Delta-Like同源物2通过激活表皮生长因子受体/PKM2信号通路促进肝细胞癌恶变

IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Carcinogenesis Pub Date : 2024-10-28 DOI:10.1002/mc.23836
Xiangye Liu, Tingting Li, Yuting Wang, Xiaoge Gao, Feitong Wang, Yang Chen, Kaisheng Wang, Weiming Luo, Fanyun Kong, Yanbo Kou, Hongjuan You, Delong Kong, Qing Zhang, Renxian Tang
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引用次数: 0

摘要

德尔塔样同源物 2(Delta-like homolog 2,DLK2)在脂肪生成、软骨分化和某些癌症的进展中起着至关重要的作用。然而,DLK2 在肝细胞癌(HCC)进展中的关键作用仍不明确。在本研究中,我们发现 DLK2 在 HCC 中上调,与临床病理变量显著相关,是一种独立的诊断标志物。功能测试显示,DLK2 在体外和体内模型中促进了 HCC 的恶性进展。从机理上讲,DLK2 与表皮生长因子受体结合,导致表皮生长因子受体自身磷酸化,从而激活 NK-κB 通路,导致 P65 依赖性 PKM2 转录上调。此外,这还会提高 PKM2 的酶依赖性和非依赖性活性,导致癌症增殖和转移。总之,我们的研究结果证明了 DLK2 在调控 HCC 恶性进展中的一种新的促肿瘤作用和机制,表明它有可能成为一种临床诊断标志物和治疗靶点。
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Delta-Like Homolog 2 Facilitates Malignancy of Hepatocellular Carcinoma via Activating EGFR/PKM2 Signaling Pathway.

Delta-like homolog 2 (DLK2) plays a crucial role in adipogenesis, chondrogenic differentiation, and the progression of certain cancers. However, the key roles of DLK2 underlying the progression of hepatocellular carcinoma (HCC) remain ambiguous. In the current study, we demonstrate that DLK2 is upregulated in HCC, significantly correlated with clinicopathological variables and serves as an independent diagnostic marker. Functional assays reveal that DLK2 facilitates malignant progression of HCC in vitro and in vivo models. Mechanistically, DLK2 binds to EGFR resulting in its auto-phosphorylation, which activates NK-κB pathway leading to P65-dependent transcriptional upregulation of PKM2. Furthermore, that elevates both enzyme-dependent and -independent activities of PKM2 contributing to cancer proliferation and metastasis. In summary, our findings demonstrate a novel pro-tumoral role and mechanism of DLK2 in the regulation of HCC malignant progression, suggesting its potential as a clinical diagnostic marker and therapeutic target.

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来源期刊
Molecular Carcinogenesis
Molecular Carcinogenesis 医学-生化与分子生物学
CiteScore
7.30
自引率
2.20%
发文量
112
审稿时长
2 months
期刊介绍: Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.
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