The Role of Spy1 in the Development of Hepatocellular Carcinoma (original) (raw)
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Expression and prognostic role of Spy1 as a novel cell cycle protein in hepatocellular carcinoma
Experimental and Molecular Pathology, 2009
Objectives: Spy1 is a novel cell cycle regulatory gene, which can control cell proliferation and survival through the atypical activation of cyclin-dependent kinases. Recent studies suggested that deregulation of Spy1 expression plays a key role in oncogenesis. To investigate the potential roles of Spy1 in hepatocellular carcinoma (HCC), expression of Spy1 was examined in human HCC samples. Methods: Immunohistochemistry and Western blot analysis was performed for Spy1 in 61 hepatocellular carcinoma samples. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine their prognostic significance. Results: Spy1 was overexpressed in hepatocellular carcinoma as compared with the adjacent normal tissue. High expression of Spy1 was associated with histological grade and the level of alpha fetal protein (AFP) (P = 0.009 and 0.003, respectively), and Spy1 was positively correlated with proliferation marker Ki-67 (P < 0.001). Univariate analysis showed that Spy1 expression was associated with poor prognosis (P = 0.03). Multivariate analysis indicated that Spy1 and Ki-67 protein expression was an independent prognostic marker for HCC (P = 0.001 and 0.012, respectively). While in vitro, following release from serum starvation of HuH7 HCC cell, the expression of Spy1 was upregulated. Conclusions: Our results suggested that Spy1 overexpression is involved in the pathogenesis of hepatocellular carcinoma, it may be a favorable independent poor prognostic parameter for hepatocellular carcinoma.
Cyclin-like proteins tip regenerative balance in the liver to favour cancer formation
Carcinogenesis, 2019
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. A variety of factors can contribute to the onset of this disease, including viral infection, obesity, alcohol abuse and non-alcoholic fatty liver disease (NAFLD). These stressors predominantly introduce chronic inflammation leading to liver cirrhosis and finally the onset of HCC; however, approximately 20% of HCC cases arise in the absence of cirrhosis via a poorly defined mechanism. The atypical cyclin-like protein Spy1 is capable of overriding cell cycle checkpoints, promoting proliferation and has been implicated in HCC. We hypothesize that Spy1 promotes sustained proliferation making the liver more susceptible to accumulation of deleterious mutations, leading to the development of non-cirrhotic HCC. We report for the first time that elevation of Spy1 within the liver of a transgenic mouse model leads to enhanced spontaneous liver tumourigenesis. We show that the abundance of Spy1 enha...
Molecular Mechanisms Underlying Hepatocellular Carcinoma
Viruses, 2009
Hepatocarcinogenesis is a complex process that remains still partly understood. That might be explained by the multiplicity of etiologic factors, the genetic/epigenetic heterogeneity of tumors bulks and the ignorance of the liver cell types that give rise to tumorigenic cells that have stem cell-like properties. The DNA stress induced by hepatocyte turnover, inflammation and maybe early oncogenic pathway activation and sometimes viral factors, leads to DNA damage response which activates the key tumor suppressive checkpoints p53/p21 Cip1 and p16 INK4a /pRb responsible of cell cycle arrest and cellular senescence as reflected by the cirrhosis stage. Still obscure mechanisms, but maybe involving the Wnt signaling and Twist proteins, would allow pre-senescent hepatocytes to bypass senescence, acquire immortality by telomerase reactivation and get the last genetic/epigenetic hits necessary for cancerous transformation. Among some of the oncogenic pathways that might play key driving roles in hepatocarcinogenesis, c-myc and the Wnt/-catenin signaling seem of particular interest. Finally, antiproliferative and apoptosis deficiencies involving TGF-, Akt/PTEN, IGF2 pathways for instance are prerequisite for cancerous transformation. Of evidence, not only the transformed liver cell per se but the facilitating microenvironment is of fundamental importance for tumor bulk growth and metastasis.
