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Targeting Androgen Receptor Signaling in Hepatocellular Carcinoma

Dauki, Anees Milud
http://orcid.org/0000-0003-2963-7884
http://rave.ohiolink.edu/etdc/view?acc_num=osu1573936027180432

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in males worldwide. Globally, approximately 80% of HCC cases are caused by chronic viral hepatitis, hepatitis B virus (HBV) and hepatitis C virus (HCV). In addition, preclinical and clinical studies have shown sexual dimorphism in HCC whereby males are at least 2 to 4-fold more likely to develop HCC. Consequently, androgens and the androgen receptor (AR) have been implicated in HCC. The AR is a nuclear hormone receptor and transcription factor that upon binding its ligand, translocates into the nucleus resulting in downstream target gene modulation. AR also acts an oncogene in prostate cancer (PCa) where it supports prostate cell growth and survival. While AR signaling in HCC has been described by multiple groups, two major clinical trials have failed to demonstrate efficacy of traditional antiandrogen therapy in advanced HCC patients. However, the precise mechanism of AR resistance to antiandrogen therapy in HCC is poorly understood, thus limiting our ability to effectively target this protein as part of an anti-HCC treatment regimen. Hepatocarcinogenesis is a complex process involving both genetic instability and epigenetic abnormalities making the design of effective targeted therapies a challenging task. Considering the limited efficacy of available systemic anti-HCC therapies, there is urgent need for improved therapeutic strategies. Using primary HCC samples and cell lines, it was shown showed that C-terminal truncated splice variants of AR are expressed at the transcript and protein levels, localized mainly in the nucleus and demonstrate ligand-independent constitutive transcriptional activity. Differential gene expression and gene set enrichment analyses between AR-positive and AR-negative HCC cell lines from the Cancer Cell Line Encyclopedia (CCLE) revealed over representation of transcripts critical to epithelial-mesenchymal transition (EMT) in AR-positive cell lines relative to AR-negative cell lines suggesting a putative role for AR in migration and invasion in these HCC cells. Moreover, correlation analysis of gene expression in HCC patient cohorts showed a positive correlation between AR and SNAI2 expression. These findings support the role of AR in promoting hepatocellular carcinoma migration and invasion via well-characterized EMT effector proteins and implicates ligand-independent AR signaling in HCC progression, supporting the continued evaluation of AR-targeted therapy in AR-positive hepatocellular carcinoma. While the role of the androgen receptor in hepatocarcinogenesis is largely recognized, additional work is needed to elucidate the molecular basis of AR resistance to conventional antiandrogens in advanced HCC. Furthermore, novel selective androgen receptor degraders may offer potential advantages over traditional antiandrogen therapy as novel therapy for advanced HCC.
Christopher Coss (Advisor)
Phelps Mitch (Committee Chair)
Sparreboom Alex (Committee Member)
Yalowich Jack (Committee Member)
183 p.
Pharmaceuticals

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Citations

  • Dauki, A. M. (2019). Targeting Androgen Receptor Signaling in Hepatocellular Carcinoma [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1573936027180432

    APA Style (7th edition)

  • Dauki, Anees. Targeting Androgen Receptor Signaling in Hepatocellular Carcinoma. 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1573936027180432.

    MLA Style (8th edition)

  • Dauki, Anees. "Targeting Androgen Receptor Signaling in Hepatocellular Carcinoma." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1573936027180432

    Chicago Manual of Style (17th edition)

osu1573936027180432
181
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This open access ETD is published by The Ohio State University and OhioLINK.