MTDH-stabilized DDX17 promotes tumor initiation and progression through interacting with YB1 to induce EGFR transcription in Hepatocellular Carcinoma

被引:12
作者
Chen Jin [1 ]
Dong Han-hua [1 ]
Liu Qiu-meng [1 ]
Ning Deng [1 ]
Du Peng-Chen [1 ]
Mo Jie [1 ]
Xu Lei [1 ]
Zhang Xue-Wu [1 ]
Liang Hui-fang [1 ]
Chen Yan [2 ]
Chen Xiao-ping [1 ,3 ,4 ,5 ]
Zhang Bi-xiang [1 ,3 ,4 ,5 ]
机构
[1] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll,Hubei Key Lab Hepatopancreatobili, Hepat Surg Ctr,Clin Med Res Ctr Hepat Surg Hubei, Wuhan, Peoples R China
[2] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Gen Surg, Wuhan, Peoples R China
[3] Minist Educ, Key Lab Organ Transplantat, Wuhan, Peoples R China
[4] Natl Hlth Commiss, Key Lab Organ Transplantat, Wuhan, Peoples R China
[5] Chinese Acad Med Sci, Key Lab Organ Transplantat, Wuhan, Peoples R China
基金
中国国家自然科学基金;
关键词
ASTROCYTE-ELEVATED GENE-1; CELL-GROWTH; CANCER; ACTIVATION; METASTASIS; METADHERIN; PROTEIN; PROLIFERATION; RESISTANCE; ONCOGENE;
D O I
10.1038/s41388-022-02545-x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:169 / 183
页数:15
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