155 A biomarker function of HMGA2 in cutaneous squamous cell carcinoma development

Abstract

The high mobility group AT-hook 2 (HMGA2) gene encodes a transcription factor that is expressed during embryonic development but down-regulated in adult tissues. Re-expression of HMGA2 in adult tissues is often associated with both benign and malignant tumor formation. HMGA2 has been identified as a biomarker of melanoma progression and prognosis, but its role in non-melanoma skin cancer development remains controversial. In this study, we measured HMGA2 expression in normal human keratinocytes and found a significant decrease in HMGA2 mRNA expression in adult keratinocytes compared to neonatal keratinocytes. HMGA2 is highly expressed in human cutaneous squamous cell carcinoma (SCC) cell lines and primary human SCC tumors, but not detected in adjacent normal skin. In mouse skin, Hmga2 has been found to be translocated from the cell membrane into the nucleus during DMBA/TPA-induced skin tumorigenesis. While Hmga2 expression is absent in the hair follicle in non-UV-irradiated mouse, UV irradiation increased Hmga2 expression in both the epidermis and hair follicles. In agreement, we found enhanced Hmga2 expression in UV-induced mouse skin SCCs and also Hmga2 reactivation in the dermis from UV-irradiated mice. Furthermore, oncogene depletion such as FOXM1 and TRIP13 in human SCC cell lines using CRISPR/Cas9 decreased the expression of HMGA2 coupled with decreased cell proliferation and survival. Taken together, these results demonstrate that the upregulation of HMGA2 is an important biomarker of skin SCC tumorigenesis. Moreover, understanding of the mechanism for HMGA2 overexpression in skin hair follicle cells can develop the new drug for skin cancer treatment.