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

Abstract

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.

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Fig. 1: DDX17 is a novel MTDH-binding protein in HCC.
Fig. 2: MTDH stabilizes and deubiquitinates DDX17.
Fig. 3: DDX17 promotes the growth and metastasis of HCC.
Fig. 4: DDX17 promotes the tumorigenesis of HCC.
Fig. 5: RNA sequencing identifies EGFR as a downstream effector of DDX17.
Fig. 6: DDX17 interacts with YB1 and enhances the transcription of EGFR.
Fig. 7: DDX17 mediates the effect of MTDH on HCC progression through the EGFR-pERK pathway.
Fig. 8: DDX17 is upregulated and positively correlates with MTDH in HCC.

Data availability

The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81874189 to Bi-xiang Zhang, No. 82003003 to Jin Chen).

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CX, ZB, and CY conceived and designed the study. CJ, DH, and LQ performed the experiments. ND, DP, and MJ collected the clinical specimens and data. GQ, XL, and ZX performed the statistical analysis. CJ drafted the manuscript. LH, ZB, and CX contributed to the critical revision of the paper. All authors read and approved the final manuscript.

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Correspondence to Chen Yan, Chen Xiao-ping or Zhang Bi-xiang.

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Jin, C., Han-hua, D., Qiu-meng, L. et al. MTDH-stabilized DDX17 promotes tumor initiation and progression through interacting with YB1 to induce EGFR transcription in Hepatocellular Carcinoma. Oncogene 42, 169–183 (2023). https://doi.org/10.1038/s41388-022-02545-x

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