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Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation.

ABSTRACT: Snail is a major transcriptional factor that induces epithelial-mesenchymal transition (EMT). In this study, we explore the effect of Snail on tumor immunity. Snail knockdown in mouse ovarian cancer cells suppresses tumor growth in immunocompetent mice, associated with an increase of CD8+ tumor-infiltrating lymphocytes and a decrease of myeloid-derived suppressor cells (MDSCs). Snail knockdown reduces the expression of CXCR2 ligands (CXCL1 and CXCL2), chemokines that attract MDSCs to the tumor via CXCR2. Snail upregulates CXCR ligands through NF-kB pathway, and most likely, through direct binding to the promoters. A CXCR2 antagonist suppresses MDSC infiltration and delays tumor growth in Snail-expressing mouse tumors. Ovarian cancer patients show elevated serum CXCL1/2, which correlates with Snail expression, MDSC infiltration, and short overall survival. Thus, Snail induces cancer progression via upregulation of CXCR2 ligands and recruitment of MDSCs. Blocking CXCR2 represents an immunological therapeutic approach to inhibit progression of Snail-high tumors undergoing EMT.

SUBMITTER: Taki M

PROVIDER: S-EPMC5923228 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation.

Taki Mana M Abiko Kaoru K Baba Tsukasa T Hamanishi Junzo J Yamaguchi Ken K Murakami Ryusuke R Yamanoi Koji K Horikawa Naoki N Hosoe Yuko Y Nakamura Eijiro E Sugiyama Aiko A Mandai Masaki M Konishi Ikuo I Matsumura Noriomi N

Nature communications 20180427 1

Snail is a major transcriptional factor that induces epithelial-mesenchymal transition (EMT). In this study, we explore the effect of Snail on tumor immunity. Snail knockdown in mouse ovarian cancer cells suppresses tumor growth in immunocompetent mice, associated with an increase of CD8<sup>+</sup> tumor-infiltrating lymphocytes and a decrease of myeloid-derived suppressor cells (MDSCs). Snail knockdown reduces the expression of CXCR2 ligands (CXCL1 and CXCL2), chemokines that attract MDSCs to ...[more]

PMID: 29703902

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Project description:Ovarian cancer is an inflammation-associated malignancy with a high mortality rate. CXCR2 expressing ovarian cancers are aggressive with poorer outcomes. We previously demonstrated that CXCR2-driven ovarian cancer progression potentiated NF-?B activation through EGFR-transactivated Akt. Here, we identified the chemokine signature involved in CXCR2-driven ovarian cancer progression using a mouse peritoneal xenograft model for ovarian cancer spreading with CXCR2-negative (SKA) and positive (SKCXCR2) cells generated previously from parental SKOV-3 cells. Compared to SKA bearing mice, SKCXCR2 bearing mice had the following characteristics: 1) shorter survival time, 2) greater tumor spreading in the peritoneal cavity and 3) higher tumor weight in the omentum and pelvic site. Particularly, SKCXCR2-derived tumor tissues induced higher activation of the NF-?B signaling pathway, while having no change in EGFR-activated signaling such as Raf, MEK, Akt, mTOR and Erk compared to SKA-derived tumors. Chemokine PCR array revealed that CCL20 mRNA levels were significantly increased in SKCXCR2-derived tumor tissues. The CCL20 promoter activity was regulated by NF-?B dependent pathways. Interestingly, all three ?B-like sites in the CCL20 promoter were involved in regulating CCL20 and the proximal region between -92 and -83 was the most critical ?B-like site. In addition, SKCXCR2-derived tumor tissues maintained high CCL20 mRNA expression and induced greater CCL24 and CXCR4 compared to SKCXCR2 cells, indicating the shift of chemokine network during the peritoneal spreading of tumor cells via interaction with other cell types in tumor microenvironment. Furthermore, we compared expression profiling array between human ovarian cancer cell lines and tumor tissues based on GEO datasets. The expression profiles in comparison with cell lines revealed that dominant chemokines expressed in ovarian tumor tissues are likely shifted from CXCL1-3 and 8 to CCL20. Taken together, the progression of ovarian cancer in the peritoneal cavity involves NF-?B-mediated CCL20 as a main chemokine network, which is potentiated by CXCR2 expression.

Dataset Information

Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation.

Publications

Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation.

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