MTDH-stabilized DDX17 promotes tumor initiation and progression through interacting with YB1 to induce EGFR transcription in Hepatocellular Carcinoma
MTDH-stabilized DDX17 promotes tumor initiation and progression through interacting with YB1 to induce EGFR transcription in Hepatocellular Carcinoma
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MTDH 稳定的 DDX17 通过与 YB1 相互作用诱导肝细胞癌中的 EGFR 转录来促进肿瘤的发生和进展
DOI：
10.1038/s41388-022-02545-x
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发表时间：
2022-11-17
期刊：
影响因子：
8
通讯作者：
Zhang Bi-xiang，bx
中科院分区：
文献类型：
--
作者：
Chen Jin，Jin;Dong Han-hua，Hanhua;Zhang Bi-xiang，bx
Metadherin（MTDH）是在包括肝细胞癌（HCC）在内的多种癌症中已确定的癌基因。然而，MTDH促进HCC中癌症相关信号通路的确切机制仍然未知。在这项研究中，我们确定DDX 17作为MTDH的一种新的结合伴侣。此外，MTDH通过抑制DDX 17的泛素化而增加DDX 17的蛋白水平。我们证实DDX 17是一个新的癌基因，在肝癌组织中显著上调表达。DDX 17的高表达与肿瘤的血管浸润、TNM分期、BCLC分期及预后不良密切相关。体外和体内试验表明，DDX 17是MTDH的下游靶点，在肿瘤的发生和发展中起着至关重要的作用。从机制上讲，DDX 17作为一种转录调节因子，与细胞核中的Y-box结合蛋白1（YB 1）相互作用，进而驱动YB 1与其靶向表皮生长因子受体（EGFR）基因启动子结合，以增加其转录。这反过来增加了EGFR的表达和下游MEK/pERK信号通路的激活。我们的研究结果表明，DDX 17，MTDH稳定，作为一个强大的癌基因在肝癌和DDX 17/YB 1/EGFR轴有助于肝癌的肿瘤发生和转移。
Metadherin (MTDH) is a well-established oncogene in various cancers including Hepatocellular Carcinoma (HCC). However, the precise mechanism through which MTDH promotes cancer-related signaling pathways in HCC remains unknown. In this study, we identified DDX17 as a novel binding partner of MTDH. Furthermore, MTDH increased the protein level of DDX17 by inhibiting its ubiquitination. We confirmed that DDX17 was a novel oncogene, with dramatically upregulated expression in HCC tissues. The increased expression of DDX17 was closely associated with vascular invasion, TNM stage, BCLC stage, and poor prognosis. In vitro and in vivo tests demonstrated that DDX17, a downstream target of MTDH, played a crucial role in tumor initiation and progression. Mechanistically, DDX17 acted as a transcriptional regulator that interacted with Y-box binding protein 1 (YB1) in the nucleus, which in turn drove the binding of YB1 to its target epidermal growth factor receptor (EGFR) gene promoter to increase its transcription. This in turn increased expression of EGFR and the activation of the downstream MEK/pERK signaling pathway. Our results identify DDX17, stabilized by MTDH, as a powerful oncogene in HCC and suggest that the DDX17/YB1/EGFR axis contributes to tumorigenesis and metastasis of HCC.