MRTX1133通过METTL14/LINC02159/FOXC2轴激活铁下垂活性，减缓KRASG12D突变型结直肠癌的进展。

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2025-02-01 DOI:10.1016/j.tranon.2024.102235

Junwei Zou , Xiuhua Shi , Zhaoying Wu , Siyuan Zuo , Xiaolei Tang , Hailang Zhou , Yong Huang

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引用次数: 0

摘要

结直肠癌（CRC）是全球第三大最常诊断的癌症，也是导致癌症相关死亡的第二大原因。研究表明，KRAS突变的结直肠癌患者，尤其是KRASG12D发生转移的风险增加。新出现的证据表明，长链非编码rna （lncRNAs）在各种癌症的发生和进展中至关重要，调节多种生物学过程，但KRASG12D突变与CRC中lncRNAs之间的联系尚不清楚。因此，本研究旨在鉴定一种参与krasg12d突变CRC的新型lncRNA，并阐明其分子机制。GSE201412数据集中差异表达的lncRNAs分析显示，在KRASG12D抑制剂MTRX1133治疗后，LINC02159的表达显著上调。来自GTEx数据库的数据表明，LINC02159在CRC肿瘤组织中高表达，并与更好的患者预后相关。体外和体内实验表明，LINC02159在结直肠癌进展中起肿瘤抑制作用。具体来说，在krasg12d突变的CRC细胞中，LINC02159的敲低否定了MRTX1133对肿瘤发生的抑制作用及其对铁下垂的促进作用。LINC02159的表达受METTL14的调控，METTL14的敲低降低了LINC02159的m6A甲基化，导致其在CRC细胞中的表达增加。此外，LINC02159通过去泛素化稳定FOXC2的表达。援救实验进一步阐明了METTL14/LINC02159/FOXC2信号轴对krasg12d突变CRC中MRTX1133的抑制作用至关重要。我们的研究通过鉴定介导药物反应的METTL14/LINC02159/FOXC2信号轴，为MRTX1133治疗krasg12d突变的CRC的治疗潜力提供了新的见解。我们的研究结果强调了了解lncrna在癌症中的分子机制对于开发有效的靶向治疗的重要性。

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MRTX1133 attenuates KRASG12D mutated-colorectal cancer progression through activating ferroptosis activity via METTL14/LINC02159/FOXC2 axis

Colorectal cancer (CRC) ranks as the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Studies have shown that CRC patients with KRAS mutations, especially KRAS^G12D, have an increased risk of metastasis. Emerging evidence indicates that long non-coding RNAs (lncRNAs) are crucial in the carcinogenesis and progression of various cancers, regulating multiple biological processes but the link between KRAS^G12D mutations and lncRNAs in CRC remains unclear. Therefore, this study was designed to identify a novel lncRNA involved in KRAS^G12D-mutated CRC and to elucidate its molecular mechanisms. The analysis of differentially expressed lncRNAs in the GSE201412 dataset revealed that LINC02159 was significantly upregulated following treatment with the KRAS^G12D inhibitor MTRX1133 Data from the GTEx database indicated that LINC02159 is highly expressed in CRC tumour tissues and is associated with better patient outcomes. In vitro and in vivo experiments suggest that LINC02159 acts as a tumour suppressor in CRC progression. Specifically, LINC02159 knockdown negated the inhibitory effects of MRTX1133 on tumourigenesis and its promotive effect on ferroptosis in KRAS^G12D-mutated CRC cells. LINC02159 expression is regulated by METTL14, with METTL14 knockdown decreasing m6A methylation of LINC02159, leading to its increased expression in CRC cells. Additionally, LINC02159 stabilised FOXC2 expression through de-ubiquitination. Rescue experiments further clarified that the METTL14/LINC02159/FOXC2 signalling axis is crucial for the inhibitory effects of MRTX1133 in KRAS^G12D-mutated CRC. Our study provides novel insights into the therapeutic potential of MRTX1133 in treating KRAS^G12D-mutated CRC by identifying a METTL14/LINC02159/FOXC2 signalling axis that mediates drug response. Our findings highlight the importance of understanding the molecular mechanisms of lncRNAs in cancer to develop effective targeted therapies.

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.