m(6) A modification of lncRNA PCAT6 promotes bone metastasis in prostate cancer through IGF2BP2-mediated IGF1R mRNA stabilization.
m(6) A modification of lncRNA PCAT6 promotes bone metastasis in prostate cancer through IGF2BP2-mediated IGF1R mRNA stabilization.
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lncRNA PCAT6的m6A修饰通过IGF2BP2介导的IGF1R mRNA稳定促进前列腺癌骨转移
DOI：
10.1002/ctm2.426
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发表时间：
2021-06
影响因子：
10.6
通讯作者：
Peng X
中科院分区：
文献类型：
--
作者：
Lang C;Yin C;Lin K;Li Y;Yang Q;Wu Z;Du H;Ren D;Dai Y;Peng X
骨转移是前列腺癌（PCa）患者肿瘤相关死亡的主要原因。长链非编码RNA（lncRNAs）已被充分证明参与多种癌症的进展。然而，lncRNAs在前列腺癌骨转移中的作用在很大程度上仍不清楚。
通过RT - qPCR和原位杂交实验，在已发表的数据集中分析前列腺癌相关转录本的表达，并在临床样本和细胞系中进一步验证。进行集落形成实验、MTT实验、细胞周期分析、EdU实验、Transwell迁移和侵袭实验、伤口愈合实验以及体内实验，以研究前列腺癌相关转录本6（PCAT6）在前列腺癌骨转移和肿瘤生长中的作用。开展生物信息学分析、RNA下拉实验和RIP实验，以鉴定与PCAT6结合的蛋白质以及PCAT6的潜在靶点。在体内进一步探索通过反义寡核苷酸（ASO）靶向PCAT6的治疗潜力。
PCAT6在发生骨转移的前列腺癌组织中表达上调，且PCAT6表达升高预示着前列腺癌患者预后不良。功能实验发现，敲低PCAT6在体外可显著抑制前列腺癌细胞的侵袭、迁移和增殖，在体内可抑制骨转移和肿瘤生长。从机制上讲，METTL3介导的m6A修饰以依赖IGF2BP2的方式促进了PCAT6的上调。此外，PCAT6通过PCAT6 / IGF2BP2 / IGF1R RNA - 蛋白质三维复合物增强IGF1R mRNA的稳定性，从而上调IGF1R的表达。重要的是，体内ASO抑制PCAT6显示出对前列腺癌骨转移的治疗潜力。最后，在前列腺癌组织和细胞中进一步证实了METTL3、IGF2BP2、IGF1R和PCAT6的临床相关性。
我们的研究揭示了一种新的分子机制，即m6A诱导的PCAT6 / IGF2BP2 / IGF1R轴促进前列腺癌骨转移和肿瘤生长，这表明PCAT6可能作为一种有前景的预后标志物和针对骨转移性前列腺癌的治疗靶点。
1. PCAT6在骨转移阳性的前列腺癌中表达上调，且PCAT6上调与前列腺癌患者预后不良相关。
2. PCAT6通过与IGF2BP2相互作用稳定IGF1R mRNA，从而促进前列腺癌骨转移。
3. METTL3介导的m6A修饰以依赖IGF2BP2的方式导致PCAT6上调。
Bone metastasis is the leading cause of tumor‐related death in prostate cancer (PCa) patients. Long noncoding RNAs (lncRNAs) have been well documented to be involved in the progression of multiple cancers. Nevertheless, the role of lncRNAs in PCa bone metastasis remains largely unclear. The expression of prostate cancer‐associated transcripts was analyzed in published datasets and further verified in clinical samples and cell lines by RT‐qPCR and in situ hybridization assays. Colony formation assay, MTT assay, cell cycle analysis, EdU assay, Transwell migration and invasion assays, wound healing assay, and in vivo experiments were carried out to investigate the function of prostate cancer‐associated transcript 6 (PCAT6) in bone metastasis and tumor growth of PCa. Bioinformatic analysis, RNA pull‐down, and RIP assays were conducted to identify the proteins binding to PCAT6 and the potential targets of PCAT6. The therapeutic potential of targeting PCAT6 by antisense oligonucleotides (ASO) was further explored in vivo. PCAT6 was upregulated in PCa tissues with bone metastasis and increased PCAT6 expression predicted poor prognosis in PCa patients. Functional experiments found that PCAT6 knockdown significantly inhibited PCa cell invasion, migration, and proliferation in vitro, as well as bone metastasis and tumor growth in vivo. Mechanistically, METTL3‐mediated m6A modification contributed to PCAT6 upregulation in an IGF2BP2‐dependent manner. Furthermore, PCAT6 upregulated IGF1R expression by enhancing IGF1R mRNA stability through the PCAT6/IGF2BP2/IGF1R RNA‐protein three‐dimensional complex. Importantly, PCAT6 inhibition by ASO in vivo showed therapeutic potential against bone metastasis in PCa. Finally, the clinical correlation of METTL3, IGF2BP2, IGF1R, and PCAT6 was further demonstrated in PCa tissues and cells. Our study uncovers a novel molecular mechanism by which the m6A‐induced PCAT6/IGF2BP2/IGF1R axis promotes PCa bone metastasis and tumor growth, suggesting that PCAT6 may serve as a promising prognostic marker and therapeutic target against bone‐metastatic PCa. 1. PCAT6 is upregulated in bone metastasis‐positive prostate cancer and PCAT6 upregulation correlates with poor prognosis in patients with prostate cancer. 2. PCAT6 promotes prostate cancer bone metastasis by stabilizing IGF1R mRNA through interacting with IGF2BP2. 3. METTL3‐mediated m6A modification leads to the upregulation of PCAT6 in an IGF2BP2‐dependent manner.
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影响因子：
64.8
作者：
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影响因子：
13.8
作者：
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通讯作者：
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影响因子：
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作者：
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