The MRVI1-AS1/ATF3 signaling loop sensitizes nasopharyngeal cancer cells to paclitaxel by regulating the Hippo-TAZ pathway
The MRVI1-AS1/ATF3 signaling loop sensitizes nasopharyngeal cancer cells to paclitaxel by regulating the Hippo-TAZ pathway
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MRVI1-AS1/ATF3信号环路通过调节Hippo-TAZ通路使鼻咽癌细胞对紫杉醇敏感
作者：
Zhu Yuxing;He Dong;Bo Hao;Liu Zexian;Xiao Mengqing;Xiang Liang;Zhou Ji;a;Liu Yan;Liu Xiaoming;Gong Lian;Ma Yanni;Zhou Yanhong;Zhou Ming;Xiong Wei;Yang Fei;Xing Xiaowei;Li Ruhong;Li Wei;Cao Ke
长链非编码RNA（lncRNA）在恶性肿瘤的发生、发展及化疗耐药中起重要作用，但其影响鼻咽癌紫杉醇化疗敏感性的机制尚不清楚。在本研究中，CNE-1和HNE-2紫杉醇耐药细胞及其亲本株的lncRNA阵列显示，紫杉醇耐药株的MRVI 1-AS 1（鼠逆转录病毒整合位点1同源物反义RNA 1）表达显著低于亲本株，并且MRVI 1-AS 1在体外和体内的过表达增加紫杉醇化疗敏感性。此外，MRVI 1-AS 1通过同时抑制miR-513 a-5 p（microRNA-513 a-5 p）和miR-27 b-3 p表达水平上调ATF 3（转录激活因子3），从而增加NPC紫杉醇化疗敏感性。染色质免疫沉淀和实时荧光定量PCR结果表明，ATF 3对MRVI 1-AS 1的调节具有正反馈作用。此外，MRVI 1-AS 1和ATF 3可以形成正反馈环，促进Hippo-TAZ（tafazzin）信号通路调节因子RASSF 1（Ras association domain family member 1）的表达，从而抑制TAZ的表达。MTT（3-[4，5-dimethylthiazol-2-yl]-2，5 diphenyltetrazolium bromide）比色法和流式细胞仪检测显示，TAZ浓度降低可增加鼻咽癌细胞对紫杉醇的敏感性。总体而言，结果表明，MRVI 1-AS 1/ATF 3信号通路可以通过调节Hippo-TAZ信号通路来增加NPC紫杉醇化疗敏感性。因此，靶向环可能是一种新的NPC治疗策略。
Long non-coding RNA (lncRNA) plays an important role in malignant tumor occurrence, development, and chemoresistance, but the mechanism of how they affect nasopharyngeal cancer (NPC) paclitaxel chemosensitivity is unclear. In this study, lncRNA array of CNE-1 and HNE-2 paclitaxel-resistant cells and their parental strains revealed that the paclitaxel-resistant strains had significantly lower MRVI1-AS1 (murine retrovirus integration site 1 homolog antisense RNA 1) expression than the parental strains, and that MRVI1-AS1 overexpression in vitro and in vivo increased paclitaxel chemosensitivity. Further, MRVI1-AS1 upregulated ATF3 (activating transcription factor 3) by simultaneously inhibiting miR-513a-5p (microRNA-513a-5p) and miR-27b-3p expression levels to increase NPC paclitaxel chemosensitivity. Chromatin immunoprecipitation and quantitative real-time PCR showed that ATF3 could feed-back MRVI1-AS1 regulation positively. Furthermore, MRVI1-AS1 and ATF3 could form a positive feedback loop, which promoted the expression of RASSF1 (Ras association domain family member 1), a Hippo–TAZ (tafazzin) signaling pathway regulatory factor, thereby inhibiting TAZ expression. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) assay and flow cytometry showed that the decreased TAZ increased NPC cell paclitaxel chemosensitivity. Overall, the results indicate that the MRVI1-AS1/ATF3 signaling pathway can increase NPC paclitaxel chemosensitivity by modulating the Hippo–TAZ signaling pathway. Therefore, targeting the loop may be a new NPC treatment strategy.