Editorial: Recent advances in the understanding of hepatocellular carcinogenesis
Frontiers in Oncology
Editorial on the Research Topic Recent advances in the understanding of hepatocellular carcinogenesis Hepatocellular Carcinoma (HCC) is one of the deadliest cancers worldwide and a major health problem across the globe Suresh et al. (1). A better understanding of its multifactorial underpinnings and disease pathogenesis will aid in the design of novel and targeted therapeutic strategies for HCC. This special collection of original and review articles on Recent Advances in the Understanding of Hepatocellular Carcinogenesis provides new insights on the complexity of the disease. The crucial role of miRNAs and associated RISC complex in the development and progression of HCC is highlighted (2-4). Several miRNAs (miR-631, miR-532-3p, miR-125b) showed tumor suppressor activities in HCC via targeting of various pathways, including receptor-type protein tyrosine phosphatase epsilon (PTPRE), WEE1 G2 checkpoint kinase, TGF-b1 signalling associated SMAD2 protein and MMP-2, MMP-9, and MMP-14 (Chen et al., Ma et al., Kim et al.). Previous work also demonstrated that TGF-b1 signalling and MMP9 were involved in HCC development (5, 6). A network meta-analysis showed that single nucleotide polymorphisms (SNPs) of miR-196a2 rs11614913 are significantly associated with the initiation and development of HCC (Zhang et al.). SNPs and epithelial mesenchymal transition (EMT)-related genes are associated with Hepatitis B virus (HBV)-related HCC (Liu et al.) (5). The tryptophan 2,3dioxygenase (TDO2) enzyme promotes EMT of HCC through the Kyn-AhR pathway, with Kyn being the main product of Trp metabolism (Li et al.). Comprehensive analysis by Zhu et al. proposed a novel prognostic signature involving four differentially coexpressed hub genes CDCA8, KIF20A, KIF2C and CEP55 that associate with HCC (Zhu et al.). Bioinformatic analysis using the TCGA database identified methylation status of PDK4 and CTF1 in survival prediction and as treatment biomarkers for HCC (Liang et al.).
We applied a genome-wide microarray analysis to three transgenic mouse models of liver cancer in which targeted overexpression of c-Myc, E2f1, and a combination of the two was driven by the albumin promoter. Although gene expression profiles in HCC derived in all three transgenic lines were highly similar, oncogene-specific gene expression signatures were identified at an early dysplastic stage of hepatocarcinogenesis. Overexpression of E2f1 was associated with a strong alteration in lipid metabolism, and Srebp1was identified as a candidate transcription factor responsible for lipogenic enzyme induction. The molecular signature of c-Myc overexpression included the induction of more than 60 genes involved in the translational machinery that correlated with an increase in liver mass. In contrast, the combined activity of c-Myc and E2f1 specifically enhanced the expression of genes involved in mitochondrial metabolism-particularly the components of the respiratory chain-and correlated with an increased ATP synthesis. Thus, the results suggest that E2f1, c-Myc, and their combination may promote liver tumor development by distinct mechanisms. In conclusion, determination of tissue-specific oncogene expression signatures might be useful to identify conserved expression modules in human cancers. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2006;44:1003-1011.) Abbreviations: HCC, hepatocellular carcinoma; CDK, cyclin-dependent kinase; PPAR-␥, peroxisome proliferator-activated receptor ␥; ATP, adenosine triphosphate; CoA, coenzyme A; Srebp1, sterol regulatory element binding factor 1. From the
Etiology-dependent molecular mechanisms in human hepatocarcinogenesis
Hepatology, 2007
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is characterized by aggressive tumor behavior coupled with poor prognosis. Various etiologies have been linked to HCC development, most prominently chronic hepatitis B and C virus infections as well as chronic alcohol consumption. In approximately 10% of HCCs, the etiology remains cryptic; however, recent epidemiological data suggest that most of these cryptogenic HCCs develop due to nonalcoholic steatohepatitis. To identify etiology-dependent DNA copy number aberrations and genes relevant to hepatocarcinogenesis, we performed array-based comparative genomic hybridization of 63 HCCs of well-defined etiology and 4 HCC cell lines followed by gene expression profiling and functional analyses of candidate genes. For a 10-megabase chromosome region on 8q24, we observed etiology-dependent copy number gains and MYC overexpression in viral and alcohol-related HCCs, resulting in up-regulation of MYC target genes. Cryptogenic HCCs showed neither 8q24 gains, nor MYC overexpression, nor target gene activation, suggesting that tumors of this etiology develop by way of a distinct MYC-independent pathomechanism. Furthermore, we detected several etiology-independent small chromosome aberrations, including amplification of MDM4 on 1q32.1 and frequent gains of EEF1A2 on 20q13.33. Both genes were overexpressed in approximately half the HCCs examined, and gene silencing reduced cell viability as well as proliferation and increased apoptosis rates in HCC cell lines. Conclusion: Our findings suggest that MDM4 and EEF1A2 act as etiology-independent oncogenes in a significant percentage of HCCs. (HEPATOLOGY 2008;47:511-520.)
From chronic liver disorders to hepatocellular carcinoma: Molecular and genetic pathways
World journal of gastrointestinal oncology, 2010
Hepatocarcinogenesis is a process attributed to progressive genomic changes that alter the hepatocellular phenotype producing cellular intermediates that evolve into hepatocellular carcinoma (HCC). During the preneoplastic phase, the liver is often the site of chronic hepatitis and/or cirrhosis, and these conditions induce liver regeneration with accelerated hepatocyte cycling in an organ that is otherwise proliferatively at rest. Hepatocyte regeneration is accelerated by upregulation of mitogenic pathways involving molecular and genetic mechanisms. Hepatic growth factors, inhibitors and triggers may also play a role. This process leads to the production of monoclonal populations of aberrant and dysplastic hepatocytes that have telomerase re-expression, microsatellite instability, and occasionally structural aberrations in genes and chromosomes. Development of dysplastic hepatocytes in foci and nodules and the emergence of HCC are associated with the accumulation of irreversible str...
