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SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 and c-MET

Oncogene volume 39, pages 7279–7295 (2020)Cite this article

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Abstract

Metastasis is the main reason for high mortality in hepatocellular carcinoma (HCC) patients and the molecular mechanism remains unclear. Therefore, it is important to elucidate the mechanism underlying HCC metastasis. Here, we report a novel role of SIX homeobox 4 (SIX4), one of the SIX gene family, in promoting HCC metastasis. The elevated expression of SIX4 was positively correlated with loss of tumor encapsulation, microvascular invasion, higher TNM stage, and poor prognosis in human HCC. SIX4 expression was an independent and significant risk factor for the recurrence and survival in HCC patients. Upregulation of SIX4 promoted HCC invasion and metastasis, whereas downregulation of SIX4 decreased HCC invasion and metastasis. SIX4 transactivated Yes1 associated transcriptional regulator (YAP1) and MET proto-oncogene, receptor tyrosine kinase (MET) expression through directly binding to their promoters. Knockdown of YAP1 and c-MET inhibited SIX4-medicated HCC metastasis, while the stable overexpression of YAP1 and c-MET reversed the decreased metastasis induced by SIX4 knockdown. Hepatocyte growth factor (HGF), the specific ligand of c-MET, upregulated SIX4 expression through ERK/NF-κB pathway. Knockdown of SIX4 significantly decreased HGF-enhanced HCC metastasis. In human HCC tissues, SIX4 expression was positively correlated with nuclear YAP1, c-MET and HGF expression. Patients with positive coexpression of SIX4/ nuclear YAP1, SIX4/c-MET or HGF/SIX4 had the poorest prognosis. Moreover, the combination treatment of YAP1 inhibitor Verteporfin and c-MET inhibitor Capmatinib significantly suppressed SIX4-mediated HCC metastasis. In conclusion, SIX4 is a prognostic biomarker in HCC patients and targeting the HGF-SIX4-c-MET positive feedback loop may provide a promising strategy for the treatment of SIX4-driven HCC metastasis.

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Fig. 1: Overexpression of SIX4 promotes HCC metastasis and indicates poor prognosis in HCC patients.
Fig. 2: YAP1 and MET are two direct transcriptional targets of SIX4.
Fig. 3: SIX4 promotes HCC invasion and metastasis through upregulating YAP1 and c-MET.
Fig. 4: HGF upregulates SIX4 expression through ERK/NF-kB signaling pathway.
Fig. 5: SIX4 is essential for HGF-induced HCC metastasis.
Fig. 6: SIX4 expression is positively correlated with nuclear YAP1 and c-MET expression in human HCC tissues.
Fig. 7: Combined treatment of YAP1 and c-MET inhibitor blocks SIX4-medicated HCC Metastasis.

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Acknowledgements

Research was supported by grants from the National Key Research and Development Program of China 2018YFC1312103 (LX), National Natural Science Foundation of China No. 81871911 (WH), No. 81972237 (LX), and No. 81772623 (LX).

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  1. Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Qin He, Zhuoying Lin, Zhihui Wang, Dean Tian, Mei Liu & Limin Xia

  2. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Clinical Medicine Research Center for Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, 430030, Hubei, China

    Wenjie Huang

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He, Q., Lin, Z., Wang, Z. et al. SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 and c-MET. Oncogene 39, 7279–7295 (2020). https://doi.org/10.1038/s41388-020-01500-y

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