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TOP1MT缺陷通过刺激胃癌中PDK4的表达增强糖酵解。

Deficiency of TOP1MT enhances glycolysis through the stimulation of PDK4 expression in gastric cancer.

作者信息

Wang Hongqiang, Sun Xutao, Yang Chen, Li Ziqi, Jin Danwen, Zhu Wenwen, Yu Ze

机构信息

Cancer Chemotherapy Center, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China.

Department of General Surgery, Zhoushan Hospital, Wenzhou Medical University, No. 739 Dingshen Road, Lincheng New District, Zhoushan, Zhejiang, 316021, China.

出版信息

Cancer Metab. 2024 Jan 10;12(1):2. doi: 10.1186/s40170-024-00330-w.

DOI:10.1186/s40170-024-00330-w
PMID:38200513
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10777619/
Abstract

BACKGROUND

Abnormal glucose metabolism is one of the determinants of maintaining malignant characteristics of cancer. Targeting cancer metabolism is regarded as a new strategy for cancer treatment. Our previous studies have found that TOP1MT is a crucial gene that inhibits glycolysis and cell metastasis of gastric cancer (GC) cells, but the mechanism of its regulation of glycolysis remains unclear.

METHODS

Transcriptome sequencing data, clinic-pathologic features of GC from a variety of public databases, and WGCNA were used to identify novel targets of TOP1MT. Immunohistochemical results of 250 patients with GC were used to analyze the relative expression relationship between TOP1MT and PDK4. The function of TOP1MT was investigated by migration assays and sea-horse analysis in vitro.

RESULTS

We discovered a mitochondrial topoisomerase I, TOP1MT, which correlated with a higher risk of metastasis. Functional experiments revealed that TOP1MT deficiency promotes cell migration and glycolysis through increasing PDK4 expression. Additionally, the stimulating effect of TOP1MT on glycolysis may be effectively reversed by PDK4 inhibitor M77976.

CONCLUSIONS

In brief, our work demonstrated the critical function of TOP1MT in the regulation of glycolysis by PDK4 in gastric cancer. Inhibiting glycolysis and limiting tumor metastasis in GC may be accomplished by suppressing PDK4.

摘要

背景

葡萄糖代谢异常是维持癌症恶性特征的决定因素之一。靶向癌症代谢被视为一种新的癌症治疗策略。我们之前的研究发现TOP1MT是抑制胃癌（GC）细胞糖酵解和细胞转移的关键基因，但其调节糖酵解的机制仍不清楚。

方法

利用来自各种公共数据库的转录组测序数据、GC的临床病理特征以及加权基因共表达网络分析（WGCNA）来鉴定TOP1MT的新靶点。使用250例GC患者的免疫组织化学结果分析TOP1MT与PDK4之间的相对表达关系。通过体外迁移试验和海马分析研究TOP1MT的功能。

结果

我们发现一种线粒体拓扑异构酶I，即TOP1MT，其与转移风险较高相关。功能实验表明，TOP1MT缺陷通过增加PDK4表达促进细胞迁移和糖酵解。此外，PDK4抑制剂M77976可有效逆转TOP1MT对糖酵解的刺激作用。

结论

简而言之，我们的研究证明了TOP1MT在胃癌中通过PDK4调节糖酵解的关键作用。抑制GC中的糖酵解和限制肿瘤转移可能通过抑制PDK4来实现。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/c75161daa557/40170_2024_330_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/e6a90167725c/40170_2024_330_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/f58c5f38f3d3/40170_2024_330_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/85f2f1050d12/40170_2024_330_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/d9954307a239/40170_2024_330_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/8256ae1c2635/40170_2024_330_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/f444f78f9779/40170_2024_330_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/44dc8b7880e5/40170_2024_330_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/ed133b81d344/40170_2024_330_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/c75161daa557/40170_2024_330_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/e6a90167725c/40170_2024_330_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/f58c5f38f3d3/40170_2024_330_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/85f2f1050d12/40170_2024_330_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/d9954307a239/40170_2024_330_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/8256ae1c2635/40170_2024_330_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/f444f78f9779/40170_2024_330_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/44dc8b7880e5/40170_2024_330_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/ed133b81d344/40170_2024_330_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b01e/10777619/c75161daa557/40170_2024_330_Fig9_HTML.jpg

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