Keratinocytes from Gorlin Syndrome-induced pluripotent stem cells are resistant against UV radiation
Keratinocytes from Gorlin Syndrome-induced pluripotent stem cells are resistant against UV radiation
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来自戈林综合征诱导的多能干细胞的角质形成细胞对紫外线辐射具有抵抗力
DOI：
10.1007/s00795-020-00264-4
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发表时间：
2020
影响因子：
1.8
通讯作者：
Azuma Toshifumi
中科院分区：
文献类型：
--
作者：
Morita Nana;Onodera Shoko;Nakamura Yuriko;Nakamura Takashi;Takahashi Shin-ichi;Nomura Takeshi;Azuma Toshifumi
Gorlin综合征（GS）是一种涉及Patched 1（PTCH 1）突变的常染色体显性遗传病。PTCH 1是hedgehog（Hh）的一种受体和抑制剂，可抑制Hh通路下游的Smoothened（SMO）分子，PTCH 1突变可导致多种GS疾病，包括镰状钙化、牙源性角化细胞和基底细胞癌（BCC）。由于PTCH 1是散发性BCC的主要驱动基因，GS患者具有BCC的特征性倾向。为了阐明BCC易感性GS患者的病理机制，我们研究了衍生自先前产生和报道的GS患者特异性iPS细胞（G-OFiPSC）的角质形成细胞。我们发现来源于G-OFiPSC（GKC）的角质形成细胞具有增加的Hh靶分子表达。照射后GKC对紫外线诱导的细胞凋亡有较强的抵抗力，抗凋亡分子BCL 2的表达明显增加。一些参与DNA修复、细胞周期调控、衰老和遗传毒性应激的分子如TP 53、BRCA 1和GADD 45 A仅在GKC中增加。GKC通过上调控制DNA修复的分子而被指示抵抗UV照射，并且即使在UV引起的DNA损伤下也具有遗传毒性。GKC的抗凋亡特性可能有助于BCC。
Gorlin syndrome (GS) is an autosomal dominant genetic disorder involvingPatched 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).PTCH1mutations causes a variety of GS conditions including falx calcification, odontogenic keratocytes and basal cell carcinomas (BCC). BecausePTCH1is 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, BRCA1andGADD45Aincreased 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.