Date of Award

2017

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

College

College of Graduate Studies

First Advisor

Philip H. Howe

Second Advisor

Steven L. Carroll

Third Advisor

J. Alan Diehl

Fourth Advisor

Robert M. Gemmill

Fifth Advisor

Shaun K. Olsen

Abstract

Interleukin like EMT-Inducer (ILEI, FAM3C) is a secreted factor that contributes to the epithelial-to-mesenchymal transition (EMT), a cell biological process that confers metastatic properties to a tumor cell. Initially, we found that ILEI mRNA is highly expressed in melanoma metastases but not in primary tumors, suggesting that ILEI contributes to the malignant properties of melanoma. While melanoma is not an epithelial cell-derived tumor and does not undergo a traditional EMT, melanoma undergoes a similar process known as phenotype switching in which high MITF (micropthalmia-related transcription factor) expressing proliferative cells (MITF-high) switch to a low expressing invasive state (MITF-low). We observed that MITF-high proliferative cells express low levels of ILEI (ILEI-low) and MITF-low invasive cells express high levels of ILEI (ILEI-high). Next, we used in vitro and in vivo assays to show that knockdown of ILEI attenuates invasive potential but does not affect MITF expression or chemoresistance. We used gene expression analysis to show that ILEI regulates several genes involved in the MITF-low invasive phenotype including JARID1B (KDM5B), HIF-2 (EPAS1), and BDNF. Gene set enrichment analysis suggested that ILEI-regulated genes are enriched for JUN signaling, a known regulator of the MITF-low invasive phenotype. Additionally, we found that inducing phenotype switching towards the MITF-low invasive state increases ILEI mRNA expression, whereas phenotype switching towards the MITF-high proliferative state decreases ILEI mRNA expression. Mechanistically, we found that the transcription factor upstream stimulatory factor 1 (USF1) regulates FAM3C transcription. In conclusion, we demonstrate that phenotype switching regulates ILEI expression through USF1, and that ILEI in turn regulates the invasive potential of MITF-low melanoma cells.

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