Loss of CELF2 promotes skin tumorigenesis and increases drug resistance

Abstract

AbstractBackgroundCELF2 belongs to the CELF RNA‐binding protein family and exhibits antitumor activity in various tumor models. Analysis of the pan‐cancer TCGA database reveals that CELF2 expression strongly correlates with favorable prognosis among cancer patients. The function of CELF2 in nonmelanoma skin cancer has not been studied.MethodsWe used shRNA‐mediated knockdown (KD) of CELF2 expression in human squamous cell carcinoma (SCC) cells to investigate how CELF2 impacted SCC cell proliferation, survival, and xenograft tumor growth. We determined CELF2 expression in human SCC tissues and adjacent normal skin using immunofluorescence staining. Additionally, we investigated the changes in CELF2 and its target gene expression during UV‐induced and chemical‐induced skin tumorigenesis by western blotting.ResultsCELF2 KD significantly increased SCC cell proliferation, colony growth, and SCC xenograft tumor growth in immunodeficient mice. CELF2 KD in SCC cells led to activation of KRT80 and GDF15, which can potentially promote cell proliferation and tumor growth. While control SCC cells were sensitive to anticancer drugs such as doxorubicin, SCC cells with CELF2 KD became resistant to drug‐induced tumor growth retardation. Finally, we found CELF2 expression diminished during both UV‐ and chemical‐induced skin tumorigenesis in mice, consistent with reduced CELF2 expression in human SCC tumors compared to adjacent normal skin.ConclusionThis study shows for the first time that CELF2 loss occurs during skin tumorigenesis and increases drug resistance in SCC cells, highlighting the possibility of targeting CELF2‐regulated pathways in skin cancer prevention and therapies.