Article

Gene Deletions and Amplifications in Human Hepatocellular Carcinomas Correlation with Hepatocyte Growth Regulation

Department of Pathology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15241, USA.
American Journal Of Pathology (Impact Factor: 4.6). 02/2012; 180(4):1495-508. DOI: 10.1016/j.ajpath.2011.12.021
Source: PubMed

ABSTRACT Tissues from 98 human hepatocellular carcinomas (HCCs) obtained from hepatic resections were subjected to somatic copy number variation (CNV) analysis. Most of these HCCs were discovered in livers resected for orthotopic transplantation, although in a few cases, the tumors themselves were the reason for the hepatectomies. Genomic analysis revealed deletions and amplifications in several genes, and clustering analysis based on CNV revealed five clusters. The LSP1 gene had the most cases with CNV (46 deletions and 5 amplifications). High frequencies of CNV were also seen in PTPRD (21/98), GNB1L (18/98), KIAA1217 (18/98), RP1-1777G6.2 (17/98), ETS1 (11/98), RSU1 (10/98), TBC1D22A (10/98), BAHCC1 (9/98), MAML2 (9/98), RAB1B (9/98), and YIF1A (9/98). The existing literature regarding hepatocytes or other cell types has connected many of these genes to regulation of cytoskeletal architecture, signaling cascades related to growth regulation, and transcription factors directly interacting with nuclear signaling complexes. Correlations with existing literature indicate that genomic lesions associated with HCC at the level of resolution of CNV occur on many genes associated directly or indirectly with signaling pathways operating in liver regeneration and hepatocyte growth regulation.

0 Followers
 · 
106 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepatocellular carcinoma (HCC) is the most commonly diagnosed form of liver cancer with high morbidity and mortality. Copy number variation analysis (CNV) of human HCC revealed that leukocyte specific protein-1 (LSP1) had the highest number of cases with CNV. LSP1, a F-actin binding protein, is expressed in hematopoietic cells and interacts with Kinase Suppressor of Ras (KSR), a scaffold for the ERK/MAPK pathway. The expression of LSP1 in liver and its role in normal hepatocellular function and carcinogenesis remains unknown. Therefore, LSP1 mRNA and protein levels were analyzed in normal hepatocytes in culture, rat liver following partial hepatectomy (PHx), and hepatoma cell lines. In culture and after PHx, LSP1 increased after the termination of hepatocyte proliferation. To investigate LSP1 function in HCC, shRNA was utilized to stably knock down LSP1 expression in the JM1 rat hepatoma cell line. Loss of LSP1 in JM1 cells resulted in dramatic upregulation of cyclin D1 and pERK2, increased cell proliferation and migration. Co-immunoprecipitation and immunofluoresence analysis displayed an interaction and co-localization between LSP1, KSR and F-actin in the JM1 cells and liver during regeneration. Conversely, expression of LSP1 in JM2 rat hepatoma cell line led to decreased proliferation. Enhanced expression of LSP1 in mouse hepatocytes during liver regeneration following injection of an LSP1 expression plasmid also led to decreased hepatocyte proliferation. Conclusion: LSP1 is expressed in normal hepatocytes and liver following PHx after the termination of proliferation. In rat hepatoma cell lines and mouse liver in vivo, LSP1 functions as a negative regulator of proliferation and migration. Given the high frequency of LSP1 CNV in human HCC, LSP1 may be a novel target for diagnosis and treatment of HCC. (Hepatology 2014;)
    Hepatology 02/2015; 61(2). DOI:10.1002/hep.27444 · 11.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Accumulated studies have suggested that single nucleotide polymorphisms (SNPs) in microRNAs are associated with risk of colorectal cancer (CRC). OBJECTIVE: We tested our hypothesis that rs11014002 in hsa-miR-603 may be associated with CRC risk with a crosstalk of life-related factors. METHODS: We conducted a case-control study which included 102 CRC patients and 204 matched cancer-free controls in Xiaoshan County. RESULTS: We observed that subjects with rs11014002 CT/TT genotype had an increased susceptibility for CRC (CT vs. CC: odds ratio (OR) = 2.352, 95% confidence interval (CI): 1.142-4.840, P = 0.020; CT+TT vs. CC: OR = 2.031, 95% CI: 1.063-3.883, P = 0.032). After stratification by lifestyle-related factors, similar results were found among nonsmokers (CT vs. CC: OR = 2.753, 95% CI: 1.085-6.983, P = 0.033; CT+TT vs. CC: OR = 2.971, 95% CI: 1.188-7.435, P = 0.020) and non-alcohol drinkers (CT+TT vs. CC: OR = 3.279, 95% CI: 1.071-10.033, P = 0.037). CONCLUSIONS: Our data suggest that hsa-miR-603 may be involved in colorectal tumorigenesis, and the genetic polymorphism in hsa-miR-603 is associated with CRC susceptibility.
    Cancer biomarkers: section A of Disease markers 01/2014; 14(4):225-31. DOI:10.3233/CBM-140395 · 1.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Protein tyrosine phosphatases (PTPs) play an important role in regulating cell signaling events in coordination with tyrosine kinases to control cell proliferation, apoptosis, survival, migration, and invasion. Receptor-type protein tyrosine phosphatases (PTPRs) are a subgroup of PTPs that share a transmembrane domain with resulting similarities in function and target specificity. In this review, we summarize genetic and epigenetic alterations including mutation, deletion, amplification, and promoter methylation of PTPRs in cancer and consider the consequences of PTPR alterations in different type of cancers. We also summarize recent developments using PTPRs as prognostic or predictive biomarkers and/or direct targets. Increased understanding of the role of PTPRs in cancer may provide opportunities to improve therapeutic approaches.
    Ai zheng = Aizheng = Chinese journal of cancer 10/2014; 34(2). DOI:10.5732/cjc.014.10146

Full-text (2 Sources)

Download
16 Downloads
Available from
Jun 2, 2014