Nuclear Medicine Department, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
Oncology Department, Xiangya Hospital, Central South University, Changsha, No. 87 Xiangya Road, Changsha, Hunan, 410008, People's Republic of China.
J Exp Clin Cancer Res. 2018 Nov 21;37(1):279. doi: 10.1186/s13046-018-0950-9.
Thyroid cancer is one of the most prevalent malignancies in endocrine system. Further understanding and revealing the molecular mechanism underlying thyroid cancer are indispensable for the development of effective diagnosis and treatments. In the present study, we attempted to provide novel basis for targeted therapy for thyroid cancer from the aspect of lncRNA-miRNA-mRNA interaction.
The expression and cellular function of XIST (X-inactive specific transcript) was determined. miRNAs which may be direct targets of XIST were screened for from online GEO database and miR-34a was selected. Next, the predicted binding between XIST and miR-34a, and the dynamic effect of XIST and miR-34a on downstream MET (hepatocyte growth factor receptor)-PI3K (phosphoinositide 3-kinase)-AKT (α-serine/threonine-protein kinase) signaling was evaluated.
XIST was significantly up-regulated in thyroid cancer tissues and cell lines; XIST knockdown suppressed the cell proliferation in vivo and the tumor growth in vitro. Based on online database and online tool prediction results, miR-34a was underexpressed in thyroid cancer and might be a direct target of XIST. Herein, we confirmed the negative interaction between XIST and miR-34a; moreover, XIST knockdown could reduce the protein levels of MET, a downstream target of miR-34a, and the phosphorylation of PI3K and AKT. In thyroid cancer tissues, MET mRNA and protein levels of MET were up-regulated; MET was positively correlated with XIST while negatively correlated with miR-34a, further confirming that XIST serves as a ceRNA for miR-34a through sponging miR-34a, competing with MET for miR-34a binding, and finally modulating thyroid cancer cell proliferation and tumor growth.
In the present study, we provided novel experimental basis for targeted therapy for thyroid cancer from the aspect of lncRNA-miRNA-mRNA interaction.
甲状腺癌是内分泌系统最常见的恶性肿瘤之一。进一步了解和揭示甲状腺癌的分子机制对于开发有效的诊断和治疗方法是必不可少的。在本研究中，我们试图从 lncRNA-miRNA-mRNA 相互作用的角度为甲状腺癌的靶向治疗提供新的依据。
测定 XIST（X 染色体失活特异性转录本）的表达和细胞功能。从在线 GEO 数据库筛选可能是 XIST 的直接靶标的 miRNAs，并选择 miR-34a。接下来，评估 XIST 和 miR-34a 之间的预测结合以及 XIST 和 miR-34a 对下游 MET（肝细胞生长因子受体）-PI3K（磷酸肌醇 3-激酶）-AKT（α-丝氨酸/苏氨酸蛋白激酶）信号的动态影响。
XIST 在甲状腺癌组织和细胞系中显著上调；XIST 敲低抑制体内细胞增殖和体外肿瘤生长。基于在线数据库和在线工具预测结果，miR-34a 在甲状腺癌中表达下调，可能是 XIST 的直接靶标。在此，我们证实了 XIST 和 miR-34a 之间的负相互作用；此外，XIST 敲低可降低 MET 的蛋白水平，MET 是 miR-34a 的下游靶标，PI3K 和 AKT 的磷酸化。在甲状腺癌组织中，MET mRNA 和蛋白水平上调；MET 与 XIST 呈正相关，与 miR-34a 呈负相关，进一步证实 XIST 通过海绵 miR-34a 作为 miR-34a 的 ceRNA，与 MET 竞争 miR-34a 结合，最终调节甲状腺癌细胞增殖和肿瘤生长。
在本研究中，我们从 lncRNA-miRNA-mRNA 相互作用的角度为甲状腺癌的靶向治疗提供了新的实验依据。
