UMR 7275, Centre National de la Recherche Scientifique, Institut de Pharmacologie Moléculaire et Cellulaire, 660 route des Lucioles, F-06560 Valbonne, France.
Carcinogenesis. 2014 May;35(5):1110-20. doi: 10.1093/carcin/bgt490. Epub 2013 Dec 28.
Incidence of cutaneous squamous cell carcinomas (cSCCs) constantly increases in the Caucasian population. Developing preferentially on precancerous lesions such as actinic keratoses due to chronic sunlight exposure, cSCCs result from the malignant transformation of keratinocytes. Although a resection of the primary tumor is usually curative, a subset of aggressive cSCCs shows a high risk of recurrence and metastases. The characterization of the molecular dysfunctions involved in cSCC development should help to identify new relevant targets against these aggressive cSCCs. In that context, we have used small RNA sequencing to identify 100 microRNAs (miRNAs) whose expression was altered during chemically induced mouse skin tumorigenesis. The decreased expression of the miR-193b/365a cluster during tumor progression suggests a tumor suppressor role. Ectopic expression of these miRNAs in tumor cells indeed inhibited their proliferation, clonogenic potential and migration, which were stimulated in normal keratinocytes when these miRNAs were blocked with antisense oligonucleotides. A combination of in silico predictions and transcriptome analyses identified several target genes of interest. We validated KRAS and MAX as direct targets of miR-193b and miR-365a. Repression of these targets using siRNAs mimicked the effects of miR-193b and miR-365a, suggesting that these genes might mediate, at least in part, the tumor-suppressive action of these miRNAs.
皮肤鳞状细胞癌（cSCC）在白种人群中的发病率持续上升。由于慢性阳光暴露，cSCC 主要在癌前病变如光化性角化病上发展，是由角质形成细胞的恶性转化引起的。虽然原发性肿瘤的切除通常是治愈性的，但一部分侵袭性 cSCC 具有高复发和转移的风险。cSCC 发展中涉及的分子功能障碍的特征应该有助于确定针对这些侵袭性 cSCC 的新相关靶标。在这种情况下，我们使用小 RNA 测序来鉴定在化学诱导的小鼠皮肤肿瘤发生过程中表达改变的 100 个 microRNAs（miRNAs）。miR-193b/365a 簇在肿瘤进展过程中的表达降低表明其具有肿瘤抑制作用。这些 miRNA 在肿瘤细胞中的异位表达确实抑制了它们的增殖、克隆形成潜力和迁移，而当这些 miRNA 被反义寡核苷酸阻断时，正常角质形成细胞中的这些功能受到刺激。通过计算机预测和转录组分析的组合，确定了几个感兴趣的靶基因。我们验证了 KRAS 和 MAX 是 miR-193b 和 miR-365a 的直接靶标。使用 siRNA 抑制这些靶标模仿了 miR-193b 和 miR-365a 的作用，表明这些基因可能至少部分介导了这些 miRNA 的肿瘤抑制作用。
