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Inhibition of MEK suppresses hepatocellular carcinoma growth through independent MYC and BIM regulation

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Abstract

Background

Hepatocellular carcinoma (HCC) is an aggressive malignancy. In HCC, mitogen-activated protein kinase (MAPK) signaling is overactivated. The MAPK kinase (MEK) inhibitor trametinib has been approved to treat several types of advanced cancers with a BRAF mutation. Herein, we examined whether trametinib has efficacy against HCC.

Methods

The effects of trametinib on cell viability, proliferation and tumor growth were assessed in HCC-derived cell lines and mouse xenograft models. Western blot analysis and immunohistochemistry were used to identify key regulators critical for HHC cell proliferation and tumor growth.

Results

We found that trametinib dose-dependently inhibited the viability and proliferation of HCC cells. We also found that a strong suppression of MEK by trametinib downregulated the pro-survival protein MYC, but upregulated the pro-apoptotic protein BIM. This dual differential regulation of MYC and BIM was found to be accompanied by upregulation of a MYC-targeted cyclin dependent kinase inhibitor, p27kip1 (p27), and an apoptosis marker, cleaved poly (ADP ribose) polymerase 1 (PARP), indicating a concurrent modulation of cell cycle- and apoptosis-related pathways. Importantly, we found that MYC overexpression did not block increased BIM in trametinib-treated HCC cells, indicating that MAPK signaling independently regulates MYC and BIM. Finally, we found that trametinib in vivo inhibited HepG2 xenograft tumor growth and attenuated tumor invasion into surrounding tissues. Consistent with the in vitro findings, MYC expression was found to be reduced, while p27 expression was found to be elevated, and BIM expression and cleaved PARP levels were found to be increased in trametinib-treated xenograft tumors.

Conclusions

Collectively, our data indicate that trametinib exhibits efficacy in treating HCC cells via distinct regulation of the MYC and BIM pathways. As such, targeting MEK to block MAPK signaling with trametinib may provide novel treatment opportunities for HCC.

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Acknowledgements

The work was supported by the National Natural Science Foundation of China (81301141, 81100274 and 81570522) and the National Natural Science Foundation of Jiangsu Province of China (BK20131387). This work was also supported in part by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) at Nanjing Medical University.

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Authors and Affiliations

  1. Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China

    Xiqiao Zhou

  2. Howard University, Dixon Building, Room 210, 600 W. Street NW, Washington, DC, 20059, USA

    Ailin Zhu & Xinbin Gu

  3. Department of Physiology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, China

    Ailin Zhu & Guiqin Xie

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  1. Xiqiao Zhou
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Contributions

GX, XG and XZ participated in the design of the study. XZ performed most in vitro and in vivo experiments. AZ carried out the Western blot analyses. XZ and AZ collected and analyzed all the data. GX and XG drafted and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Guiqin Xie.

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Zhou, X., Zhu, A., Gu, X. et al. Inhibition of MEK suppresses hepatocellular carcinoma growth through independent MYC and BIM regulation. Cell Oncol. 42, 369–380 (2019). https://doi.org/10.1007/s13402-019-00432-4

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