Abstract
Cutaneous squamous cell carcinoma (cSCC) is prevalent in the world, accounting for a huge part of non-melanoma skin cancer. Most cSCCs are associated with a distinct pre-cancerous lesion, the actinic keratosis (AK). However, the progression trajectory from normal skin to AK and cSCC has not been fully demonstrated yet. To identify genes involved in this progression trajectory and possible therapeutic targets for cSCC, here we constructed a UV-induced cSCC mouse model covering the progression from normal skin to AK to cSCC, which mimicked the solar UV radiation perfectly using the solar-like ratio of UVA and UVB, firstly. Then, transcriptome analysis and a series of bioinformatics analyses and cell experiments proved that Rorα is a key transcript factor during cSCC progression. Rorα could downregulate the expressions of S100a9 and Sprr2f in cSCC cells, which can inhibit the proliferation and migration in cSCC cells, but not the normal keratinocyte. Finally, further animal experiments confirmed the inhibitory effect of cSCC growth by Rorα in vivo. Our findings showed that Rorα would serve as a potential novel target for cSCC, which will facilitate the treatment of cSCC in the future.
Highlights
Cutaneous squamous cell carcinoma is the second most common non-melanoma skin cancer with 1.8 million incidences in a global context in 20171
Eight SHK-1 Hairless mice were used for the present study, among which four mice were in the ultraviolet free (UVF) group and four were in the ultraviolet radiation (UVR) group (Fig. 1a)
After mice developed into Cutaneous squamous cell carcinoma (cSCC), cSCC tumor samples and matched normal skin (NS) and actinic keratosis (AK) (grade 1 (AK1) and grade 2 (AK2)) samples were isolated from the UVR group (Fig. 1a)
Summary
Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer with 1.8 million incidences in a global context in 20171. The progressions of cSCC from normal skin (NS) are determined by genetic susceptibility and environment risk factors including ultraviolet radiation, carcinogenic chemicals, and immunosuppressive drugs[2]. CSCC is characterized by a relatively low risk of metastasis and with long-term survival after treatment, there were still. Fourteen susceptive loci and 13 candidate genes including DEF8, IRF4, MC1R, etc. Associated with high cSCC risk were identified by genome-wide association studies in different populations[8,9,10]. Except for the susceptive genes, high aberrated genes were investigated in cSCC patients by whole-exome sequencing technology. The expression profile of cSCC has been quantified by either gene expression chips or RNA-sequencing (RNA-seq) technology, and a large number of differentially expressed
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