell metabolic reprogramming may provide a potential avenue for cancer treatment.Materials and methodsIn total, 41 pairs of matched samples of primary hepatocellular carcinoma (HCC) and adjacent non-cancerous liver tissues were collected. Afterward, we performed quantitative reverse transcriptase polymerase chain reaction to investigate carnitine palmitoyltransferase-2 (CPT2) expression and then systematically analyzed its relationship with clinicopathologic features. We further performed proliferation, colony formation, migration and invasion, drug resistance, and lipogenesis assays to determine the function of CPT2 in HCC.ResultsIn this study, we have identified CPT2 which is the rate-limiting enzyme of fatty acid oxidation, downregulated in HCC and was significantly associated with tumor histological differentiation and venous invasion. In vitro studies demonstrated that knockdown of CPT2 remarkably enhanced the tumorigenic activity and metastatic potential of hepatoma cells. In addition, CPT2 silencing induced chemoresistance to cisplatin. Mechanistically, low expression of CPT2 promoted cancer cell lipogenesis via upregulation of stearoyl-CoA desaturase-1, the key enzyme involved in the synthesis of monounsaturated fatty acids, at both mRNA and protein levels in hepatoma cell line.ConclusionAltogether, our findings demonstrate that CPT2 has a critical role in HCC progression and chemoresistance and may potentially serve as a novel prognostic marker and therapeutic target for HCC treatment.
| S-EPMC5975610 | biostudies-literature
Project description:UVRAG (UV radiation resistance associated) is an important regulator of mammalian macroautophagy/autophagy by interacting with BECN1, PIK3C3, and RUBCN. Phosphorylation of UVRAG by MTORC1 negatively regulates autophagosome maturation under nutrient-enriched conditions. However, how UVRAG ubiquitination is regulated is still unknown. Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux. We also demonstrate that CSNK1A1-mediated UVRAG phosphorylation at Ser522 disrupts the binding of SMURF1 to UVRAG through PPxY motif and blocks UVRAG ubiquitination-mediated autophagosome maturation. Interestingly, ZRANB1 is phosphorylated at Thr35, and Ser209 residues by CSNK1A1, and this phosphorylation activates its deubiquitinating activity. Importantly, we provide in vitro and in vivo evidence that UVRAG ubiquitination at lysine residues 517 and 559 or prevention of Ser522 phosphorylation by D4476, a CSNK1A1 inhibitor, enhances the lysosomal degradation of EGFR, which significantly inhibits hepatocellular carcinoma (HCC) growth. Furthermore, UVRAG S522 phosphorylation levels correlate with ZRANB1 T35/S209 phosphorylation levels and poor prognosis in HCC patients. These findings identify a novel molecular mechanism by which ubiquitination and phosphorylation of UVRAG regulate its function in autophagosome maturation and HCC growth, encouraging further study of their potential therapeutic implications. Abbreviations: ATG: autophagy related; BafA1: bafilomycin A1; BECN1: beclin 1; CHX: cycloheximide; CSNK1A1/CK1α: casein kinase 1 alpha 1; CQ: chloroquine; DUB: deubiquitinase; EBSS: Earle's balanced salt solution; EGF: epidermal growth factor; GFP: green fluorescent protein; GST: glutathione S-transferase; HBSS: Hanks balanced salts solution; HCC: hepatocellular carcinoma; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MEFs: mouse embryo fibroblasts; mRFP: monomeric red fluorescent protein; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PTMs: post-translational modifications; RUBCN: rubicon autophagy regulator; siRNA: small interfering RNA; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1: sequestosome 1; Ub-AMC: ubiquitin-7-amido-4-methylcoumarin: a fluorogenic substrate; UVRAG: UV radiation resistance associated; ZRANB1/TRABID: zinc finger RANBP2-type containing 1.
| S-EPMC6613838 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the most lethal cancer worldwide, characterized with high heterogeneity and inclination to metastasize. Emerging evidence suggests that BAP31 gets involved in cancer progression with different kinds. It still remains unknown whether and how BAP31 plays a role in HCC metastasis. Epithelial-mesenchymal transition (EMT) has been a common feature in tumor micro-environment, whose inducer TGF-β increased BAP31 expression in this research. Elevated expression of BAP31 was positively correlated with tumor size, vascular invasion and poor prognosis in human HCC. Ectopic expression of BAP31 promoted cell migration and invasion while BAP31 knockdown markedly attenuated metastatic potential in HCC cells and mice orthotopic xenografts. BAP31 induced EMT process, and enhanced the expression level of EMT-related factor Snail and decreased contents and membrane distribution of E-cadherin. BAP31 also activated AKT/β-catenin pathway, which mediated its promotional effects on HCC metastasis. AKT inhibitor further counteracted the activated AKT/β-catenin/Snail upon BAP31 over-expression. Moreover, silencing Snail in BAP31-overexpressed cells impaired enhanced migratory and invasive abilities of HCC cells. In HCC tissues, BAP31 expression was positively associated with Snail. In conclusion, BAP31 promotes HCC metastasis by activating AKT/β-catenin/Snail pathway. Thus, our study implicates BAP31 as potential prognostic biomarker, and provides valuable information for HCC prognosis and treatment.
| S-EPMC8231437 | biostudies-literature