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The miR-561-5p/CX₃CL1 Signaling Axis Regulates Pulmonary Metastasis in Hepatocellular Carcinoma Involving CX₃CR1⁺ Natural Killer Cells Infiltration.

ABSTRACT: Natural killer (NK) cell can inhibit tumor initiation and regulates metastatic dissemination, acting as key mediators of the innate immune response. Intrinsic factors modulating NK cells infiltration and its anticancer activity remain poorly characterized. We investigated the roles of dysregulation of micro(mi)RNAs and NK cells in progression of hepatocellular carcinoma (HCC). Methods: Small RNA sequencing were used to detect the miRNA profiles of tumor tissues from HCC patients with (n=14) or without (n=13) pulmonary metastasis and HCC cell lines with different pulmonary metastatic potentials. Chemokine expression profiling and bioinformatics were used to detect the downstream target of candidate target. In gain- and loss-of-function assays were used to investigate the role of miRNA in HCC progression. Different subsets of NK cells were isolated and used for chemotaxis and functional assays in vivo and in vitro. In situ hybridization and immunohistochemical analyses were performed to detect the expression of miRNA in tumor tissues from 242 HCC patients undergoing curative resection from 2010. Results: Three miRNAs (miR-137, miR-149-5p, and miR-561-5p) were identified to be associated with pulmonary metastasis in patients with HCC. miR-561-5p was most highly overexpressed in metastatic HCC tissues and high-metastatic-potential HCC cell lines. In gain- and loss-of-function assays in a murine model, miR-561-5p promoted tumor growth and spread to the lungs. Yet, miR-561-5p did not appear to affect cellular proliferation and migration in vitro. Bioinformatics and chemokine expression profiling identified chemokine (C-X₃-C motif) ligand 1 (CX₃CL1) as a potential target of miR-561-5p. Furthermore, miR-561-5p promoted tumorigenesis and metastasis via CX₃CL1-dependent regulation of CX₃CR1⁺ NK cell infiltration and function. CX₃CR1⁺ NK cells demonstrated stronger in vivo anti-metastatic activity relative to CX₃CR1^- NK cells. CX₃CL1 stimulated chemotactic migration and cytotoxicity in CX₃CR1⁺ NK cells via STAT3 signaling. Blockade of CX₃CL1, CX₃CR1, or of pSTAT3 signaling pathways attenuated the antitumor responses. Clinical samples exhibited a negative correlation between miR-561-5p expression and levels of CX₃CL1 and CX₃CR1⁺ NK cells. High miR-561-5p abundance, low CX₃CL1 levels, and low numbers of CX₃CR1⁺ NK cells were associated with adverse prognosis. Conclusion: We delineated a miR-561-5p/CX3CL1/NK cell axis that drives HCC metastasis and demonstrated that CX₃CR1⁺ NK cells serve as potent antitumor therapeutic effectors.

SUBMITTER: Chen EB

PROVIDER: S-EPMC6643446 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The miR-561-5p/CX3CL1 Signaling Axis Regulates Pulmonary Metastasis in Hepatocellular Carcinoma Involving CX3CR1+ Natural Killer Cells Infiltration.

Chen Er-Bao EB Zhou Zheng-Jun ZJ Xiao Kun K Zhu Gui-Qi GQ Yang Yi Y Wang Biao B Zhou Shao-Lai SL Chen Qing Q Yin Dan D Wang Zheng Z Shi Ying-Hong YH Gao Dong-Mei DM Chen Jie J Zhao Yan Y Wu Wei-Zhong WZ Fan Jia J Zhou Jian J Dai Zhi Z

Theranostics 20190709 16

Natural killer (NK) cell can inhibit tumor initiation and regulates metastatic dissemination, acting as key mediators of the innate immune response. Intrinsic factors modulating NK cells infiltration and its anticancer activity remain poorly characterized. We investigated the roles of dysregulation of micro(mi)RNAs and NK cells in progression of hepatocellular carcinoma (HCC). Methods: Small RNA sequencing were used to detect the miRNA profiles of tumor tissues from HCC patients with (n=1 ...[more]

