FNDC3B 3′-UTR shortening escapes from microRNA-mediated gene repression and promotes nasopharyngeal carcinoma progression
FNDC3B 3′-UTR shortening escapes from microRNA-mediated gene repression and promotes nasopharyngeal carcinoma progression
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DOI：
10.1111/cas.14394
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发表时间：
2020-05-19
期刊：
影响因子：
5.7
通讯作者：
Liu, Na
中科院分区：
文献类型：
--
作者：
Li, Ying-Qing;Chen, Yang;Liu, Na
选择性多聚腺苷酸化（阿帕）诱导3 '-UTR的缩短，正在成为癌症发展和进展的重要特征。然而，APA诱导鼻咽癌（NPC）3 '-UTR缩短的作用和机制仍不清楚。根据我们先前的测序研究，含有纤连蛋白III型结构域的3B（FNDC 3B）倾向于使用近端多聚腺苷酸化位点并产生较短的3 '-UTR。因此，我们发现FNDC 3B具有较短的3 '-UTR，能够逃避miRNA介导的基因抑制，并导致其在NPC中的表达增加。敲低FNDC 3B基因可抑制鼻咽癌细胞的增殖、迁移、侵袭和转移。FNDC 3B的过表达，尤其是3 '-UTR较短的FNDC 3B的过表达，促进了NPC的进展。进一步的机制研究表明，FNDC 3B能够与肌球蛋白重链9（myosin heavy chain 9，MYH 9）结合并稳定MYH 9，从而激活Wnt/beta-catenin信号通路。此外，MYH 9可逆转FNDC 3B基因敲低对NPC的抑制作用。综上所述，我们的研究结果表明FNDC 3B mRNA的3 '-UTR缩短介导了其在NPC中的过表达，并通过靶向MYH 9促进了NPC的进展。新发现的FNDC 3B-MYH 9-Wnt/β-连环蛋白轴可能代表NPC个体化治疗的潜在靶点。
Alternative polyadenylation (APA), which induces shortening of the 3 '-UTR, is emerging as an important feature in cancer development and progression. Nevertheless, the effects and mechanisms of APA-induced 3 '-UTR shortening in nasopharyngeal carcinoma (NPC) remain largely unclear. Fibronectin type III domain containing 3B (FNDC3B) tended to use proximal polyadenylation site and produce shorter 3 '-UTR according to our previous sequencing study. Herein, we found that FNDC3B with shorter 3 '-UTR could escape from miRNA-mediated gene repression, and caused its increased expression in NPC. Knocking down of FNDC3B inhibited NPC cell proliferation, migration, invasion, and metastasis in vitro and in vivo. Overexpression of FNDC3B, especially those with shorter 3 '-UTR, promoted NPC progression. Furthermore, the mechanism study revealed that FNDC3B could bind to and stabilize myosin heavy chain 9 (MYH9) to activate the Wnt/beta-catenin signaling pathway. In addition, MYH9 could reverse the inhibitory effects of FNDC3B knockdown in NPC. Altogether, our results suggested that the 3 '-UTR shortening of FNDC3B mRNA mediated its overexpression in NPC and promoted NPC progression by targeting MYH9. This newly identified FNDC3B-MYH9-Wnt/beta-catenin axis could represent potential targets for individualized treatment in NPC.