Dysregulation of the MiR-449b target TGFBI alters the TGFβ pathway to induce cisplatin resistance in nasopharyngeal carcinoma.
Dysregulation of the MiR-449b target TGFBI alters the TGFβ pathway to induce cisplatin resistance in nasopharyngeal carcinoma.
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DOI：
10.1038/s41389-018-0050-x
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发表时间：
2018-05-22
期刊：
影响因子：
6.2
通讯作者：
Liu FF
中科院分区：
文献类型：
--
作者：
Bissey PA;Law JH;Bruce JP;Shi W;Renoult A;Chua MLK;Yip KW;Liu FF
尽管鼻咽癌（NPC）的局部控制有所改善，但远处转移（DM）和化疗耐药仍是死亡的主要原因。这项研究确定了miR-449 b的新作用，miR-449 b是NPC DM经验证的四种miRNA签名中的过表达基因，通过直接靶向转化生长因子β诱导的（TGFBI）导致化疗耐药。体外shRNA介导的TGFBI下调诱导了PTEN和AKT的磷酸化，增加了顺铂耐药性。相反，TGFBI的过表达使NPC细胞对顺铂敏感。在接受同步放化疗（CRT）治疗的NPC患者中，通过RNA测序和免疫组织化学（IHC）评估，总生存期（OS）与miR-449 b显著负相关，与TGFBI mRNA和蛋白表达直接相关。从机制上讲，免疫共沉淀证明TGFBI与pro-TGFβ1竞争整合素受体结合。TGFBI降低导致pro-TGFβ1活化和TGFβ1经典/非经典途径诱导的顺铂耐药增加。因此，miR-449 b的过表达降低了TGFBI，从而改变了TGFBI和pro-TGFβ1之间的平衡，揭示了NPC中化疗耐药的新机制。
Despite the improvement in locoregional control of nasopharyngeal carcinoma (NPC), distant metastasis (DM), and chemoresistance persist as major causes of mortality. This study identified a novel role for miR-449b, an overexpressed gene in a validated four-miRNA signature for NPC DM, leading to chemoresistance via the direct targeting of transforming growth factor beta-induced (TGFBI). In vitro shRNA-mediated downregulation of TGFBI induced phosphorylation of PTEN and AKT, increasing cisplatin resistance. Conversely, the overexpression of TGFBI sensitized the NPC cells to cisplatin. In NPC patients treated with concurrent chemoradiotherapy (CRT), the overall survival (OS) was significantly inversely correlated with miR-449b, and directly correlated with both TGFBI mRNA and protein expression, as assessed by RNA sequencing and immunohistochemistry (IHC). Mechanistically, co-immunoprecipitation demonstrated that TGFBI competes with pro-TGFβ1 for integrin receptor binding. Decreased TGFBI led to increased pro-TGFβ1 activation and TGFβ1 canonical/noncanonical pathway-induced cisplatin resistance. Thus, overexpression of miR-449b decreases TGFBI, thereby altering the balance between TGFBI and pro-TGFβ1, revealing a novel mechanism of chemoresistance in NPC.
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影响因子：
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作者：
Bruce JP;Hui AB;Shi W;Perez-Ordonez B;Weinreb I;Xu W;Haibe-Kains B;Waggott DM;Boutros PC;O'Sullivan B;Waldron J;Huang SH;Chen EX;Gilbert R;Liu FF
通讯作者：
Liu FF
DOI：
10.1002/hed.20833
发表时间：
2008-07
影响因子：
2.9
作者：
Chou, Josephine;Lin, Yu-Ching;Kim, Jae;You, Liang;Xu, Zhidong;He, Biao;Jablons, David M.
通讯作者：
Jablons, David M.
影响因子：
3.6
作者：
Chow JY;Cabral JA;Chang J;Carethers JM
通讯作者：
Carethers JM
DOI：
10.1097/00000421-200206000-00002
发表时间：
2002-06-01
影响因子：
2.6
作者：
Huncharek, M;Kupelnick, B
通讯作者：
Kupelnick, B
鼻咽癌中 flotillin-1 的上调通过激活 TGF-β 信号传导促进侵袭和转移。
影响因子：
--
作者：
Cao S;Cui Y;Xiao H;Mai M;Wang C;Xie S;Yang J;Wu S;Li J;Song L;Guo X;Lin C
通讯作者：
Lin C