Weiwen Long (Advisor), Madhavi Kadakia (Committee Member), Hongmei Ren (Committee Member)
Master of Science (MS)
Non-melanoma skin cancer (NMSC) is a group of skin cancer that includes basal cell carcinoma of the skin (BCC), squamous cell carcinoma of the skin (SCC), actinic keratoses, a precursor to SCC, and other rare cutaneous carcinomas. p63, a member of the p53 gene family, is an important regulator for epithelial tissue growth and development. ∆Np63α, a main isoform of p63, is highly expressed in NMSC and plays essential roles in NMSCs development. Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the MAPK family. It possesses a single phosphorylation site (serine 189) in its activation loop, which makes it different from the conventional MAPKs. Similar to ∆Np63α, the expression level of ERK3 is upregulated in cutaneous SCC and actinic keratoses. While ERK3 has been shown to promote invasiveness of squamous cell lung cancer, little is known about ERK3’s role in NMSCs. In addition, how ERK3 expression is upregulated in NMSCs remains largely unknown. Given that the expression levels of both ∆Np63α and ERK3 are upregulated in NMSCs, we wanted to test whether ∆Np63α, as a transcriptional factor, regulates ERK3 expression in SCCs and if ERK3 acts as a downstream mediator of ∆Np63α in controlling NMSCs cell growth and invasiveness. We showed that ∆Np63α and ERK3 are co-overexpressed and there was a positive correlation between their expression in the skin from normal humans, and patients with actinic keratosis, squamous cell carcinomas, and basal cell carcinoma. We further showed that while silencing ∆Np63α reduced ERK3 expression level in HaCaT keratinocytes and A431 squamous cell carcinoma cells, overexpression of ∆Np63α increased ERK3 expression level in H1299. Therefore, ∆Np63α positively regulates ERK3 expression. Moreover, silencing either ∆Np63α or ERK3 greatly enhanced A431 cell migration. Importantly, restoration of ERK3 expression rescued the increased cell migration observed upon silencing ∆Np63α. Knockdown of ERK3 in squamous cells does not show a significant effect on cell proliferation. This study demonstrates that ERK3 is positively regulated by ∆Np63α and mediates ∆Np63α’s roles in controlling cell migration in NMSC.
Department or Program
Department of Biochemistry and Molecular Biology
Year Degree Awarded
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