Interaction of lncRNA MIR100HG with hnRNPA2B1 facilitates m(6)A-dependent stabilization of TCF7L2 mRNA and colorectal cancer progression.
Interaction of lncRNA MIR100HG with hnRNPA2B1 facilitates m(6)A-dependent stabilization of TCF7L2 mRNA and colorectal cancer progression.
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lncRNA MIR100HG 与 hnRNPA2B1 的相互作用促进 TCF7L2 mRNA 的 m6A 依赖性稳定和结直肠癌进展
DOI：
10.1186/s12943-022-01555-3
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发表时间：
2022-03-12
期刊：
影响因子：
37.3
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Liu H;Li D;Sun L;Qin H;Fan A;Meng L;Graves-Deal R;Glass SE;Franklin JL;Liu Q;Wang J;Yeatman TJ;Guo H;Zong H;Jin S;Chen Z;Deng T;Fang Y;Li C;Karijolich J;Patton JG;Wang X;Nie Y;Fan D;Coffey RJ;Zhao X;Lu Y
上皮向间充质转化(EMT)是一个与肿瘤转移和耐药相关的过程，其中非编码RNA(NcRNAs)起着关键作用。我们先前的研究表明，miR-100和miR-125b嵌入ncRNA宿主基因MIR100HG的第三内含子，在结直肠癌(CRC)中对抗表皮生长因子受体(EGFR)单抗西妥昔单抗具有耐药性。然而，MIR100HG转录本本身是否在西妥昔单抗耐药或EMT中起作用尚不清楚。通过建立公共CRC数据库，分析了MIR100HG与EMT的相关性。体外和体内研究MIR100HG在结直肠癌EMT、转移和西妥昔单抗耐药中的生物学作用。应用RNAScope和免疫组织化学染色方法分析MIR100HG、hnRNPA2B1和TCF7L2在西妥昔单抗进展患者和转移患者结直肠癌组织中的表达情况。MIR100HG的表达与EMT标志物密切相关，是EMT的正向调节因子。MIR100HG在体内外对西妥昔单抗耐药，并促进肿瘤细胞的侵袭和转移。HnRNPA2B1被鉴定为MIR100HG的结合伙伴。在机制上，MIR100HG通过与hnRNPA2B1相互作用，维持Wnt/β-catenin信号的主要转录共激活因子TCF7L2mRNA的稳定性。在MIR100HG存在下，hnRNPA2B1识别TCF7L2mRNA的N6-甲基腺苷(M6A)位点。TCF7L2进而激活MIR100HG转录，形成前馈调控环。MIR100HG/hnRNPA2B1/TCF7L2轴在发生局部或远处转移或与西妥昔单抗耐药相关的疾病进展的结直肠癌患者的标本中增强。MIR100HG和hnRNPA2B1相互作用，通过调节TCF7L2 mRNA的稳定性来控制Wnt信号在结直肠癌中的转录活性。我们的发现证实MIR100HG是结直肠癌中一种有效的EMT诱导剂，可能通过激活MIR100HG/hnRNPA2B1/TCF7L2反馈环而导致西妥昔单抗耐药和转移。网上版载有补充材料，可在10.1186/s12943-022-01555-3查阅。
Epithelial-to-mesenchymal transition (EMT) is a process linked to metastasis and drug resistance with non-coding RNAs (ncRNAs) playing pivotal roles. We previously showed that miR-100 and miR-125b, embedded within the third intron of the ncRNA host gene MIR100HG, confer resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in colorectal cancer (CRC). However, whether the MIR100HG transcript itself has a role in cetuximab resistance or EMT is unknown. The correlation between MIR100HG and EMT was analyzed by curating public CRC data repositories. The biological roles of MIR100HG in EMT, metastasis and cetuximab resistance in CRC were determined both in vitro and in vivo. The expression patterns of MIR100HG, hnRNPA2B1 and TCF7L2 in CRC specimens from patients who progressed on cetuximab and patients with metastatic disease were analyzed by RNAscope and immunohistochemical staining. The expression of MIR100HG was strongly correlated with EMT markers and acted as a positive regulator of EMT. MIR100HG sustained cetuximab resistance and facilitated invasion and metastasis in CRC cells both in vitro and in vivo. hnRNPA2B1 was identified as a binding partner of MIR100HG. Mechanistically, MIR100HG maintained mRNA stability of TCF7L2, a major transcriptional coactivator of the Wnt/β-catenin signaling, by interacting with hnRNPA2B1. hnRNPA2B1 recognized the N6-methyladenosine (m6A) site of TCF7L2 mRNA in the presence of MIR100HG. TCF7L2, in turn, activated MIR100HG transcription, forming a feed forward regulatory loop. The MIR100HG/hnRNPA2B1/TCF7L2 axis was augmented in specimens from CRC patients who either developed local or distant metastasis or had disease progression that was associated with cetuximab resistance. MIR100HG and hnRNPA2B1 interact to control the transcriptional activity of Wnt signaling in CRC via regulation of TCF7L2 mRNA stability. Our findings identified MIR100HG as a potent EMT inducer in CRC that may contribute to cetuximab resistance and metastasis by activation of a MIR100HG/hnRNPA2B1/TCF7L2 feedback loop. The online version contains supplementary material available at 10.1186/s12943-022-01555-3.
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影响因子：
19
作者：
Bakir B;Chiarella AM;Pitarresi JR;Rustgi AK
通讯作者：
Rustgi AK
HNRNPA2B1通过ERK/蜗牛信号通路调节胰腺癌细胞中上皮 - 间质转变。
影响因子：
5.8
作者：
Dai S;Zhang J;Huang S;Lou B;Fang B;Ye T;Huang X;Chen B;Zhou M
通讯作者：
Zhou M
影响因子：
16.8
作者：
Dhir, Ashish;Dhir, Somdutta;Proudfoot, Nick J.;Jopling, Catherine L.
通讯作者：
Jopling, Catherine L.
影响因子：
4.8
作者：
Fähling, M;Mrowka, R;Thiele, BJ
通讯作者：
Thiele, BJ
影响因子：
6
作者：
Boesch M;Spizzo G;Seeber A
通讯作者：
Seeber A