title: Modulations of cell cycle checkpoints during HCV associated disease.
abstract: BACKGROUND
  Impaired proliferation of hepatocytes has been reported in chronic Hepatitis C virus infection. Considering the fundamental role played by cell cycle proteins in controlling cell proliferation, altered regulation of these proteins could significantly contribute to HCV disease progression and subsequent hepatocellular carcinoma (HCC). This study aimed to identify the alterations in cell cycle genes expression with respect to early and advanced disease of chronic HCV infection.
  
  
  METHODS
  Using freshly frozen liver biopsies, mRNA levels of 84 cell cycle genes in pooled RNA samples from patients with early or advanced fibrosis of chronic HCV infection were studied. To associate mRNA levels with respective protein levels, four genes (p27, p15, KNTC1 and MAD2L1) with significant changes in mRNA levels (> 2-fold, p-value < 0.05) were selected, and their protein expressions were examined in the liver biopsies of 38 chronic hepatitis C patients.
  
  
  RESULTS
  In the early fibrosis group, increased mRNA levels of cell proliferation genes as well as cell cycle inhibitor genes were observed. In the advanced fibrosis group, DNA damage response genes were up-regulated while those associated with chromosomal stability were down-regulated. Increased expression of CDK inhibitor protein p27 was consistent with its mRNA level detected in early group while the same was found to be negatively associated with liver fibrosis. CDK inhibitor protein p15 was highly expressed in both early and advanced group, but showed no correlation with fibrosis. Among the mitotic checkpoint regulators, expression of KNTC1 was significantly reduced in advanced group while MAD2L1 showed a non-significant decrease.
  
  
  CONCLUSIONS
  Collectively these results are suggestive of a disrupted cell cycle regulation in HCV-infected liver. The information presented here highlights the potential of identified proteins as predictive factors to identify patients with high risk of cell transformation and HCC development.
authors: Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan. saira.khalidb@gmail.com
authors: Saira
authors: S
authors: Sarfraz
authors: Saeed
authors: S
authors: Hamid
authors: Syed
authors: S
authors: Ali
authors: Wasim
authors: W
authors: Jafri
authors: Anwar A
authors: AA
authors: Siddiqui
mesh_terms: D000328:Adult; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D020869:Gene Expression Profiling; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics*; D064246:Mad2 Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D055815:Young Adult
chemical_list: D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; C489309:KNTC1 protein, human; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27