Date of Award
8-1-2022
Degree Name
Master of Science
Department
Pharmacology
First Advisor
Elble, Randolph
Abstract
Human CLCA2 is a candidate tumor promoter for head and neck squamous cell carcinoma (HNSCC). HNSCC is the sixth most common cancer worldwide, with 890,000 new cases and 450,000 deaths in 2018. We observed that CLCA2 expression is upregulated in HNSCC, and HNSCC cell lines with high expression of CLCA2 and EGFR showed enhanced sensitivity to the EGFR inhibitor gefitinib, suggesting CLCA2 overexpression as a predictive marker for the response to EGFR-targeting agents in HNSCC therapy. However, the precise role of CLCA2 in HNSCC is not established. Our data demonstrate that CLCA2 expression is induced by cell detachment in TE11 HNSCC cell line, suggesting a role of CLCA2 in promoting anoikis resistance in detached HNSCC cells. Accordingly, doxycycline-induced CLCA2 knockdown reduced TE11 cell viability under detached cell culture conditions and reduced tumorsphere formation in methylcellulose 3-D cell culture. It also sensitized cells to the chemotherapeutic drugs gefitinib and cisplatin. Unexpectedly, the CLCA2 knockdown also dramatically inhibited migration of TE11 cells in vitro. Similar results were observed using the immortalized keratinocyte cell line HaCaT. Mechanistically, CLCA2 knockdown had no effect on EGFR or ERK activity in TE11 cells, in contrast to previous results in other cell lines. However, we discovered that cleavage of E-cadherin at a novel position was inhibited by knockdown of CLCA2. The cleavage produced a 50Kda cleavage product that had not been previously reported. Further studies are needed to establish how CLCA2 induces the cleavage and how E-cadherin signaling is affected. Taken together, our results introduce CLCA2 as a promising target and/or biomarker for EGFR-directed therapy in HNSCC.
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