Identification and Validation of the N6-Methyladenosine RNA Methylation Regulator YTHDF1 as a Novel Prognostic Marker and Potential Target for Hepatocellular Carcinoma.
Identification and Validation of the N6-Methyladenosine RNA Methylation Regulator YTHDF1 as a Novel Prognostic Marker and Potential Target for Hepatocellular Carcinoma.
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N6-甲基腺苷 RNA 甲基化调节因子 YTHDF1 作为肝细胞癌新型预后标记物和潜在靶点的鉴定和验证。
DOI：
10.3389/fmolb.2020.604766
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发表时间：
2020
影响因子：
5
通讯作者：
Zheng W
中科院分区：
文献类型：
--
作者：
Bian S;Ni W;Zhu M;Song Q;Zhang J;Ni R;Zheng W
目的：N6-甲基腺苷（m6 A）RNA甲基化与多种恶性肿瘤有关。本研究旨在确定基于m6 A甲基化调节因子的肝细胞癌（HCC）预后特征，并为HCC治疗提供候选靶点。研究方法：进行最小绝对收缩和选择算子（LASSO）分析以识别癌症基因组图谱（TCGA）数据集中的风险特征。在国际癌症基因组联盟（ICGC）和全基因组泛癌症分析（PCAWG）数据集中进一步验证了风险特征。转染靶向YTHDF 1的短发夹状RNA（shRNA）后，分别通过细胞计数试剂盒（CCK-8）、伤口愈合试验、Transwell、流式细胞术和异种移植瘤试验评价HCC细胞的生物学活性。通过过度表达富集分析（ORA）/基因集富集分析（GSEA）预测YTHDF 1介导的可能机制，并通过Western blotting验证。结果：m6 A RNA甲基化调节因子的过表达与HCC患者的恶性临床病理特征相关。考克斯回归和LASSO分析确定了5种m6 A甲基化调节剂（KIAA 1429、ZC 3 H13、YTHDF 1、YTHDF 2和胃L3）的风险特征。根据TCGA中的HCC病例，还在ICGC和PCAWG数据集中确定了风险特征的预后价值。在分析TCGA和基因表达Omnibus（GEO）中的表达和临床意义之后，选择YTHDF 1进行进一步的实验验证。YTHDF 1基因在体外可显著抑制肝癌细胞的增殖、迁移和侵袭，并促进肝癌细胞的凋亡。此外，沉默YTHDF 1抑制体内异种移植肿瘤的生长。YTHDF 1可能通过促进上皮-间质转化（EMT）和激活AKT/糖原合成酶激酶（GSK）-3β/β-catenin信号通路促进肿瘤细胞的侵袭性表型。结论：目前的研究确定了一个强大的风险签名组成的m6 A RNA甲基化调控HCC预后。此外，YTHDF 1是肝癌治疗的潜在分子靶点。
Purpose: N6-methyladenosine (m6A) RNA methylation has been implicated in various malignancies. This study aimed to identify the m6A methylation regulator-based prognostic signature for hepatocellular carcinoma (HCC) as well as provide candidate targets for HCC treatment. Methods: The least absolute shrinkage and selection operator (LASSO) analyses were performed to identify a risk signature in The Cancer Genome Atlas (TCGA) datasets. The risk signature was further validated in International Cancer Genome Consortium (ICGC) and Pan-Cancer Analysis of Whole Genomes (PCAWG) datasets. Following transfection of short hairpin RNA (shRNA) targeting YTHDF1, the biological activities of HCC cells were evaluated by Cell Counting Kit-8 (CCK-8), wound-healing, Transwell, flow cytometry, and xenograft tumor assays, respectively. The potential mechanisms mediated by YTHDF1 were predicted by overrepresentation enrichment analysis (ORA)/gene set enrichment analysis (GSEA) and validated by Western blotting. Results: Overexpression of m6A RNA methylation regulators was correlated with malignant clinicopathological characteristics of HCC patients. The Cox regression and LASSO analyses identified a risk signature with five m6A methylation regulators (KIAA1429, ZC3H13, YTHDF1, YTHDF2, and METTL3). In accordance with HCC cases in TCGA, the prognostic value of risk signature was also determined in ICGC and PCAWG datasets. Following analyzing the expression and clinical implications in TCGA and Gene Expression Omnibus (GEO), YTHDF1 was chosen for further experimental validation. Knockdown of YTHDF1 significantly inhibited the proliferation, migration, and invasion of HCC cells, as well as enhanced the apoptosis in vitro. Moreover, silencing YTHDF1 repressed the growth of xenograft tumors in vivo. Mechanism investigation indicated that YTHDF1 might promote the aggressive phenotypes by facilitating epithelial–mesenchymal transition (EMT) and activating AKT/glycogen synthase kinase (GSK)-3β/β-catenin signaling. Conclusion: The current study identified a robust risk signature consisting of m6A RNA methylation regulators for HCC prognosis. In addition, YTHDF1 was a potential molecular target for HCC treatment.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
PDLIM1通过激活肝细胞癌中的Hippo信号传导抑制肿瘤转移
影响因子：
13.5
作者：
Huang, Zhao;Zhou, Jian-Kang;Peng, Yong
通讯作者：
Peng, Yong
影响因子：
4.7
作者：
Bai, Yang;Yang, Chunxing;Zhang, Yi
通讯作者：
Zhang, Yi