PMID: 31367257

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Project description:A coordinated host immune response mediated via chemokine network plays a crucial role in boosting defense mechanisms against pathogenic infections. The speed of Ag presentation and delivery by CD11c+ dendritic cells (DCs) to cognate T cells in lymphoid tissues may decide the pathological severity of the infection. Here, we investigated the role of CX3CR1 in the neuroinflammation induced by infection with Japanese encephalitis virus (JEV), a neurotrophic virus. Interestingly, CX3CR1 deficiency strongly enhanced susceptibility to JEV only after peripheral inoculation via footpad. By contrast, both CX3CR1+/+ and CX3CR1-/- mice showed comparable susceptibility to JEV following inoculation via intranasal and intraperitoneal routes. CX3CR1-/- mice exhibited lethal neuroinflammation after JEV inoculation via footpad route, showing high mortality, morbidity, pro-inflammatory cytokine expression, and uncontrolled CNS-infiltration of peripheral leukocytes including Ly-6Chi monocytes and Ly-6Ghi granulocytes. Furthermore, the absence of CX3CR1+CD11c+ DCs appeared to enhance susceptibility of CX3CR1-/- mice to JE after peripheral JEV inoculation. CX3CR1 ablation impaired the migration of CX3CR1+CD11c+ DCs from JEV-inoculated sites to draining lymph nodes (dLNs), resulting in decreased NK cell activation and JEV-specific CD4+/CD8+ T-cell responses. However, CX3CR1-competent mice showed rapid temporal expression of viral Ags in dLNs. Subsequently, JEV was rapidly cleared, with concomitant generation of antiviral NK cell activation and T-cell responses mediated by rapid migration of JEV Ag+CX3CR1+CD11c+ DCs. Using biallelic functional CX3CR1 expression system, the functional expression of CX3CR1 on CD11chi DCs appeared to be essentially required for inducing rapid and effective responses of NK cell activation and Ag-specific CD4+ T cells in dLNs. Strikingly, adoptive transfer of CX3CR1+CD11c+ DCs was found to completely restore the resistance of CX3CR1-/- recipients to JEV, as corroborated by the rapid delivery of JEV Ags in dLNs and attenuation of neuroinflammation in the CNS. Collectively, these results indicate that CX3CR1+CD11c+ DCs play an important role in generating rapid and effective responses of antiviral NK cell activation and Ag-specific T cells after peripheral inoculation with the virus, thereby resulting in conferring resistance to viral infection by reducing the peripheral viral burden.

Project description:BackgroundAngiostrongylus cantonensis (A. cantonensis), is a food-borne zoonotic parasite that can cause central nervous system (CNS) injury characterized by eosinophilic meningitis. However, the pathogenesis of angiostrongylosis remains elusive. Natural killer cells (NK cells) are unique innate lymphocytes important in early defense against pathogens. The aim of this study was to investigate the role of NK cells in A. cantonensis infection and to elucidate the key factors that recruit NK cells into the CNS.MethodsMouse model of A. cantonensis infection was established by intragastric administration of third-stage larvae. The expression of cytokines and chemokines at gene and protein levels was analyzed by qRT-PCR and ELISA. Distribution of NK cells was observed by immunohistochemistry and flow cytometry. NK cell-mediated cytotoxicity against YAC-1 cells was detected by LDH release assay. The ability of NK cells to secrete cytokines was determined by intracellular flow cytometry and ELISA. Depletion and adoptive transfer of NK cells in vivo was induced by tail vein injection of anti-asialo GM1 rabbit serum and purified splenic NK cells, respectively. CX3CL1 neutralization experiment was performed by intraperitoneal injection of anti-CX3CL1 rat IgG.ResultsThe infiltration of NK cells in the CNS of A. cantonensis-infected mice was observed from 14 dpi and reached the peak on 18 and 22 dpi. Compared with uninfected splenic NK cells, the CNS-infiltrated NK cells of infected mice showed enhanced cytotoxicity and increased IFN-γ and TNF-α production ability. Depletion of NK cells alleviated brain injury, whereas adoptive transfer of NK cells exacerbated brain damage in A. cantonensis-infected mice. The expression of CX3CL1 in the brain tissue and its receptor CX3CR1 on the CNS-infiltrated NK cells were both elevated after A. cantonensis infection. CX3CL1 neutralization reduced the percentage and absolute number of the CNS-infiltrated NK cells and relieved brain damage caused by A. cantonensis infection.ConclusionsOur results demonstrate that the up-regulated CX3CL1 in the brain tissue recruits NK cells into the CNS and aggravates brain damage caused by A. cantonensis infection. The findings improve the understanding of the pathogenesis of angiostrongyliasis and expand the therapeutic intervention in CNS disease.

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The miR-561-5p/CX₃CL1 Signaling Axis Regulates Pulmonary Metastasis in Hepatocellular Carcinoma Involving CX₃CR1⁺ Natural Killer Cells Infiltration.

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The miR-561-5p/CX<sub>3</sub>CL1 Signaling Axis Regulates Pulmonary Metastasis in Hepatocellular Carcinoma Involving CX<sub>3</sub>CR1<sup>+</sup> Natural Killer Cells Infiltration.

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