Genetic and Epigenetic Control of Molecular Alterations in Hepatocellular Carcinoma

Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy.
Experimental Biology and Medicine (Impact Factor: 2.17). 06/2009; 234(7):726-36. DOI: 10.3181/0901-MR-40
Source: PubMed


Comparative analysis of hepatocellular carcinoma (HCC) in rat strains that are either susceptible or resistant to the induction of HCC has allowed the mapping of genes responsible for inherited predisposition to HCC. These studies show that the activity of several low penetrance genes and a predominant susceptibility gene regulate the development of hepatocarcinogenesis in rodents. These studies shed light on the epidemiology of human HCC. The identified genes regulate resistance to hepatocarcinogenesis by affecting the capacity of the initiated cells to grow autonomously and to progress to HCC. Analysis of the molecular alterations showed highest iNos cross-talk with IKK/NF-kB and RAS/ERK pathways in most aggressive liver lesions represented by HCC in the susceptible F344 rats. Unrestrained extracellular signal-regulated kinase (Erk) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (Dusp1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex was highest in more aggressive HCC of genetically susceptible rats. Furthermore, deregulation of G1 and S phases of the cell cycle occurs in HCC of susceptible F344 rats, leading to pRb hyperphosphorylation and elevated DNA synthesis, whereas a block to G1-S transition is present in the HCC of resistant BN rats. Importantly, similar alterations in the signaling pathways that regulate cell cycle progression were found in human HCC with poorer prognosis (as defend by patients' survival length), whereas human HCC with better prognosis had molecular characteristics similar to the lesions in the HCC of resistant rat strains. This review discusses the role of molecular alterations involved in the acquisition of resistance or susceptibility to HCC and the importance of genetically susceptible and resistant rat models for the identification of prognostic markers, and chemopreventive or therapeutic targets for the biological network therapy of human disease.

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Available from: Francesco Feo
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    • "Owing to its profound physiological role and functional importance in metabolism and homeostasis, pertinent succession of cell cycle in liver epithelial cells is of prime importance to maintain cellular proliferation (Alam et al., 2009; Feo et al., 2009; Boobis, 2010). The fidelity of DNA replication and division along with the correct ordering of cell cycle events are governed by cell cycle checkpoints (Afshari and Barrett, 1993). "
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    ABSTRACT: Liver is often exposed to plethora of chemical toxins. Owing to its profound physiological role and central function in metabolism and homeostasis, pertinent succession of cell cycle in liver epithelial cells is of prime importance to maintain cellular proliferation. Although recent evidence has displayed a strong association between exposures to methyl isocyanate (MIC), one of the most toxic isocyanates, and neoplastic transformation, molecular characterization of the longitudinal effects of MIC on cell cycle regulation has never been performed. Here, we sequentially delineated the status of different proteins arbitrating the deregulation of cell cycle in liver epithelial cells treated with MIC. Our data reaffirms the oncogenic capability of MIC with elevated DNA damage response proteins pATM and γ-H2AX, deregulation of DNA damage check point genes CHK1 and CHK2, altered expression of p53 and p21 proteins involved in cell cycle arrest with perturbation in GADD-45 expression in the treated cells. Further, alterations in cyclin A, cyclin E, CDK2 levels along with overexpression of mitotic spindle checkpoints proteins Aurora A/B, centrosomal pericentrin protein, chromosomal aberrations, and loss of Pot1a was observed. Thus, MIC impacts key proteins involved in cell cycle regulation to trigger genomic instability as a possible mechanism of developmental basis of liver carcinogenesis. © 2011 Wiley Periodicals, Inc. Environ Toxicol, 2011.
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    • "Cks1 is also highly overexpressed in the majority of different cancer subtypes afflicting the gastrointestinal system and in most cases is strongly correlated to increased Skp2 expression and reduced p27Kip1 expression. Cks1 has been implicated in development of oral squamous cell carcinoma [131–133], salivary gland tumors [106], esophageal carcinomas [80,134,135], gastric carcinoma [20,136], colorectal carcinoma [108], gall bladder carcinoma [137] and hepatocellular carcinoma [19, 138–142]. Similarly Cks1 is believed to play a role in development and progression of several other types of cancers such as endometrial cancer [143], ovarian tumors [144–147], prostate cancer [148], testicular cancer [149], non small cell lung carcinomas (NSCLC) [111,150], cutaneous squamous cell carcinoma [151], melanoma [15], urothelial carcinoma and renal cell carcinomas [152,153], glioblastoma and CNS tumors [154,155], head and neck carcinoma [156], fibrosarcoma [157], and myxofibrosarcoma [158]. "
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    ABSTRACT: Deregulation of the cell cycle results in loss of normal control mechanisms that prevent aberrant cell proliferation and cancer progression. Regulation of the cell cycle is a highly complex process with many layers of control. One of these mechanisms involves timely degradation of CDK inhibitors (CKIs) like p27(Kip1) by the ubiquitin proteasomal system (UPS). Cks1 is a 9 kDa protein which is frequently overexpressed in different tumor subtypes, and has pleiotropic roles in cell cycle progression, many of which remain to be fully characterized. One well characterized molecular role of Cks1 is that of an essential adaptor that regulates p27(Kip1) abundance by facilitating its interaction with the SCF-Skp2 E3 ligase which appends ubiquitin to p27(Kip1) and targets it for degradation through the UPS. In addition, emerging research has uncovered p27(Kip1)-independent roles of Cks1 which have provided crucial insights into how it may be involved in cancer progression. We review here the structural features of Cks1 and their functional implications, and also some recently identified Cks1 roles and their involvement in breast and other cancers.
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    • "In conclusion, the results of both long-term carcinogenicity studies and of genetic investigation of HCC from rodent models may provide important insights into the mechanisms of hepatocarcinogenesis, helping to identify some critical initiating events that lead to carcinogenesis, as well as progression markers and therapeutic targets (Feo et al., 2009; Hoenerhoff et al., 2011). "

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