Keratinocytes from Gorlin Syndrome-induced pluripotent stem cells are resistant against UV radiation
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ORIGINAL PAPER
Keratinocytes from Gorlin Syndrome‑induced pluripotent stem cells are resistant against UV radiation Nana Morita1 · Shoko Onodera2 · Yuriko Nakamura3 · Takashi Nakamura2 · Shin‑ichi Takahashi4 · Takeshi Nomura3 · Toshifumi Azuma2 Received: 1 June 2020 / Accepted: 28 July 2020 © The Japanese Society for Clinical Molecular Morphology 2020
Abstract 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 as 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. Keywords iPS cells · Gorlin syndrome · Keratinocytes · BCC · Apoptosis
Introduction Gorlin syndrome (GS), also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome, was first reported by Gorlin and Goltz in 1960 [1]. This syndrome is an autosomal dominant disorder characterized by a variety of developmental disorders and neoplasia. Despite variations * Toshifumi Azuma [email protected] 1
Department of Oral Medicine and Hospital Dentistry, Tokyo Dental College, 5‑11‑13, Sugano, Ichikawa, Chiba 272‑8513, Japan
2
Department of Biochemistry, Tokyo Dental College, 2‑9‑18, Kanda‑Misaki‑chou, Chiyoda, Tokyo 101‑0061, Japan
3
Department of Oral Oncology, Oral and Maxillofacial Surgery, Tokyo Dental College, 5‑11‑13, Sugano, Ichikawa, Chiba 272‑8513, Japan
4
Department of Dermatology, Tokyo Dental College Ichikawa General Hospital, 5‑11‑13, Sugano, Ichikawa, Chiba 272‑8513, Japan
between races, prevalence is estimated at 1:31,000 to 1:256,000 [2–5]. GS is most commonly caused by a genetic mutation in the gene patched 1 (PTCH1)—a suppressor of the hedgehog (Hh) pathway [5–9]. Other mutations found in PTCH2 or SUFU negative regulator of hedgehog signaling (SUFU) genes are also considered to be causative for GS [10, 11], although they are rare. Recently we observed and reported that GS patients have multiple mutations
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