1] Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China [2] Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China.
Oncogene. 2014 Jan 23;33(4):514-24. doi: 10.1038/onc.2012.598. Epub 2013 Jan 21.
Previous studies have demonstrated that microRNA (miRNA) expression is altered in human cancer. However, the molecular mechanism underlying these changes in miRNA expression remains unclear. In this study, we investigated the epigenetic modification of miR-124 genes and the potential function of miR-124 in pancreatic cancer. Using pyrosequencing analysis, we found that miR-124 genes (including miR-124-1, miR-124-2 and miR-124-3) are highly methylated in pancreatic cancer tissues compared with in non-cancerous tissues. Hypermethylation mediated the silencing of miR-124, which was a frequent event in pancreatic duct adenocarcinoma (PDAC). Furthermore, miR-124 downregulation was significantly associated with worse survival of PDAC patients. Functional studies showed that miR-124 inhibited cell proliferation, invasion and metastasis. Furthermore, we characterized Rac1 as a direct target of miR-124, and miR-124 interacted with the 3'-untranslated region of Rac1, which we showed to be a putative tumor promoter in pancreatic cancer. Thus, the miR-124-mediated downregulation of Rac1 led to the inactivation of the MKK4-JNK-c-Jun pathway. Therefore, our study demonstrates that miR-124 is a tumor suppressor miRNA that is epigenetically silenced in pancreatic cancer. Our findings suggest a previously unidentified molecular mechanism involved in the progression and metastasis of pancreatic cancer.
先前的研究表明，microRNA（miRNA）在人类癌症中的表达发生改变。然而，miRNA 表达变化的分子机制仍不清楚。在这项研究中，我们研究了 miR-124 基因的表观遗传修饰及其在胰腺癌中的潜在功能。通过焦磷酸测序分析，我们发现与非癌组织相比，胰腺癌组织中 miR-124 基因（包括 miR-124-1、miR-124-2 和 miR-124-3）高度甲基化。高甲基化介导了 miR-124 的沉默，这是胰腺导管腺癌（PDAC）中常见的事件。此外，miR-124 的下调与 PDAC 患者的生存率降低显著相关。功能研究表明，miR-124 抑制细胞增殖、侵袭和转移。此外，我们将 Rac1 鉴定为 miR-124 的直接靶标，并且 miR-124 与 Rac1 的 3'-非翻译区相互作用，我们发现 Rac1 是胰腺癌中的潜在肿瘤促进因子。因此，miR-124 介导的 Rac1 下调导致 MKK4-JNK-c-Jun 通路失活。因此，我们的研究表明，miR-124 是一种肿瘤抑制 miRNA，在胰腺癌中被表观遗传沉默。我们的研究结果表明，miR-124 在胰腺癌的进展和转移中涉及一个以前未被识别的分子机制。
