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Plac1 Is a Key Regulator of the Inflammatory Response and Immune Tolerance In Mammary Tumorigenesis.

ABSTRACT: Plac1 is an X-linked trophoblast gene expressed at high levels in the placenta, but not in adult somatic tissues other than the testis. Plac1 however is re-expressed in several solid tumors and in most human cancer cell lines. To explore the role of Plac1 in cancer progression, Plac1 was reduced by RNA interference in EO771 mammary carcinoma cells. EO771 "knockdown" (KD) resulted in 50% reduction in proliferation in vitro and impaired tumor growth in syngeneic mice; however, tumor growth in SCID mice was equivalent to tumor cells expressing a non-silencing control RNA, suggesting that Plac1 regulated adaptive immunity. Gene expression profiling of Plac1 KD cells indicated reduction in several inflammatory and immune factors, including Cxcl1, Ccl5, Ly6a/Sca-1, Ly6c and Lif. Treatment of mice engrafted with wild-type EO771 cells with a Cxcr2 antagonist impaired tumor growth, reduced myeloid-derived suppressor cells and regulatory T cells, while increasing macrophages, dendritic cells, NK cells and the penetration of CD8+ T cells into the tumor bed. Cxcl1 KD phenocopied the effects of Plac1 KD on tumor growth, and overexpression of Cxcl1 partially rescued Plac1 KD cells. These results reveal that Plac1 modulates a tolerogenic tumor microenvironment in part by modulating the chemokine axis.

SUBMITTER: Yuan H

PROVIDER: S-EPMC5890253 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Plac1 Is a Key Regulator of the Inflammatory Response and Immune Tolerance In Mammary Tumorigenesis.

Yuan Hongyan H Wang Xiaoyi X Shi Chunmei C Jin Lu L Hu Jianxia J Zhang Alston A Li James J Vijayendra Nairuthya N Doodala Venkata V Weiss Spencer S Tang Yong Y Weiner Louis M LM Glazer Robert I RI

Scientific reports 20180409 1

Plac1 is an X-linked trophoblast gene expressed at high levels in the placenta, but not in adult somatic tissues other than the testis. Plac1 however is re-expressed in several solid tumors and in most human cancer cell lines. To explore the role of Plac1 in cancer progression, Plac1 was reduced by RNA interference in EO771 mammary carcinoma cells. EO771 "knockdown" (KD) resulted in 50% reduction in proliferation in vitro and impaired tumor growth in syngeneic mice; however, tumor growth in SCID ...[more]

PMID: 29632317

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Project description:Increasing evidence supports the involvement of microRNAs (miRNA) in the regulation of inflammation in human neurological disorders. In the present study we investigated the role of miR-146a, a key regulator of the innate immune response, in the modulation of astrocyte-mediated inflammation. Using Taqman PCR and in situ hybridization, we studied the expression of miR-146a in epilepsy-associated glioneuronal lesions which are characterized by prominent activation of the innate immune response. In addition, cultured human astrocytes were used to study the regulation of miR-146a expression in response to proinflammatory cytokines. qPCR and western blot were used to evaluate the effects of overexpression or knockdown of miR-146a on IL-1? signaling. Downstream signaling in the IL-1? pathway, as well as the expression of IL-6 and COX-2 were evaluated by western blot and ELISA. Release several cytokines was evaluated using a human magnetic multiplex cytokine assay on a Luminex® 100™/200™ platform. Increased expression of miR-146a was observed in glioneuronal lesions by Taqman PCR. MiR-146a expression in human glial cell cultures was strongly induced by IL-1? and blocked by IL-1? receptor antagonist. Modulation of miR-146a expression by transfection of astrocytes with anti-miR146a or mimic, regulated the mRNA expression levels of downstream targets of miR-146a (IRAK-1, IRAK-2 and TRAF-6) and the expression of IRAK-1 protein. In addition, the expression of IL-6 and COX-2 upon IL-1? stimulation was suppressed by increased levels of miR-146a and increased by the reduction of miR-146a. Modulation of miR-146a expression affected also the release of several cytokines such as IL-6 and TNF-?. Our observations indicate that in response to inflammatory cues, miR-146a was induced as a negative-feedback regulator of the astrocyte-mediated inflammatory response. This supports an important role of miR-146a in human neurological disorders associated with chronic inflammation and suggests that this miR may represent a novel target for therapeutic strategies.

Dataset Information

Plac1 Is a Key Regulator of the Inflammatory Response and Immune Tolerance In Mammary Tumorigenesis.

Publications

Plac1 Is a Key Regulator of the Inflammatory Response and Immune Tolerance In Mammary Tumorigenesis.

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