Defense Date

2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Integrative Life Sciences

First Advisor

Mark Reimers

Abstract

Introduction and methods: Hepatocellular carcinoma (HCC) remains a difficult disease to study even after a decade of genomic analysis. Metabolic and cell-cycle perturbations are known, large changes in tumors that add little to our understanding of the development of tumors, but generate “noise” that obscures potentially important smaller scale expression changes in “driver genes”. Recently, some researchers have suggested that HCC shares pathways involving the master regulators of embryonic development. Here, we investigated the involvement and specificity of developmental genes in HCV-cirrhosis and HCV-HCC. We obtained microarray studies from 30 patients with HCV-cirrhosis and 49 patients with HCV-HCC and compared to 12 normal livers. Differential gene expression is specific to liver development genes: 86 of 202 (43%) genes specific to liver development had differential expression between normal and cirrhotic or HCC samples. Of 60 genes with paralogous function, which are specific to development of other organs and have known associations with other cancer types, none were expressed in either adult normal liver or tumor tissue. Developmental genes are widely differentially expressed in both cirrhosis and early HCC, but not late HCC: 69 liver development genes were differentially expressed in cirrhosis, and 58 of these (84%) were also dysregulated in early HCC. 19/58 (33%) had larger-magnitude changes in cirrhosis and 5 (9%) had larger-magnitude changes in early HCC. 16 (9%) genes were uniquely altered in early tumors, while only 2 genes were uniquely changed in late-stage (T3 and T4) HCC. Together, these results suggest that the involvement of the master regulators of liver development are active in the pre-cancerous cirrhotic liver and in cirrhotic livers with emerging tumors but play a limited role in the transition from early to late stage HCC. Common patterns of coordinated developmental gene expression include: (1) Dysregulation of BMP2 signaling in cirrhosis followed by overexpression of BMP inhibitors in HCC. BMP inhibitor GPC3 was overexpressed in nearly all tumors, while GREM1 was associated specifically with recurrence-free survival after ablation and transplant. (2) Cirrhosis tissues acquire a progenitor-like signature including high expression of Vimentin, EPCAM, and KRT19, and these markers remain over-expressed to a lesser extent in HCC. (3) Hepatocyte proliferation inhibitors (HPI) E-cadherin (CDH1), BMP2, and MST1 were highly expressed in cirrhosis and remained over-expressed in 16 HCC patients who were transplanted with excellent recurrence-free survival (94% survival after 2 years; mean recurrence-free survival = 5.6 yrs), while loss in early HCC was associated with early recurrence and (2 year). Loss of HPI overexpression was also correlated with overexpression of c-MET and loss of STAT3, LAMA2, FGFR2, CITED2, KIT, SMAD7, GATA6, ERBB2, and NOTCH2.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

December 2012

Included in

Life Sciences Commons

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