MicroRNA-29c-5p suppresses gallbladder carcinoma progression by directly targeting CPEB4 and inhibiting the MAPK pathway.
MicroRNA-29c-5p suppresses gallbladder carcinoma progression by directly targeting CPEB4 and inhibiting the MAPK pathway.
复制标题
MicroRNA-29c-5p通过直接靶向CPEB4并抑制MAPK通路抑制胆囊癌进展
DOI：
10.1038/cdd.2016.146
复制
发表时间：
2017-03
影响因子：
12.4
通讯作者：
Liu YB
中科院分区：
文献类型：
--
作者：
Shu YJ;Bao RF;Jiang L;Wang Z;Wang XA;Zhang F;Liang HB;Li HF;Ye YY;Xiang SS;Weng H;Wu XS;Li ML;Hu YP;Lu W;Zhang YJ;Zhu J;Dong P;Liu YB
胆囊癌（GBC）是世界范围内癌症相关死亡的主要原因，其预后仍然很差，5年生存率约为5%。鉴于microRNAs（miRNAs）在肿瘤转移中的重要作用，我们旨在分析转移相关miRNAs miR-29 c-5 p在GBC中的表达和功能。我们验证了miR-29 c-5 p在GBC中的表达显著下调，并且与40例临床随访的GBC患者的淋巴结转移、总生存期和无病生存期密切相关。miR-29 c-5 p的异位过表达在体外显著抑制增殖、转移和集落形成并诱导凋亡，并且通过MAPK途径抑制体内致瘤性。细胞质多聚腺苷酸化元件结合蛋白4（CPEB 4）被鉴定为miR-29 c-5 p的关键效应靶点。增强miR-29 c-5 p的表达可显著抑制CPEB 4的表达，恢复CPEB 4的表达可逆转miR-29 c-5 p对GBC细胞增殖和转移的抑制作用。转化生长因子-β（TGF-β）通过下调miR-29 c-5 p上调CPEB 4，导致MAPK通路活化。结论：TGF-β/miR-29 c-5 p/CPEB 4轴在GBC的发病机制和不良预后中具有关键作用，提示miR-29 c-5 p是一种肿瘤抑制性miRNA，可能作为GBC潜在的预后生物标志物或治疗靶点。
Gallbladder cancer (GBC) is a leading cause of cancer-related deaths worldwide, and its prognosis remains poor, with a 5-year survival rate of~ 5%. Given the crucial role of microRNAs (miRNAs) in cancer metastasis, we aimed to analyze the expression and function of the metastasis-associated miRNA miR-29c-5p in GBC. We validated that expression of miR-29c-5p was significantly downregulated in GBC and was closely associated with lymph node metastasis, overall survival and disease-free survival in 40 GBC patients who were followed clinically. Ectopic overexpression of miR-29c-5p dramatically repressed proliferation, metastasis, and colony formation and induced apoptosis in vitro, and it suppressed tumorigenicity in vivo through the MAPK pathway. Cytoplasmic polyadenylation element binding protein 4 (CPEB4) was identified as a critical effector target of miR-29c-5p. Enforced expression of miR-29c-5p significantly inhibited the expression of CPEB4, and restoration of CPEB4 expression reversed the inhibitory effects of miR-29c-5p on GBC cell proliferation and metastasis. Transforming growth factor-β (TGF-β) upregulated CPEB4 by downregulating miR-29c-5p, leading to MAPK pathway activation. In conclusion, the TGF-β/miR-29c-5p/CPEB4 axis has a pivotal role in the pathogenesis and poor prognosis of GBC, suggesting that miR-29c-5p is a tumor-suppressive miRNA that may serve as potential prognostic biomarker or therapeutic target for GBC.