LncRNA CCAT1 facilitates the progression of gastric cancer via PTBP1-mediated glycolysis enhancement.
LncRNA CCAT1 facilitates the progression of gastric cancer via PTBP1-mediated glycolysis enhancement.
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DOI：
10.1186/s13046-023-02827-6
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发表时间：
2023-09-23
影响因子：
11.3
通讯作者：
Shan, Baoen
中科院分区：
文献类型：
--
作者：
Zhang, Cong;Wang, Huixia;Liu, Qingwei;Dai, Suli;Tian, Guo;Wei, Xintong;Li, Xiaoya;Zhao, Lianmei;Shan, Baoen
胃癌是消化系统最常见的恶性肿瘤之一。作为癌症的标志，能量相关的代谢重编程受到多种因素的操纵，包括长链非编码RNA（lncRNA）。值得注意的是，lncRNA CCAT 1已被鉴定为肿瘤进展中的关键调节因子。然而，CCAT 1参与GC代谢重编程的确切分子机制仍不清楚。进行功能获得和丧失实验以评估CCAT 1在肿瘤发生和GC糖酵解中的作用。通过生物信息学分析和质谱、RNA下拉、RNA免疫沉淀等机制实验，揭示了CCAT 1的潜在相互作用蛋白，阐明了CCAT 1在GC糖酵解中的调控机制。采用裸鼠移植瘤实验观察CCAT 1对胃癌细胞的作用。在这项研究中，我们确定了CCAT 1表达在GC患者的组织和血浆外泌体以及GC细胞系中显著升高。功能实验表明，CCAT 1基因的敲除可通过降低糖酵解酶的表达和糖酵解速率，显著抑制GC细胞的增殖、迁移和侵袭能力。相反，CCAT 1的过度表达表现出相反的效果。CCAT 1与PTBP 1相互作用，通过抑制泛素介导的降解过程有效地维持其稳定性。PTBP 1作为一种重要的剪接因子，促进PKM 1向PKM 2的转化，从而增强GC细胞的糖酵解活性，最终促进GC的进展。我们的研究结果表明，CCAT 1通过PTBP 1/PKM 2/糖酵解途径在促进GC细胞的增殖、迁移和侵袭中起着重要作用，从而表明CCAT 1作为GC的生物标志物和治疗靶点的潜力。在线版本包含补充材料，可通过10.1186/s13046-023-02827-6获得。
Gastric cancer (GC) is one of the most prevalent malignant tumors of the digestive system. As a hallmark of cancer, energy-related metabolic reprogramming is manipulated by multiple factors, including long non-coding RNAs (lncRNAs). Notably, lncRNA CCAT1 has been identified as a crucial regulator in tumor progression. Nevertheless, the precise molecular mechanisms underlying the involvement of CCAT1 in metabolic reprogramming of GC remain unclear. Gain- and loss-of-function experiments were performed to evaluate the roles of CCAT1 in tumorigenesis and glycolysis of GC. Bioinformatics analyses and mechanistic experiments, such as mass spectrometry (MS), RNA-pulldown, and RNA immunoprecipitation (RIP), were employed to reveal the potential interacting protein of CCAT1 and elucidate the regulatory mechanism of CCAT1 in GC glycolysis. Moreover, the nude mice xenograft assay was used to evaluate the effect of CCAT1 on GC cells in vivo. In this study, we identified that CCAT1 expression was significantly elevated in the tissues and plasma exosomes of GC patients, as well as GC cell lines. Functional experiments showed that the knockdown of CCAT1 resulted in a substantial decrease in the proliferation, migration and invasion of GC cells both in vitro and in vivo through decreasing the expression of glycolytic enzymes and glycolytic rate. Conversely, overexpression of CCAT1 exhibited contrasting effects. Mechanistically, CCAT1 interacted with PTBP1 and effectively maintained its stability by inhibiting the ubiquitin-mediated degradation process. As a critical splicing factor, PTBP1 facilitated the transition from PKM1 to PKM2, thereby augmenting the glycolytic activity of GC cells and ultimately fostering the progression of GC. Our findings demonstrate that CCAT1 plays a significant role in promoting the proliferation, migration, and invasion of GC cells through the PTBP1/PKM2/glycolysis pathway, thus suggesting CCAT1’s potential as a biomarker and therapeutic target for GC. The online version contains supplementary material available at 10.1186/s13046-023-02827-6.
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