Progenitor-derived hepatocellular carcinoma model in the rat
Hepatology, 2010
Human hepatocellular carcinoma (HCC) is a heterogeneous disease of distinct clinical subgroups. A principal source of tumor heterogeneity may be cell type of origin which in liver includes hepatocyte and/or adult stem/progenitor cells. To address this issue, we investigated the molecular mechanisms underlying the fate of the enzyme-altered preneoplastic lesions in the resistant hepatocyte (RH) model. Sixty samples classified as focal lesions, adenoma, early and advanced HCCs were micro-dissected after morphological and immunohistochemical evaluation and subjected to global gene expression profiling. The analysis of progression of the persistent GSTP + focal lesions to fully developed HCC showed that about 50% of persistent nodules and all HCCs expressed CK19 whereas 14% of remodeling nodules were CK19 + . Unsupervised hierarchical clustering of the expression profiles also grouped the samples according to CK19 expression. Further, supervised analysis using the differentially expressed genes in each cluster combined with the gene connectivity tools identified 1308 unique genes and a predominance of the AP-1/JUN network in the CK19 + lesions. In contrast, the CK19-negative cluster exhibited only limited molecular changes (156 differentially expressed genes vs. normal liver) consistent with remodeling towards differentiated phenotype. Finally, comparative functional genomics revealed a stringent clustering of CK19 + early lesions and advanced HCCs with human HCCs characterized by poor prognosis. Furthermore, the CK19 associated gene expression signature accurately predicted the patient survival (P<0.009) and tumor recurrence (P<0.006).
Reviews on Recent Clinical Trials, 2007
Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. Strategies for identification of new markers/therapeutic targets include discovery of early molecular changes during hepatocarcinogenesis, relevant to preneoplastic lesions progression to full malignancy in rodent models, and evaluation of these changes in human hepatocellular carcinomas (HCCs). Activation of ERB receptor family, MAPK, JAK-STAT, -Catenin cascades, c-Myc targets, iNOS-IKK/MAT1A-NF-kB axis, Ornithine decarboxylase, Cyclins and CDKs occurs in human and rodent hepatocarcinogenesis. This is associated with downregulation of the cell cycle inhibitors p16 INK4A and p53 and TGF-/SMAD signaling. Oncosuppressor genes, including p16 INK4A , E-CAD, and DLC-1 are often hypermethylated in humans and rodents. Moreover, protection of cell cycle from p16 INK4A inhibition by upregulation of CDC37, HSP90, and CRM1 correlates to HCC progression. A body of evidence indicates that inhibition of key genes of aforementioned signaling pathways by antisense or siRNA approaches or specific inhibitors restraints growth of in vitro cultured or in vivo xenografted HCCs. Efforts are currently dedicated to improve transduction efficiency. HCC cells may escape gene therapy by various mechanisms. Attempts to overcome this difficulty include discovery of new therapeutic targets, gene therapy directed to different molecular targets essential for tumor cell survival and specifically directed to HCC subtypes.
Scientific Reports
Chronic liver injury is a risk factor for cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms that regulate the decision between normal injury repair and neoplastic initiation are unclear. Doublecortin-like kinase 1 (DCLK1), a tumor stem cell marker, is induced during cirrhosis and HCC. Here, we demonstrate that DCLK1-overexpressing primary human hepatocytes formed spheroids in suspension cultures. Spheroids derived from DCLK1-overexpressing hepatoma cells showed high level expression of active β-catenin, α-fetoprotein, and SOX9, suggesting that DCLK1 overexpression induces clonogenicity and dedifferentiated phenotypes in hepatoma cells. DCLK1 overexpression in hepatoma cells also increased phosphorylation of GSK-3β at Ser 9 . This was associated with an induction of a 48-kDa active β-catenin with a preserved hypophosphorylated N-terminus that interacted with nuclear TCF-4 resulting in luciferase reporter activity and cyclin D1 expression. DCLK1 downregulation inhibited 48-kDa β-catenin expression. The proteasome inhibitor bortezomib did not block the 48-kDa β-catenin, instead, caused a threefold accumulation, suggesting a proteasome-independent mechanism. Liver tissues from patients with cirrhosis and HCC revealed epithelial co-staining of DCLK1 and active β-catenin, and cleaved E-cadherin. Repopulated DCLK1overexpressing primary human hepatocytes in humanized FRG mouse livers demonstrated active β-catenin. In conclusion, DCLK1 regulates oncogenic signaling and clonogenicity of hepatocytes by a novel non-canonical/atypical β-catenin-dependent mechanism.