METTL14-dependent maturation of pri-miR-17 regulates mitochondrial homeostasis and induces chemoresistance in colorectal cancer.
METTL14-dependent maturation of pri-miR-17 regulates mitochondrial homeostasis and induces chemoresistance in colorectal cancer.
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依赖于METTL14的Pri-miR-17成熟调控线粒体稳态并诱导结直肠癌化疗耐药。
DOI：
10.1038/s41419-023-05670-x
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发表时间：
2023-02-21
影响因子：
9
通讯作者：
Zhang, Yue
中科院分区：
文献类型：
--
作者：
Sun, Kangyue;Chen, Lu;Li, Yiwen;Huang, Bing;Yan, Qun;Wu, Changjie;Lai, Qiuhua;Fang, Yuxin;Cai, Jianqun;Liu, Yongfeng;Chen, Junsheng;Wang, Xinke;Zhu, Yuxuan;Dong, Shuyu;Tan, Jieyu;Li, Aimin;Liu, Side;Zhang, Yue
miR-17- 5 p参与结直肠癌的增殖和转移，而N6-甲基腺苷（m6 A）修饰是真核生物中最常见的RNA修饰。然而，miR-17- 5 p是否通过m6 A修饰促进CRC的化疗敏感性尚不清楚。在本研究中，我们发现miR-17- 5 p的过表达在体外和体内均导致细胞凋亡减少和5-氟尿嘧啶（5-FU）治疗的药物敏感性降低，表明miR-17- 5 p导致5-FU化疗耐药。生物信息学分析表明，miR-17- 5 p介导的化疗耐药性与线粒体稳态有关。miR-17- 5 p直接与线粒体融合蛋白2（MFN 2）的3'非翻译区结合，导致线粒体融合减少和线粒体分裂和线粒体自噬增强。同时，甲基转移酶样蛋白14（methyltransferase-like protein 14，简称L14）在结直肠癌中表达下调，导致m6 A水平降低。此外，低水平的胃L14促进了pri-miR-17和miR-17- 5 p的表达。进一步的实验表明，由胃L14引发的m6 A mRNA甲基化通过减少YTHDC 2对“GGACC”结合位点的识别来抑制pri-miR-17 mRNA的衰减。胃癌L14/miR-17- 5 p/MFN 2信号轴可能在CRC的5-FU化疗耐药中起关键作用。
miR-17-5p has been found to be involved in the proliferation and metastasis of colorectal cancer (CRC), and N6-methyladenosine (m6A) modification is the most common RNA modification in eukaryotes. However, whether miR-17-5p contributes to chemotherapy sensitivity in CRC via m6A modification is unclear. In this study, we found that overexpression of miR-17-5p led to less apoptosis and lower drug sensitivity in vitro and in vivo under the 5-fluorouracil (5-FU) treatment, which indicated miR-17-5p led to 5-FU chemotherapy resistance. Bioinformatic analysis suggested that miR-17-5p-mediated chemoresistance was associated with mitochondrial homeostasis. miR-17-5p directly bound to the 3’ untranslated region of Mitofusin 2 (MFN2), leading to decreased mitochondrial fusion and enhanced mitochondrial fission and mitophagy. Meanwhile, methyltransferase-like protein 14 (METTL14) was downregulated in CRC, resulting in lower m6A level. Moreover, the low level of METTL14 promoted the expression of pri-miR-17 and miR-17-5p. Further experiments suggested that m6A mRNA methylation initiated by METTL14 inhibits pri-miR-17 mRNA decay via reducing the recognition of YTHDC2 to the “GGACC” binding site. The METTL14/miR-17-5p/MFN2 signaling axis may play a critical role in 5-FU chemoresistance in CRC.
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DOI：
10.1016/j.jcmgh.2021.12.011
发表时间：
2022
影响因子：
7.2
作者：
Luo M;Huang Z;Yang X;Chen Y;Jiang J;Zhang L;Zhou L;Qin S;Jin P;Fu S;Peng L;Li B;Fang Y;Pu W;Gong Y;Liu Y;Ren Z;Liu QL;Wang C;Xiao F;He D;Zhang H;Li C;Xu H;Dai L;Peng Y;Zhou ZG;Huang C;Chen HN
通讯作者：
Chen HN
影响因子：
48
作者：
Molinie B;Wang J;Lim KS;Hillebrand R;Lu ZX;Van Wittenberghe N;Howard BD;Daneshvar K;Mullen AC;Dedon P;Xing Y;Giallourakis CC
通讯作者：
Giallourakis CC
重楼皂素 II 通过调节线粒体裂变和 NF-κB 通路抑制结直肠癌发生
影响因子：
9.3
作者：
Chen M;Ye K;Zhang B;Xin Q;Li P;Kong AN;Wen X;Yang J
通讯作者：
Yang J
影响因子：
37.3
作者：
Chen, Xiaoxiang;Xu, Mu;Wang, Shukui
通讯作者：
Wang, Shukui
DOI：
10.1073/pnas.1321114111
发表时间：
2014-04-29
影响因子：
11.1
作者：
Kim, Seong-Jun;Syed, Gulam H.;Siddiqui, Aleem
通讯作者：
Siddiqui, Aleem