Revealing the Roles of Keratin 8/18-Associated Signaling Proteins Involved in the Development of Hepatocellular Carcinoma.
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ABSTRACT:
SUBMITTER: Lim Y
PROVIDER: S-EPMC8232640 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND & AIMS:Steatohepatitis (SH) and SH-associated hepatocellular carcinoma (HCC) are of considerable clinical significance. SH is morphologically characterized by steatosis, liver cell ballooning, cytoplasmic aggregates termed Mallory-Denk bodies (MDBs), inflammation, and fibrosis at late stage. Disturbance of the keratin cytoskeleton and aggregation of keratins (KRTs) are essential for MDB formation. METHODS:We analyzed livers of aged Krt18-/- mice that spontaneously developed in the majority of cases SH-associated HCC independent of sex. Interestingly, the hepatic lipid profile in Krt18-/- mice, which accumulate KRT8, closely resembles human SH lipid profiles and shows that the excess of KRT8 over KRT18 determines the likelihood to develop SH-associated HCC linked with enhanced lipogenesis. RESULTS:Our analysis of the genetic profile of Krt18-/- mice with 26 human hepatoma cell lines and with data sets of >300 patients with HCC, where Krt18-/- gene signatures matched human HCC. Interestingly, a high KRT8/18 ratio is associated with an aggressive HCC phenotype. CONCLUSIONS:We can prove that intermediate filaments and their binding partners are tightly linked to hepatic lipid metabolism and to hepatocarcinogenesis. We suggest KRT8/18 ratio as a novel HCC biomarker for HCC.
| S-EPMC6234703 | biostudies-literature
Project description:Keratin 8 and keratin 18 (K8/K18) are intermediate filament proteins that form the obligate heteropolymers in hepatocytes and protect the liver against toxins. The mechanisms of protection include the regulation of signaling pathway associated with cell survival. Previous studies show K8/K18 binding with Akt, which is a well-known protein kinase involved in the cell survival signaling pathway. However, the role of K8/K18 in the Akt signaling pathway is unclear. In this study, we found that K8/K18-Akt binding is downregulated by K8/K18 phosphorylation, specifically phosphorylation of K18 ser7/34/53 residues, whereas the binding is upregulated by K8 gly-62-cys mutation. K8/K18 expression in cultured cell system tends to enhance the stability of the Akt protein. A comparison of the Akt signaling pathway in a mouse system with liver damage shows that the pathway is downregulated in K18-null mice compared with nontransgenic mice. K18-null mice with Fas-induced liver damage show enhanced apoptosis combined with the downregulation of the Akt signaling pathway, i.e., lower phosphorylation levels of GSK3β and NFκB, which are the downstream signaling factors in the Akt signaling pathway, in K18-null mice compared with the control mice. Our study indicates that K8/K18 expression protects mice from liver damage by participating in enhancing the Akt signaling pathway.
| S-EPMC8430995 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Numerous signalling pathways are involved in hepatocellular carcinoma. Piperlongumine is a potential candidate for the treatment of hepatocellular carcinoma. Therefore, it is of interest to document the molecular docking analysis of piperlongumine with different apoptotic proteins involved in Hepatocellular Carcinoma. Piperlongumine was docked with the HCC targets such as vascular endothelial growth factor (VEGF), epidermal growth factor receptor, Aurora-2, Nuclear factor Kappa-B (NF-KB), Jak2 Kinase, Fibroblast growth factor receptor 4, Bcl-2-like protein 1,Apopain, and Apoptosis regulator Bcl-2 using in-silico technique with the software grid-based ligand docking with energies. Piperlongumine exhibited the highest negative energy value (E-value) of -6.58 kcal/mol with vascular endothelial growth factor receptor 2, followed by -5.46, -5.34, -5.31, and -5.29 kcal/mol with 1M17, 2BMC, 1SVC, 4C61, 4XCU with epidermal growth factor receptor, aurora-2, nuclear factor Kappa-B (NF-KB), Jak2 kinase, and fibroblast growth factor receptor 4 (FGFR4), respectively for further consideration.
