Effect of miR-142-3p on the M2 Macrophage and Therapeutic Efficacy Against Murine Glioblastoma

Xu, Shuo; Wei, Jun; Wang, Fei; Kong, Ling Yuan; Ling, Xiao Yang; Nduom, Edjah K.; Gabrusiewicz, Konrad; Doucette, Tiffany; Yang, Yuhui; Yaghi, Nasser K.; Fajt, Virginia R.; Levine, Jonathan M.; Qiao, Wei; Li, Xin Gang; Lang, Frederick F.; Rao, Ganesh; Fuller, Gregory N.; Calin, George A.; Heimberger, Amy B.

doi:10.1093/jnci/dju162

Cited by 116 publications

(89 citation statements)

References 36 publications

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“…1E). The change of cell morphology is an approach widely used to assess the phenotype of macrophages (10,(21)(22)(23)(24). Specifically, Su et al (10) showed that macrophages that are polarized to M2-like TAMs by cancer cell-derived lactate exhibit stretched and elongated morphology.…”

Section: Resultsmentioning

confidence: 99%

Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis

Chen

Zuo

Xiong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

346

280

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Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor-macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor-macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment.reast cancer is the most frequently diagnosed nonskin type of malignancy, and the second leading cause of cancer-related death in women. The 5-y survival rate is 89% in patients who have primary breast cancer, whereas the medium survival of patients with metastatic breast cancer is only 1-2 y (1, 2). Metastasis is the primary cause of breast cancer-related deaths; however, the molecular mechanisms underlying this process are still poorly understood. It has been well established that the tumor microenvironment plays an important role in breast cancer metastasis (3-6). Tumor-associated macrophages (TAMs) make up the largest population of stromal cells that suppress antitumor immunity and foster tumor progression in mouse models of breast cancer (3,(6)(7)(8). TAMs also promote metastasis and correlate with poor prognosis in patients with breast cancer (7, 9). Conversely, TAM functions are also tightly regulated by tumor cells (10, 11). However, the mechanisms underlying this reciprocal regulation between cancer cells and macrophages during metastasis remain elusive.Macrophages are heterogeneous immune cells that can exhibit distinct functions and phenotypes depending on different microenvironment signals (9, 12). They can be broadly divided into classically activated (M1) and alternatively activated (M2) macrophages, the latter of which generally display promalignancy activity (9, 12). In solid tumors, TAMs are usually biased toward M2 (9). Due to hypoxia and glycolytic cancer cell metabolism, the tumor environment is usually acidic, which affects tumor progression by acting on both cancer cells and stromal cells, including macrophages (10,13,14). A recent study shows that cancer cell-derived lactate can educate macrophages to functional TAMs, which, in turn, promotes tumor growth (14). Nonetheless, how lactate activation of TAMs affects cancer metastasis is poorly understood. Importantly, the molecular basis by which macrophages sense and respond t...

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Section: Resultsmentioning

confidence: 99%

Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis

Chen

Zuo

Xiong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

346

280

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“…miR-142-3p has been reported to be downregulated in diverse types of cancer, including leukemia, thyroid follicular carcinomas, cervical cancer, hepatic cancer, glioblastoma, osteosarcoma and non-small cell lung cancer (16)(17)(18)(19)(20)(21)(22). miR-142-3p has been demonstrated to contribute to carcinogenesis by regulating cell cycle, cell migration, apoptosis and invasion by targeting various signaling pathways and…”

Section: Introductionmentioning

confidence: 99%

Downregulation of microRNA‑142‑3p and its tumor suppressor role in gastric cancer

et al. 2018

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“…Recent studies emphasized that manipulation of miRNAs and their oligonucleotide antagonists, including miRNA-based nanodrugs, miRNA mimics, miRNA sponge and miR-mask, represents an attractive approach for antitumor therapy (12,13). In the GBM model, miRNAs could modulate pivotal protein expressions in the signaling cascades, thus, regulate tumor malignant behaviors (14)(15)(16). We propose that by overlapping the datasets of predictive miRNAs targeting CXCR4 and the miRNA profiling between GBM tissues and adjacent normal tissues, we could identify the tumor-specific miRNAs regulating CXCR4 expression in GBMs and offer new miRNA candidates for anti-GBM strategies.…”

Section: Introductionmentioning

confidence: 99%

miR-663 Suppresses Oncogenic Function of CXCR4 in Glioblastoma

Shi

Chen

et al. 2015

Clinical Cancer Research

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Purpose: To identify the miRNA regulators of C-X-C motif chemokine receptor 4 (CXCR4) and the underlying mechanism as well as the therapeutic and prognostic values in human glioblastoma (GBM).Experimental Design: miRNA profile analyses and bioinformatics predictions were used to identify the mediators of CXCR4, which were confirmed by luciferase reporter assay, Western blot assay and immunohistochemistry. The effects of miR-663 on CXCR4-mediated GBM malignancy were investigated by gainof-function experiments. Orthotopic xenografts derived from constitutive or induced miR-663-expressing GBM cells were used to determine the antitumor effects of miR-663 and CXCR4-specific antagonist AMD3100. Bivariate correlation analyses were used to examine the correlation of miR-663 and CXCR4 levels in glioma. The prognostic values of miR-663 and CXCR4 were examined in 281 cases of astrocytic glioma from our hospital and 476 cases of GBM from The Cancer Genome Atlas database using the multivariate Cox regression analysis and Kaplan-Meier analysis.Results: miR-663 negatively regulated CXCR4 expression by targeting its coding sequence in GBM and compromised the proliferative and invasive capacities of GBM cells induced by CXCR4 overexpression. Constitutive or induced miR-663 overexpression combined with CXCR4 antagonist AMD3100 suppressed orthotopic GBM growth and prolonged tumor-bearing mice survival. Clinically, miR-663 and CXCR4 were inversely correlated in GBM and composed a valuable biomarker set in predicting the outcomes of GBM patients.Conclusions: miR-663 negatively regulated CXCR4 to inhibit its oncogenic effect. Combination of miR-663 and CXCR4 can serve as a valuable prognostic biomarker set as well as molecular targets for therapeutic intervention of GBM.

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Effect of miR-142-3p on the M2 Macrophage and Therapeutic Efficacy Against Murine Glioblastoma

Abstract: These data indicate a unique role of miR-142-3p in glioma immunity by modulating M2 macrophages through the transforming growth factor beta signaling pathway.

Cited by 116 publications

References 36 publications

Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis

Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis

Downregulation of microRNA‑142‑3p and its tumor suppressor role in gastric cancer

miR-663 Suppresses Oncogenic Function of CXCR4 in Glioblastoma

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