# TOPK Drives IL19-Mediated Crosstalk Between Cancer Cells and Fibroblasts to Promote Solar UV-Induced Skin Damage and Carcinogenesis

## TL;DR

This study shows that the protein TOPK helps sunlight-induced skin damage and cancer by regulating IL19 and interacting with fibroblasts.

## Contribution

The study identifies TOPK as a novel driver of solar UV-induced skin carcinogenesis through IL19 signaling and fibroblast crosstalk.

## Key findings

- TOPK deletion reduces solar UV-induced skin damage and inhibits cancer growth.
- TOPK regulates IL19, which promotes cancer cell growth and activates fibroblasts.
- Targeting TOPK may offer a new strategy for preventing or treating non-melanoma skin cancer.

## Abstract

Non-melanoma skin cancer is one of the most common types of cancer, and its development is closely linked to long-term exposure to sunlight. In this study, we investigated a protein called TOPK, which becomes more active after sun exposure and may play a key role in the development of skin cancer. Using laboratory models and skin cancer cells, we found that removing TOPK reduces sunlight-induced damage and slows cancer growth. We also discovered that TOPK regulates another protein, IL19, which helps cancer cells grow and influences surrounding skin tissue. Our findings suggest that targeting TOPK could be a promising strategy to prevent or treat sun-related skin cancer. This research offers new insights into how skin cancer forms and could help guide the development of future protective strategies.

Background/Objectives: Non-melanoma skin cancer (NMSC) is among the most common cancers in the United States, with solar ultraviolet (UV) radiation being a primary etiological factor. T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase activated by solar UV, has been implicated in skin carcinogenesis. This study aimed to investigate the mechanistic role of TOPK in solar UV-induced skin damage and tumor development. Methods: RNA sequencing (RNA-seq) was performed on skin tissues from wild-type (WT) and TOPK knockout (KO) mice, with or without solar UV exposure, to identify TOPK-regulated genes and pathways. Follow-up experiments using Western blotting, immunofluorescence, and luciferase assays were conducted in vitro and in vivo. Functional assays included 3D spheroid and Transwell co-culture systems involving cutaneous squamous cell carcinoma (cSCC) and fibroblast cells. Results: TOPK deletion altered gene expression profiles and inhibited solar UV-induced activation of multiple signaling pathways, including cytokine–cytokine receptor interaction, PI3K/AKT, MAPKs, PKG, cAMP, and calcium signaling. RNA-seq and protein analyses identified interleukin-19 (IL19) as a key downstream effector suppressed by TOPK deletion. In cSCC and fibroblast cells, TOPK knockdown reduced IL19 expression and secretion. IL19 promoted cSCC growth and activated PI3K/AKT, ERK, and TOPK pathways. Additionally, chronic TGFβ exposure increased IL19 expression and activated fibroblasts, as indicated by elevated αSMA and FAPα levels. Conclusions: These findings establish TOPK as a central regulator of solar UV-induced skin carcinogenesis, partially via modulation of IL19 signaling and fibroblast activation. Targeting TOPK may offer a novel strategy for the prevention and treatment of NMSC.