| S-EPMC9049083 | biostudies-literature
Project description:IntroductionHepatocellular carcinoma (HCC) is the most common type of primary liver cancers. It is an aggressive neoplasm with dismal outcome because most of the patients present with an advanced-stage disease, which precludes curative surgical options. Therefore, these patients require systemic therapies that typically induce small improvements in overall survival. Hence, it is crucial to identify new and promising therapeutic targets for HCC to improve the current outcome. The liver is a key organ in the signaling cascade triggered by the growth hormone receptor (GHR). Previous studies have shown that GHR signaling stimulates the proliferation and regeneration of liver cells and tissues; however, a definitive role of GHR signaling in HCC pathogenesis has not been identified.MethodsIn this study, we used a direct and specific approach to analyze the role of GHR in HCC development. This approach encompasses mice with global (Ghr-/- ) or liver-specific (LiGhr-/- ) disruption of GHR expression, and the injection of diethylnitrosamine (DEN) to develop HCC in these mice.ResultsOur data show that DEN induced HCC in a substantial majority of the Ghr+/+ (93.5%) and Ghr +/- (87.1%) mice but not in the Ghr-/- (5.6%) mice (P < 0.0001). Although 57.7% of LiGhr-/- mice developed HCC after injection of DEN, these mice had significantly fewer tumors than LiGhr+/+ (P < 0.001), which implies that the expression of GHR in the liver cells might increase tumor burden. Notably, the pathologic, histologic, and biochemical characteristics of DEN-induced HCC in mice resembled to a great extent human HCC, despite the fact that etiologically this model does not mimic this cancer in humans. Our data also show that the effects of DEN on mice livers were primarily related to its carcinogenic effects and ability to induce HCC, with minimal effects related to toxic effects.ConclusionCollectively, our data support an important role of GHR in HCC development, and suggest that exploiting GHR signaling may represent a promising approach to treat HCC.
| S-EPMC9391993 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is a liver cancer, highly heterogeneous both at the histopathological and molecular levels. It arises from hepatocytes as the result of the accumulation of numerous genomic alterations in various signaling pathways, including canonical WNT/β-catenin, AKT/mTOR, MAPK pathways as well as signaling associated with telomere maintenance, p53/cell cycle regulation, epigenetic modifiers, and oxidative stress. The role of WNT/β-catenin signaling in liver homeostasis and regeneration is well established, whereas in development and progression of HCC is extensively studied. Herein, we review recent advances in our understanding of how WNT/β-catenin signaling facilitates the HCC development, acquisition of stemness features, metastasis, and resistance to treatment. We outline genetic and epigenetic alterations that lead to activated WNT/β-catenin signaling in HCC. We discuss the pivotal roles of CTNNB1 mutations, aberrantly expressed non-coding RNAs and complexity of crosstalk between WNT/β-catenin signaling and other signaling pathways as challenging or advantageous aspects of therapy development and molecular stratification of HCC patients for treatment.
| S-EPMC10491942 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. The aim of this study was to identify underlying hub genes and dysregulated pathways associated with the development of HCC using bioinformatics analysis. Differentially expressed protein-coding genes were subjected to transcriptome sequencing in 11 pairs of liver cancer tissue and matched adjacent non-cancerous tissue. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, followed by protein-protein interaction (PPI) network construction. Hub genes were identified via centralities analysis and verified using published datasets. In total, 720 significantly differentially expressed protein-coding genes were identified in the samples, including 335 upregulated genes and 385 downregulated genes. The upregulated genes were significantly enriched in cell adhesion, biological adhesion and cell-cell adhesion GO terms under biological process (BP). Conversely, the downregulated genes were significantly enriched in embryonic organ morphogenesis, embryonic organ development and embryonic morphogenesis. The KEGG pathway analysis showed that the upregulated genes were enriched in ECM-receptor interaction and focal adhesion pathways. Furthermore, the downregulated genes were enriched in the ErbB, VEGF and MAPK signaling pathways. The PPI network and centralities analysis suggested that ITGA2 and 12 alternate genes were significant hub genes. These findings improve current understanding of the molecular mechanisms underlying HCC development and may be helpful in identifying candidate molecular biomarkers for use in diagnosing, treating and monitoring the prognosis of HCC.
