Lyle Stephen, Hoover Kathleen, Colpan Cansu, Zhu Zhiqing, Matijasevic Zdenka, Jones Stephen N
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
PLoS One. 2014 Jun 30;9(6):e100920. doi: 10.1371/journal.pone.0100920. eCollection 2014.
Dicer is required for the maturation of microRNA, and loss of Dicer and miRNA processing has been found to alter numerous biological events during embryogenesis, including the development of mammalian skin and hair. We have previously examined the role of miRNA biogenesis in mouse embryonic fibroblasts and found that deletion of Dicer induces cell senescence regulated, in part, by the p53 tumor suppressor. Although Dicer and miRNA molecules are thought to have either oncogenic or tumor suppressing roles in various types of cancer, a role for Dicer and miRNAs in skin carcinogenesis has not been established. Here we show that perinatal ablation of Dicer in the skin of mice leads to loss of fur in adult mice, increased epidermal cell proliferation and apoptosis, and the accumulation of widespread DNA damage in epidermal cells. Co-ablation of Dicer and p53 did not alter the timing or extent of fur loss, but greatly reduced survival of Dicer-skin ablated mice, as these mice developed multiple and highly aggressive skin carcinomas. Our results describe a new mouse model for spontaneous basal and squamous cell tumorigenesis. Furthermore, our findings reveal that loss of Dicer in the epidermis induces extensive DNA damage, activation of the DNA damage response and p53-dependent apoptosis, and that Dicer and p53 cooperate to suppress mammalian skin carcinogenesis.
Dicer是微小RNA成熟所必需的，并且已发现Dicer缺失和微小RNA加工过程的改变会在胚胎发育过程中改变众多生物学事件，包括哺乳动物皮肤和毛发的发育。我们之前研究了微小RNA生物合成在小鼠胚胎成纤维细胞中的作用，发现Dicer缺失会诱导细胞衰老，这部分受p53肿瘤抑制因子调控。尽管Dicer和微小RNA分子在各类癌症中被认为具有致癌或抑癌作用，但Dicer和微小RNA在皮肤癌发生中的作用尚未明确。在此我们表明，围产期在小鼠皮肤中敲除Dicer会导致成年小鼠掉毛，表皮细胞增殖和凋亡增加，以及表皮细胞中广泛的DNA损伤积累。同时敲除Dicer和p53并没有改变掉毛的时间或程度，但极大地降低了Dicer皮肤敲除小鼠的存活率，因为这些小鼠会发展出多发性且极具侵袭性的皮肤癌。我们的结果描述了一种用于自发性基底细胞和鳞状细胞肿瘤发生的新小鼠模型。此外，我们的发现揭示，表皮中Dicer缺失会诱导广泛的DNA损伤、DNA损伤反应激活和p53依赖性凋亡，并且Dicer和p53协同作用以抑制哺乳动物皮肤癌发生。
