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FEnane Dissertation.pdf (3.85 MB)

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HEPATOCYTE DIFFERENTIATION AND HEPATOCELLULAR CARCINOMA: RATIONALE FOR P53 INDEPENDENT THERAPY

Enane, Francis Obunyakha
http://orcid.org/0000-0002-0905-3841
http://rave.ohiolink.edu/etdc/view?acc_num=case1491570319727552

Abstract Details

2017, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
The era of genomic revolution illustrated that cancer is a genetic disease where alterations impair specific cellular pathways. For instance, cancer cells frequently physically remove cell death genes (i.e., TP53, CDKN2A) to impair apoptotic pathways. However, most systemic treatments of cancer are typically designed to engage cell cycle exit by apoptosis. This approach selects for apoptosis-resistant cancer cells and is toxic to normal cells. There is clear need for p53 independent non-apoptosis therapies in cancer. To proliferate, cells must execute a complex duplication and separation of entire cells: a process coordinated by the transcription factor MYC, whose growth and division function is conserved throughout metazoan evolution. Multicellular organisms are unique however, by potently antagonizing MYC function by genetic methods. This allows differentiation into layers of cells, tissues, organs and organ systems each with specialized biological function. The evolutionary process of specialization is uniquely regulated, and arises from stem cells that acquire tissue/lineage specification signals, attaining exponential outgrowth, while systemically differentiating into various tissue precursors. Differentiation, therefore routinely restrains the exponential growth of committed tissue precursors through potent physiologic antagonization of MYC and MYC related programs. The aberrant growth and division illustrates that differentiation derangement is emblematic of cancer. Hepatocellular carcinoma (HCC) - including that histologically classified as `well-differentiated’ by light microscopy - displays lower expression of hundreds of specialized liver differentiation genes compared to non-malignant liver. Suppression of so many differentiation genes suggests disruption to the upstream core master transcription factor circuit that coordinates physiologic programs to terminate MYC function. We demonstrate how deletion/mutation of GATA4 - a master transcription factor of hepatocyte differentiation - explained differentiation impediment of HCC, while loss of function of its key co-activators (e.g., ARID1A, ARID2, SMARCA4, and SMARCAD1), appeared to be a cause in the rest. Genetic alterations in the GATA4 pathway contribute to HCC phenotype of deranged differentiation and its corollary persistent proliferation. Suppression of terminal differentiation driving genes was by epigenetic methods providing a therapeutically actionable pathway through novel p53 independent epigenetic methods. In vitro and in vivo evaluation of this approach was non-cytotoxic to normal cells but significantly impaired HCC growth.
Saunthararajah Yogen , MD (Advisor)
Scacheri Peter , PhD (Committee Chair)
Ting Angela , PhD (Committee Member)
Li Xiaoxia , PhD (Committee Member)
Khorana Alok , MD (Committee Member)
142 p.
Biochemistry; Genetics; Medicine; Molecular Biology
Hepatocellular carcinoma, GATA4, 8p deletion, Tumor Suppressor, Differentiation therapy, Liver cancer, Epigenetics, experimental therapeutics

Recommended Citations

Citations

  • Enane, F. O. (2017). HEPATOCYTE DIFFERENTIATION AND HEPATOCELLULAR CARCINOMA: RATIONALE FOR P53 INDEPENDENT THERAPY [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1491570319727552

    APA Style (7th edition)

  • Enane, Francis. HEPATOCYTE DIFFERENTIATION AND HEPATOCELLULAR CARCINOMA: RATIONALE FOR P53 INDEPENDENT THERAPY. 2017. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1491570319727552.

    MLA Style (8th edition)

  • Enane, Francis. "HEPATOCYTE DIFFERENTIATION AND HEPATOCELLULAR CARCINOMA: RATIONALE FOR P53 INDEPENDENT THERAPY." Doctoral dissertation, Case Western Reserve University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1491570319727552

    Chicago Manual of Style (17th edition)

case1491570319727552
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© 2017, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.