Oncotarget

Research Papers:

Loss of oncogenic miR-155 in tumor cells promotes tumor growth by enhancing C/EBP-β-mediated MDSC infiltration

Sinae Kim, Jin Hoi Song, Seokho Kim, Peng Qu, Betty K. Martin, Waheed S. Sehareen, Diana C. Haines, Pengnian C. Lin, Shyam K. Sharan and Suhwan Chang _

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Oncotarget. 2016; 7:11094-11112. https://doi.org/10.18632/oncotarget.7150

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Abstract

Sinae Kim1, Jin Hoi Song2, Seokho Kim2, Peng Qu4, Betty K. Martin4, Waheed S. Sehareen4, Diana C. Haines3, Pengnian C. Lin4, Shyam K. Sharan4, Suhwan Chang1

1Department of Biomedical Sciences, Department of Physiology, University of Ulsan School of Medicine, Seoul, South Korea

2Aging Research Center, Korea Research Institute of Bioscience & Biotechnology, Taejeon, South Korea

3Pathology Histotechnology Laboratory, Leidos Inc., Frederick National Laboratory for Cancer, Frederick, MD, USA

4Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA

Correspondence to:

Shyam K. Sharan, e-mail: [email protected]

Suhwan Chang, e-mail: [email protected]

Keywords: miR-155, MDSC, C/EBP-beta, cytokine, breast cancer

Received: August 31, 2015     Accepted: January 19, 2015     Published: February 03, 2016

ABSTRACT

The oncogenic role of microRNA-155 (miR-155) in leukemia is well established but its role in other cancers, especially breast cancer, is gradually emerging. In this study we examined the effect of mir-155 loss in a well-characterized spontaneous breast cancer mouse model where Brca1 and Trp53 are deleted by K14-Cre. miR-155 is known to be up-regulated in BRCA1-deficient tumors. Surprisingly, complete loss of miR-155 (miR-155ko/ko) did not alter the tumor free survival of the mutant mice. However, we found increased infiltration of myeloid derived suppressor cells (MDSCs) in miR-155 deficient tumors. In addition, cytokine/chemokine array analysis revealed altered level of cytokines that are implicated in the recruitment of MDSCs. Mechanistically, we identified C/EBP-β, a known miR-155 target, to regulate the expression of these cytokines in the miR-155-deficient cells. Furthermore, using an allograft model, we showed that inhibition of miR-155 in cancer cells suppressed in vivo growth, which was restored by the loss of miR-155 in the microenvironment. Taken together, we have uncovered a novel tumor suppressive function of miR-155 in the tumor microenvironment, which is also dependent on miR-155 expression in the tumor cells. Because of the oncogenic as well as tumor suppressive roles of miR-155, our findings warrant caution against a systemic inhibition of miR-155 for anticancer therapy.


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