Cyclin-like proteins tip regenerative balance in the liver to favour cancer formation (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.
The Complex Relationship between Liver Cancer and the Cell Cycle: A Story of Multiple Regulations
Cancers, 2014
The liver acts as a hub for metabolic reactions to keep a homeostatic balance during development and growth. The process of liver cancer development, although poorly understood, is related to different etiologic factors like toxins, alcohol, or viral infection. At the molecular level, liver cancer is characterized by a disruption of cell cycle regulation through many molecular mechanisms. In this review, we focus on the mechanisms underlying the lack of regulation of the cell cycle during liver cancer, focusing mainly on hepatocellular carcinoma (HCC). We also provide a brief summary of novel therapies connected to cell cycle regulation.
Oncogene, 2018
Chronic liver injury triggers liver fibrosis and hepatocellular carcinoma (HCC) the third leading cause of cancer-related mortality. Cyclin E1 (CcnE1, formerly designated Cyclin E) is a regulatory subunit of the Cyclin-dependent kinase 2 (CDK2). It is overexpressed in approximately 70 % of human HCCs correlating with poor prognosis, while the relevance of its orthologue Cyclin E2 (CcnE2) is unclear. Hepatocyte-specific deletion of NF-kappa-B essential modulator (NEMO ∆hepa) leads to chronic hepatitis, liver fibrosis and HCC as well as CcnE up-regulation. To this end, we generated NEMO ∆hepa /CcnE1 −/− and NEMO ∆hepa /CcnE2 −/− double knockout mice and investigated age-dependent liver disease progression in these animals. Deletion of CcnE1 in NEMO ∆hepa mice decreased basal liver damage and reduced spontaneous liver inflammation in young mice. In contrast, loss of CcnE2 did not affect liver injury in NEMO ∆hepa livers pointing to a unique, non-redundant function of CcnE1 in chronic hepatitis. Accordingly, basal compensatory hepatocyte proliferation in NEMO ∆hepa mice was reduced by concomitant ablation of CcnE1, but not after loss of CcnE2. In aged NEMO ∆hepa mice, loss of CcnE1 resulted in significant reduction of liver tumor-igenesis, while deletion of CcnE2 had no effect on HCC formation. Conclusion: CcnE1, but not its orthologue CcnE2 substantially contributes to hepatic inflammatory response, liver disease progression and hepatocarcinogenesis in NEMO ∆hepa mice.
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.
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...
Overexpression of Cyclase-Associated Protein 2 in Multistage Hepatocarcinogenesis
Clinical Cancer Research, 2006
Hepatocellular carcinoma (HCC) associated with chronic liver disease is known to show an obvious multistage process of tumor progression. We previously identified heat shock protein 70 as a molecular marker of early HCC during investigation of expression profiling in multistage hepatocarcinogenesis. In this report, we examined cyclase-associated protein 2 (CAP2), which is also listed as an up-regulated gene in early HCC. Experimental Design: We measured the level of CAP2 mRNA by real-time quantitative PCR. We raised a polyclonal antibody against CAP2 and we confirmed the expression of CAP2 by immunoblotting and immunohistochemistry in HCC cell lines and HCC tissues. Results: According to real-time quantitative PCR, the level of CAP2 mRNA was up-regulated in early HCC when compared with noncancerous liver tissue, and it was further up-regulated in progressed HCC.We raised a polyclonal antibody against CAP2, which showed a single 53-kDa band of strong intensity in the human HCC cell lines and HCC tissues but only a weak band in the noncancerous liver tissues in Western blot analysis. Immunohistochemical examination of CAP2 revealed its significant overexpression in early HCC when compared with noncancerous and precancerous lesions and in progressed HCC when compared with early HCC. Conclusion: Our findings show that CAP2 is up-regulated in HCC when compared with noncancerous and precancerous lesions.This is the first report that proves that CAP2 is up-regulated in human cancers and that this is possibly related to multistage hepatocarcinogenesis.
Cyclin E Overexpression Responsible for Growth of Human Hepatic Tumors with p21WAF1/CIP1/SDI1
Biochemical and Biophysical Research Communications, 1998
We examined a relationship between p21WAF1/CIP1/SDI1 and cell-cycle-related proteins in 12 human liver tumor cell lines (JHH-1, -2, -4, -5, -6, -7; HLE; HuH-7; Hep3B; PLC/PRF/5; HuH-6; HepG2). Seven (JHH-1, -2, -5, -6, -7; Hep3B; HepG2) out of eight cell lines having p21WAF1/CIP1/SDI1 protein overexpressed cyclin E protein, although one of them (JHH-5) overexpressed a reduced size of cyclin E. The rest (HuH-6) of the 8 cell lines with p21WAF1/CIP1/SDI1 showed a decreased expression of cyclin E. Four cell lines (JHH-4; HLE; HuH-7; PLC/PRF/5) deficient of p21WAF1/CIP1/SDI1 protein did not overexpress cyclin E protein. As to expression of the other cell-cycle-related proteins, cyclin A, cyclin D1, CDK2 or CDK4, no significant difference was detected among the 12 cell lines. These findings indicate that the human liver tumor cell lines which have the p21WAF1/CIP1/SDI1-inducible barriers of the cell cycle progression can go through the G1/S checkpoint by overexpressing cyclin E.
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.).
Hepatology, 2002
Preneoplastic and neoplastic hepatocytes undergo c-Myc up-regulation and overgrowth in rats genetically susceptible to hepatocarcinogenesis, but not in resistant rats. Because c-Myc regulates the pRb-E2F pathway, we evaluated cell cycle gene expression in neoplastic nodules and hepatocellular carcinomas (HCCs), induced by initiation/selection (IS) protocols 40 and 70 weeks after diethylnitrosamine treatment, in susceptible Fisher 344 (F344) rats, and resistant Wistar and Brown Norway (BN) rats. No interstrain differences in gene expression occurred in normal liver. Overexpression of c-myc, Cyclins D1, E, and A, and E2F1 genes, at messenger RNA (mRNA) and protein levels, rise in Cyclin D1-CDK4, Cyclin E-CDK2, and E2F1-DP1 complexes, and pRb hyperphosphorylation occurred in nodules and HCCs of F344 rats. Expression of Cdk4, Cdk2, p16 INK4A , and p27 KIP1 did not change. In nodules and/or HCCs of Wistar and BN rats, low or no increases in c-myc, Cyclins D1, E, and A, and E2F1 expression, and Cyclin-CDKs complex formation were associated with p16 INK4A overexpression and pRb hypophosphorylation. In conclusion, these results suggest deregulation of G1 and S phases in liver lesions of susceptible rats and block of G1-S transition in lesions of resistant strains, which explains their low progression capacity. (HEPATOLOGY 2002;35: 1341-1350.)
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