Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
PLoS One. 2011;6(6):e20494. doi: 10.1371/journal.pone.0020494. Epub 2011 Jun 17.
MicroRNAs (miRNAs) are small non-coding RNAs (18-24 nucleotides) that have recently been shown to regulate gene expression during cancer progression. Dicer, a central enzyme in the multi-component miRNA biogenesis pathway, is involved in cutting precursor miRNAs to functionally mature forms. Emerging evidence shows that Dicer expression is deregulated in some human malignancies and it correlates with tumor progression, yet this role has not yet been investigated in skin cancers.
Using an anti-human monoclonal antibody against Dicer and immunohistochemistry, we compared the expression of Dicer protein among 404 clinically annotated controls and skin tumors consisting of melanocytic nevi (n = 71), a variety of melanomas (n = 223), carcinomas (n = 73) and sarcomas (n = 12). Results showed a cell-specific up-regulated Dicer in 81% of cutaneous, 80% of acrolentiginous and 96% of metastatic melanoma specimens compared to carcinoma or sarcoma specimens (P<0.0001). The expression of Dicer was significantly higher in melanomas compared to benign melanocytic nevi (P<0.0001). In patients with cutaneous melanomas, Dicer up-regulation was found to be significantly associated with an increased tumor mitotic index (P = 0.04), Breslow's depth of invasion (P = 0.03), nodal metastasis (P = 0.04) and a higher American Joint Committee on Caner (AJCC) clinical stage (P = 0.009). Using western blot analysis, we confirmed the cell-specific up-regulation of Dicer protein in vitro. A pooled-analysis on mRNA profiling in cutaneous tumors showed up-regulation of Dicer at the RNA level in cutaneous melanoma, also showing deregulation of other enzymes that participate in the biogenesis and maturation of canonical miRNAs.
Increased Dicer expression may be a clinically useful biomarker for patients with cutaneous melanoma. Understanding deregulation of Dicer and its influence on miRNA maturation is needed to predict the susceptibility of melanoma patients to miRNA-based therapy in the future.
微小 RNA（miRNA）是一类小型非编码 RNA（18-24 个核苷酸），最近研究表明其在癌症进展过程中调节基因表达。Dicer 是多组分 miRNA 生物发生途径中的核心酶，参与将前体 miRNA 切割成具有功能的成熟形式。新出现的证据表明，Dicer 的表达在一些人类恶性肿瘤中失调，并且与肿瘤进展相关，但这一作用尚未在皮肤癌中进行研究。
我们使用针对人 Dicer 的单克隆抗体和免疫组织化学方法，比较了 404 例临床注释对照和皮肤肿瘤中 Dicer 蛋白的表达，这些肿瘤包括黑素细胞痣（n=71）、多种黑色素瘤（n=223）、癌（n=73）和肉瘤（n=12）。结果显示，与癌或肉瘤标本相比，皮肤、肢端雀斑样和转移性黑色素瘤标本中 81%、80%和 96%的细胞特异性上调了 Dicer（P<0.0001）。与良性黑素细胞痣相比，黑色素瘤中 Dicer 的表达明显升高（P<0.0001）。在患有皮肤黑色素瘤的患者中，Dicer 的上调与肿瘤有丝分裂指数增加（P=0.04）、Breslow 浸润深度（P=0.03）、淋巴结转移（P=0.04）和更高的美国癌症联合委员会（AJCC）临床分期（P=0.009）显著相关。通过 Western blot 分析，我们在体外证实了 Dicer 蛋白的细胞特异性上调。对皮肤肿瘤的 mRNA 谱进行的汇总分析显示，皮肤黑色素瘤中 Dicer 的 RNA 水平上调，同时也显示了参与经典 miRNA 生物发生和成熟的其他酶的失调。
Dicer 表达增加可能是皮肤黑色素瘤患者的一种有临床意义的生物标志物。了解 Dicer 的失调及其对 miRNA 成熟的影响，对于预测黑色素瘤患者对 miRNA 为基础的治疗的敏感性是必要的。
