Expression of GLTSCR2/Pict-1 in squamous cell carcinomas of the skin.
The most important cause of cutaneous squamous cell carcinomas (SCC) is DNA damage induced by exposure to solar UV irradiation. DNA damage induced by UV irradiation is sensed by early DNA damage response (DDR) proteins. Recently, GLTSCR2 has been suggested to play a role in UV light-induced DDR. To explore the role of GLTSCR2 in the development of cutaneous SCC, we investigated the molecular mechanism underlying GLTSCR2 inactivation in response to UV irradiation. We analyzed cutaneous SCC (n=42), basal cell carcinomas (BCC; n=26), and normal skin tissue samples (n=36) and compared GLTSCR2 expression between tumor and normal tissues, using immunohistochemistry. Next, to investigate the effects of UV irradiation on GLTSCR2, we performed immunocytochemistry, RT-PCR, immunoblotting, half-life assay for GLTSCR2, and comet assay after UV irradiation in primary keratinocytes. GLTSCR2 expression in SCC was significantly lower than that of normal skin tissue (p<0.05), but not different between BCC and normal skin. In cultured primary keratinocytes, GLTSCR2 expression was decreased and translocated after UV irradiation. UV irradiation accelerated degradation of GLTSCR2 through proteasomal pathway. Knockdown of GLTSCR2 resulted in marked decrease in γH2AX foci after UV exposure. Furthermore, comet assay showed that DNA damage after UV exposure persists longer in GLTSCR2 knocked-down cells. Our data show that GLTSCR2 is downregulated in SCC of the skin and that UV light exposure decreases the stability of GLTSCR2 and sensitizes keratinocytes to DNA damage. Therefore, our data suggest that GLTSCR2 might be involved in the development and/or progression of SCC of the skin.
Department of Pathology, School of Medicine, Kyung Hee University, Seoul, 130-701, Korea.
Jee-Youn
JY
Kim
Young-Eun
YE
Cho
Jae-Hoon
JH
Park
Sun
S
Lee
D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002478:Cells, Cultured; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000528:radiation effects; D034622:RNA Interference; D034741:RNA, Small Interfering; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects*
C468783:H2AX protein, human; D006657:Histones; C500712:NOP53 protein, human; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins