Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou 310022, China.
Department of Head and Neck Tumor Surgery, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, China.
Lab Invest. 2015 Dec;95(12):1398-408. doi: 10.1038/labinvest.2015.105. Epub 2015 Sep 14.
miR-21, which is a putative tumor onco-miR and frequently overexpressed microRNA in various tumors, has been linked to tumor progression through targeting of tumor-suppressor genes. In this study, we sought to determine whether miR-21 has any role on tumor progression of salivary adenoid cystic carcinoma (SACC) and the possible mechanisms. We found that the level of miR-21 expression was significantly higher in SACC than that in normal salivary tissues, and it is also higher in tumors with metastasis than that without metastasis. Using an anti-miR-21 inhibitor in an in vitro model, downregulation of miR-21 significantly decreased the capacity of invasion and migration of SACC cells, whereas a pre-miR-21 increased the capacity of invasion and migration of SACC cells. To explore the potential mechanisms by which miR-21 regulate invasion and migration, we identified one direct miR-21 target gene, programmed cell death 4 (PDCD4), which has been implicated in invasion and metastasis. The suppression of miR-21 in metastatic SACC-LM cells significantly increased the report activity of PDCD4 promoter and the expression of PDCD4 protein. This subsequently resulted in downregulation of the p-STAT3 protein. The level of miR-21 expression positively related to the expression of PDCD4 protein and negatively related to the expression of p-STAT3 protein in SACC specimens, respectively, indicating the potential role of the STAT3-miR-21-PDCD4 pathway in these tumors. Dysregulation of miR-21 has an important role in tumor growth and invasion by targeting PDCD4. Therefore, suppression of miR-21 may provide a potential approach for the treatment of advanced SACC patients.
miR-21 是一种假定的肿瘤致癌 miRNA，在各种肿瘤中频繁过表达，已被证明通过靶向肿瘤抑制基因与肿瘤进展有关。在这项研究中，我们试图确定 miR-21 是否在唾液腺腺样囊性癌（SACC）的肿瘤进展中起作用，以及可能的机制。我们发现，miR-21 的表达水平在 SACC 中明显高于正常唾液组织，在有转移的肿瘤中也高于无转移的肿瘤。在体外模型中使用抗 miR-21 抑制剂，下调 miR-21 显著降低了 SACC 细胞侵袭和迁移的能力，而 pre-miR-21 则增加了 SACC 细胞侵袭和迁移的能力。为了探讨 miR-21 调节侵袭和迁移的潜在机制，我们鉴定了一个直接的 miR-21 靶基因，程序性细胞死亡因子 4（PDCD4），它与侵袭和转移有关。在转移性 SACC-LM 细胞中抑制 miR-21 显著增加了 PDCD4 启动子的报告活性和 PDCD4 蛋白的表达。这随后导致 p-STAT3 蛋白的下调。在 SACC 标本中，miR-21 的表达水平与 PDCD4 蛋白的表达水平呈正相关，与 p-STAT3 蛋白的表达水平呈负相关，表明 STAT3-miR-21-PDCD4 通路在这些肿瘤中可能发挥作用。miR-21 的失调通过靶向 PDCD4 在肿瘤生长和侵袭中起重要作用。因此，抑制 miR-21 可能为治疗晚期 SACC 患者提供一种潜在的方法。
