Incidence of non-melanoma skin cancer (NMSC) has been increasing since the early 90s resulting in significant disease related morbidity and mortality. Cutaneous squamous cell carcinoma (SCC), the second most common form of NMSC, has a higher rate of metastases and is more aggressive than basal cell carcinoma.
High mobility group AT hook 2 (HMGA2) is a transcription factor and has been associated with myxoid liposarcoma. Other studies have implicated this gene in adipogenesis and mesenchymal differentiation, and a gene knock out suggested a role in diet-induced obesity. HMGA2 is expressed during embryonic development but not expressed in adult tissues, re-expression has been demonstrated in breast, lung, and ovarian cancers. Previous studies have suggested a role for HMGA2 in SCC progression, however, conflicting results cloud the mechanisms.
In this study, the authors investigated the role of HMGA2 during NMSC development in response to ultra-violet irradiation (UVR).
HMGA2 was upregulated in 19 human primary SCCs compared to matched normal controls, and IHC demonstrated high expression in the tumours and no detectable expression in controls.
qPCR confirmed high expression of HMGA2 in two different SCC cell lines (SCC13 and SCC39) and transformed HaCaT cells, but low expression in adult keratinocytes and neonatal foreskin keratinocytes.
In neonatal human keratinocytes multiple UVR exposures down-regulated HMGA2 expression.
UVR also down-regulated HMGA2 expression in human SCC cells and resulted in decreased proliferation.
HMGA2 expression was then analysed in two mouse models harbouring hairless mutations that predispose mice to UVR induced skin tumorigenesis. In one model Tcrd-SKH1 mice were hairless and in the other, B6.Cg-Tyrc-2J-Hrhr/J mice had hair.
After approximately 20 weeks of UVR exposure, papilomas developed in both models. These tumours further developed into SCC in the hairless mice but not in littermates with hair.
qPCR and IHC analysis indicated that adult mice skin expressed HMGA2 at a basal level in the epidermis, unlike adult humans. HMGA2 was not detected in the follicles of haired mice.
Chronic UVR exposure resulted in elevated HMGA2 in both the epidermis and hair follicles. In the Tcrd-SKH1 model significant upregulation of HMGA2 was detected in cutaneous SCCs compared to non-tumour adjacent skin controls. The epidermis of UVR treated mice had increased thickness compared to untreated suggesting that HMGA2 increases proliferation.
Knockout of the key UV master regulators TRIP13 and FOXM1 using CRISPR/Cas9 in SCC39 cells attenuated the increased expression of HMAG2 in response to UVR.
In this study the authors investigated the role of the proto-oncogene, HMGA2 in UV-induced tumorigenesis. UVR is one of the main risk factors for skin cancer, and the role of HMGA2 is unclear. This study demonstrated higher expression of HMGA2 in SCC tumours compared to control and chronic exposure to UVR and upregulated HMGA2 in mice treated with UVR. This upregulation was observed in mice harbouring SCC tumours and mice without tumours, upregulation was also observed in hair follicles of haired mice. The authors suggest that HMAG2 is a potential biomarker for UVR-induced proliferation and further analysis in skin and hair follicles may have important clinical implications for UV exposure.
Ha, W., Hinde, A., Xie, L., Trager, M.H. and Liu, L. (2020) Biomarker function of HMGA2 in ultraviolet-induced skin cancer development. Exp Dermatol.