| S-EPMC5601144 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Currently, recent risk stratification has only focused on liver function and tumor characteristics. Thus, the purpose of this study was to develop a prognostic model based on genes involved in aerobic respiration. Matched tumor and normal tissues from TCGA and ICGC cohorts were analyzed to identify 15 overlapping differential expressed genes. Cox univariate analysis of the 15 genes in the TCGA cohort revealed they were all associated with disease-specific survival (DSS) in HCC patients. Using LASSO estimation and the optimal value for penalization coefficient lambda 12 genes were selected for the prognostic model, and then HCC patients in the TCGA cohort were dichotomized into low-risk and high-risk groups. Univariate and multivariate Cox analysis demonstrated patients in low-risk group had better survival. Validation of the risk score model with the ICGC cohort produces results consistent with those of the TCGA cohort. In conclusion, this study developed and validated a prognostic model of HCC through a comprehensive analysis of genes involved in aerobic respiration. This model may help develop personalized treatments for patients with HCC.
| S-EPMC8148449 | biostudies-literature
Project description:The tripartite motif (TRIM) protein family is a highly conserved group of E3 ligases with 77 members known in the human, most of which consist of a RING-finger domain, one or two B-box domains, and a coiled-coil domain. Generally, TRIM proteins function as E3 ligases to facilitate specific proteasomal degradation of target proteins. In addition, E3 ligase independent functions of TRIM protein were also reported. In hepatocellular carcinoma, expressions of TRIM proteins are both regulated by genetic and epigenetic mechanisms. TRIM proteins regulate multiple biological activities and signaling cascades. And TRIM proteins influence hallmarks of HCC. This review systematically demonstrates the versatile roles of TRIM proteins in HCC and helps us better understand the molecular mechanism of the development and progression of HCC.
| S-EPMC9469581 | biostudies-literature
Project description:IQ motif-containing GTPase-activating proteins IQGAP1 and IQGAP2 are highly homologous multidomain scaffolding proteins. Their major function consists of integration of Rho GTPase and Ca(2+)/calmodulin signals with cell adhesive and cytoskeletal reorganizational events. Recent studies showed that they play an important role in carcinogenesis. There is growing evidence that IQGAP2 is a novel tumor suppressor counteracting the effects of IQGAP1, an oncogene, in several cancers, especially in hepatocellular carcinoma (HCC). While HCC is highly prevalent and one of the deadliest cancers worldwide, the signaling pathways involved are not fully understood and treatment of advanced disease still represents an area of high unmet medical need. This paper compiles various findings from studies in mouse models, cell lines, and patient samples that support future development of IQGAPs into new therapeutic targets. It also discusses distinct features of IQGAP2 in an attempt to provide insight into the mechanism of the seemingly paradoxical opposing roles of the two very similar IQGAP proteins in carcinogenesis.
| S-EPMC3438877 | biostudies-literature
Project description:Global transcriptomic alterations of both coding and non-coding RNA species are a ubiquitous feature associated with human cancers including hepatocellular carcinoma (HCC). Dysregulation of RNA-binding proteins (RBPs), the key regulators of RNA processing, is one mechanism in which cancer cells select to promote tumorigenesis. We analyzed genomic alterations amongst a family of more than 800 mRNA RBPs (mRBPs) in 1,225 clinical specimens from HCC patients and found that RBPs are significantly activated through gene amplification in a subset of tumors with poor prognosis, suggesting their potential oncogenic roles in HCC progression. Amongst the top candidates, RD binding protein (RDBP) was further characterized for its oncogenic role and effects on the HCC transcriptome. While the activation of RDBP induced an oncogenic phenotype, the abrogation of RDBP in HCC cells significantly decreased cancer associated phenotypes such as cell proliferation, migration/invasion and tumorigenicity in vivo. Further microarray analyses revealed that RDBP-dependent genes were tumor-related with a significant enrichment for c-Myc targets, suggesting interplay between RDBP and c-Myc signaling. Similar data were also found in HCC clinical specimens where c-Myc amplification was uncommon. Consistently, the RDBP-dependent c-Myc target gene signature was able to predict HCC patient survival in two independent cohorts of more than 400 patients. Taken together, our results suggest that oncogenic activation of RDBP is a novel mechanism that contributes to global transcriptome imbalance that is selective for the activation of c-Myc oncogenic signaling in HCC. We used microarray analysis to determine the affects of siRNA mediated RDBP knockdown in HCC transcriptome in cell lines. Hep3b and Huh1 cells were transfected with RDBP or scramble control siRNA for 48 hours in quadruplicates. Quality control using Spearman or Pearson correlation removes outliers resulting in triplicates for each group
2015-09-23 | E-GEOD-73219 | biostudies-arrayexpress