Oncotarget

Research Papers:

BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma

Fen Liu, Chen Chen Jiang, Xu Guang Yan, Hsin-Yi Tseng, Chun Yan Wang, Yuan Yuan Zhang, Hamed Yari, Ting La, Margaret Farrelly, Su Tang Guo, Rick F. Thorne, Lei Jin, Qi Wang _ and Xu Dong Zhang

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Oncotarget. 2017; 8:69477-69492. https://doi.org/10.18632/oncotarget.17704

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Abstract

Fen Liu1,2,*, Chen Chen Jiang2,*, Xu Guang Yan3, Hsin-Yi Tseng3, Chun Yan Wang3, Yuan Yuan Zhang2, Hamed Yari3, Ting La3, Margaret Farrelly3, Su Tang Guo3, Rick F. Thorne4, Lei Jin2, Qi Wang1 and Xu Dong Zhang3

1Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China

2School of Medicine and Public Health, The University of Newcastle, NSW, Australia

3School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia

4School of Environmental and Life Sciences, University of Newcastle, NSW, Australia

*These authors contributed equally to this work

Correspondence to:

Qi Wang, email: [email protected]

Xu Dong Zhang, email: [email protected]

Keywords: CD47, BRAF/MEK inhibitors, NRF-1, melanoma, phagocytosis

Received: March 04, 2017     Accepted: April 19, 2017     Published: May 09, 2017

ABSTRACT

The expression of CD47 on the cancer cell surface transmits “don’t eat me” signalling that not only inhibits phagocytosis of cancer cells by phagocytes but also impairs anti-cancer T cell responses. Here we report that oncogenic activation of ERK plays an important role in transcriptional activation of CD47 through nuclear respiratory factor 1 (NRF-1) in melanoma cells. Treatment with BRAF/MEK inhibitors upregulated CD47 in cultured melanoma cells and fresh melanoma isolates. Similarly, melanoma cells selected for resistance to the BRAF inhibitor vemurafenib expressed higher levels of CD47. The increase in CD47 expression was mediated by ERK signalling, as it was associated with rebound activation of ERK and co-knockdown of ERK1/2 by siRNA diminished upregulation of CD47 in melanoma cells after exposure to BRAF/MEK inhibitors. Furthermore, ERK1/2 knockdown also reduced the constitutive expression of CD47 in melanoma cells. We identified a DNA fragment that was enriched with the consensus binding sites for NRF-1 and was transcriptionally responsive to BRAF/MEK inhibitor treatment. Knockdown of NRF-1 inhibited the increase in CD47, indicating that NRF-1 has a critical role in transcriptional activation of CD47 by ERK signalling. Functional studies showed that melanoma cells resistant to vemurafenib were more susceptible to macrophage phagocytosis when CD47 was blocked. So these results suggest that NRF-1-mediated regulation of CD47 expression is a novel mechanism by which ERK signalling promotes the pathogenesis of melanoma, and that the combination of CD47 blockade and BRAF/MEK inhibitors may be a useful approach for improving their therapeutic efficacy.


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