Keratinocytes from Gorlin Syndrome-induced pluripotent stem cells are resistant against UV radiation

• Published in: Medical molecular morphology Vol. 54; no. 2; pp. 69 - 78
• Main Authors: Morita, Nana, Onodera, Shoko, Nakamura, Yuriko, Nakamura, Takashi, Takahashi, Shin-ichi, Nomura, Takeshi, Azuma, Toshifumi
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.06.2021; Springer Nature B.V
• Subjects: Anatomy; Apoptosis; Asians; Autosomal dominant inheritance; Basal cell carcinoma; Basal Cell Nevus Syndrome - genetics; Basal Cell Nevus Syndrome - metabolism; Basal Cell Nevus Syndrome - physiopathology; BRCA1 protein; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; Calcification; Carcinoma; Carcinoma, Basal Cell; Cell Cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Deoxyribonucleic acid; DNA; DNA damage; DNA Repair; Gadd45A protein; Gene Expression Regulation; Genetic disorders; Genotoxicity; Gorlin syndrome; Hedgehog Proteins - metabolism; Hereditary diseases; Humans; Induced Pluripotent Stem Cells; Keratinocytes; Keratinocytes - metabolism; Keratinocytes - physiology; Keratinocytes - radiation effects; Kinases; Medicine; Medicine & Public Health; Molecular Medicine; Mutation; Original Paper; p53 Protein; Patched protein; Patched-1 Receptor - genetics; Pathology; Pluripotency; Senescence; Signal Transduction; Smoothened Receptor - genetics; Stem cells; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ultraviolet radiation; Ultraviolet Rays; Keratinocytes; BCC; Gorlin syndrome; iPS cells; Apoptosis
• ISSN: 1860-1480; 1860-1499
• DOI: 10.1007/s00795-020-00264-4

Gorlin syndrome (GS) is an autosomal dominant genetic disorder involving Patched 1 ( PTCH1 ) mutations. The PTCH1 is a receptor as well as an inhibitor of hedgehog (Hh) to sequester downstream Hh pathway molecules called Smoothened (SMO). PTCH1 mutations causes a variety of GS conditions including falx calcification, odontogenic keratocytes and basal cell carcinomas (BCC). Because PTCH1 is a major driver gene of sporadic BCC, GS patients are characteristically prone to BCC. In order to elucidate the pathological mechanism of BCC-prone GS patients, we investigated keratinocytes derived from GS patient specific iPS cells (G-OFiPSCs) which were generated and reported previously. We found that keratinocytes derived from G-OFiPSCs (GKCs) have increased expression of Hh target molecules. GKCs were irradiated and those cells showed high resistance to UV induced apoptosis. BCL2 , known as anti-apoptotic molecule as well as Hh target, significantly increased in GKCs. Several molecules involved in DNA repair, cell cycle control, senescence, and genotoxic stress such a s TP53, BRCA1 and GADD45A increased only in GKCs. GKCs are indicated to be resistant to UV irradiation by upregulating molecules which control DNA repair and genotoxic even under DNA damage caused by UV. The anti-apoptotic properties of GKCs may contribute BCC.