Author ORCID Identifier

0000-0003-1219-1089

Date of Graduation

8-2018

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Kenneth Y. Tsai

Committee Member

Elsa E. Flores

Committee Member

Hoang Nguyen

Committee Member

Swathi Arur

Committee Member

Anil Sood

Abstract

Cutaneous squamous cell carcinoma (cuSCC) is the second most common skin cancer, for which long term UV exposure and chronic wounding are the dominant risk factors. Despite these clinically established connections, little is understood about the early molecular response of human skin to UV exposure and its connection to acute wounding and cuSCC. Thus, our goal is to find common and specific signatures driven by UV-exposure and wounding as a means of developing new approaches for treating and preventing cuSCC.

Here, we perform integrated analyses of RNA-seq and miR-seq on 3 datasets: (1) UV-unexposed and acute UV-exposed human skin, (2) public dataset on acute wound healing and (3) our previously published dataset on normal skin and cuSCC from humans. We find that biological signatures and processes regulated by acute UV exposure and wounding has profound similarity.

Through RNA-seq and miR-seq on matched normal skin and cuSCC tumors from humans and a UV-driven mouse model, as well as acute UV-exposed human skin, we were able to identify a group of miRs that change both in cuSCC development and following UV exposure. We previously reported that miR-21-5p and miR-31-5p overexpression correlates with the development of UV-induced cuSCC in human. This is also true for our analysis where we find that these miRs as well as miR-21-3p are upregulated by more than 6-fold in cuSCC (compared to normal skin) and more than 2.5-fold in UV-exposed skin (compared to unexposed skin). In addition, we identify that miR-340-5p and let-7i-5p are novel candidates that have not been previously linked to either cuSCC development or the UV response of human skin.

This suggests that these changes in miRNA-RNA are important early events that regulated by both UV-exposure and wounding which eventually can promote cuSCC initiation. Thus, our findings suggest that UV-exposed skin, wound and cuSCC share various common signatures, which can be potentially validated as chemopreventive targets for cuSCC.

Keywords

microRNA, cutaneous squamous cell carcinoma

Available for download on Friday, August 09, 2019

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