Publications by authors named "Yongling Ning"

11 Publications

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Babao Dan is a robust anti-tumor agent via inhibiting wnt/β-catenin activation and cancer cell stemness.

J Ethnopharmacol 2021 Nov 28;280:114449. Epub 2021 Jul 28.

Fujian Key Laboratory of Integrative Medicine on Geriatric, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China. Electronic address:

Ethnopharmacological Relevance: Traditional Chinese Medicine (TCM) is being increasingly used worldwide due to its diverse efficacy and relatively low side effects. Babao Dan (BBD) is a well-known TCM formula that is currently used for the effective treatment of various cancers, however its underlying molecular mechanism remains unknown.

Aim Of The Study: Tumor growth and tumor recurrence are characterized by two distinct populations of cells, namely the well-differentiated cancer cells composing the majority of tumor bulk, and cancer stem cells (CSCs) involved in tumor relapse, which are both strongly associated with excessive activation of Wnt/β-catenin signaling. Our study aims to elucidate the underlying molecular mechanisms associated with the anti-tumor proliferative effects of Babao Dan (BBD).

Materials And Methods: We used a hepatoblastoma cell line HepG2 with stem cell-like traits that harbors a constitutively active mutant of β-catenin in order to study the anti-tumor ability of BBD via targeting Wnt/β-catenin signaling.

Results: BBD robustly attenuated both the intrinsic and extrinsic activation of Wnt/β-catenin pathway in HepG2 hepatoblastoma cells, as well as Wnt target genes. Moreover, BBD significantly inhibited both the proliferation of well-differentiated cancer cells, as well as the stem-like property of CSCs as evidenced by EpCAM, a Wnt target gene and a novel marker of cancer cell stemness. In addition, mice administered with BBD using HepG2 cell line derived xenograft model had marked reductions in tumor size and weight, as well as significantly decreased expressions of Wnt target genes and cancer cell stemness.

Conclusion: Our findings elucidated the underlying molecular mechanisms associated with the robust anti-tumor effects of BBD via potent inhibition of Wnt/β-catenin signaling, and implicate its use in the clinical treatment of cancers.
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http://dx.doi.org/10.1016/j.jep.2021.114449DOI Listing
November 2021

HDAC9 deficiency promotes tumor progression by decreasing the CD8 dendritic cell infiltration of the tumor microenvironment.

J Immunother Cancer 2020 06;8(1)

Medical Research Center, The Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People's Hospital, Changzhou, Jiangsu, China

Background: The tumor microenvironment (TME) contains a variety of immune cells, which play critical roles during the multistep development of tumors. Histone deacetylase 9 (HDAC9) has been reported to have either proinflammatory or anti-inflammatory effects, depending on the immune environment. In this study, we investigated whether HDAC9 in the tumor stroma regulated inflammation and antitumor immunity.

Methods: knockout mice were generated to analyze the HDAC9-associated inflammation and tumor progression. Immune cells and cytokines in TME or draining lymph nodes were quantified by flow cytometry and quantitative reverse transcription-PCR. The antigen presentation and CD8 T cell priming by tumor-infiltrating dendritic cells (DCs) were evaluated in vitro and in vivo. HDAC9-associated inflammation was investigated in a mouse model with dextran sulfate sodium-induced colitis. Correlation of HDAC9 with CD8 expression was assessed in tissue sections from patients with non-small cell lung cancer.

Results: HDAC9 deficiency promoted tumor progression by decreasing the CD8 DC infiltration of the TME. Compared with wild-type mice, the tumor-infiltrating DCs of mice displayed impaired cross-presentation of tumor antigens and cross-priming of CD8 T cells. Moreover, HDAC9 expression was significantly positively correlated with CD8 cell counts in human lung cancer stroma samples.

Conclusions: HDAC9 deficiency decreased inflammation and promoted tumor progression by decreasing CD8 DC infiltration of the TME. HDAC9 expression in the tumor stroma may represent a promising biomarker to predict the therapeutic responses of patients receiving CD8 T cell-dependent immune treatment regimens.
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http://dx.doi.org/10.1136/jitc-2020-000529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304847PMC
June 2020

Key genes and pathways in tumor-educated dendritic cells by bioinformatical analysis.

Microbiol Immunol 2020 Jan 10;64(1):63-71. Epub 2019 Oct 10.

Medical Research Center, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China.

Specific tumor microenvironment signaling might prevent the maturation of dendritic cells (DCs) with tolerogenic and immunosuppressive potential accounting for antigen-specific unresponsiveness in the lymphoid organs and in the periphery. In the present study, dendritic cells treated with LLC lung cancer cell or 4T1 breast cancer cell culture supernatants significantly down-regulated the expression of co-stimulatory molecules MHC-II, CD40, CD80, but up-regulated the inhibitory molecule PD-L1/L2, VISTA, and increased the messengerRNA levels of interleukin (IL)-6, arginase I, and IL-10, but decreased tumor necrosis factor-α and IL-12a. RNA was isolated from the dendritic cells with or without tumor supernatant stimulation and RNA sequencing was done. Then the differential expression genes were sorted, the candidate genes were analyzed and pathway enrichment analysis was done, and the associated protein-protein interaction network (PPI) was established. After integrated bioinformatical analysis, 405 (279 up-regulated and 126 down-regulated) consistently differential expression genes were identified. Using gene ontology and pathway analysis, it was found that differential expression genes were mainly enriched in the immune response, cell-cell interaction, hemostasis, and cell surface interactions with the vascular wall. The PPI data demonstrated that 236 nodes were classified with 1072 edges, and the most remarkable three modules involved 53 central node genes associated with cell survival, cell-substrate adhesion, chemotaxis, migration, immune response, and complement receptor mediated signaling pathway. These findings revealed the immune status of dendritic cells in the tumor environment.
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http://dx.doi.org/10.1111/1348-0421.12747DOI Listing
January 2020

β-Glucan induces autophagy in dendritic cells and influences T-cell differentiation.

Med Microbiol Immunol 2019 Feb 7;208(1):39-48. Epub 2018 Aug 7.

Medical Research Center, The Affiliated Changzhou No. 2 People's Hospital, Nanjing Medical University, Changzhou, 213003, China.

β-Glucan has been reported to activate dendritic cells (DCs), and activated DCs, subsequently, promote Th1 and cytotoxic T-lymphocyte priming and differentiation in vitro. However, the mechanism that regulates the immune response of β-glucan-induced DCs has not been thoroughly elucidated to date. Recent studies have drawn attention to a strong relationship between pathogen-associated molecular patterns (PAMP) recognition and autophagy for the activation of DC function. In this study, we observed that β-glucan induced the expression of a number of autophagy-related genes and the formation of autophagosomes in DCs. To further investigate whether β-glucan-induced DC activation and innate cytokine production are associated with autophagy, we utilized 3-MA to block autophagosome formation and accessed the maturation and function of DCs induced by β-glucan. We found that autophagy-deficient DCs showed downregulated expression of MHC-II and CD80, decreased TNF-α secretion, and reduced production of iNOS upon β-glucan stimulation. Further examination demonstrated that blockade of autophagy in β-glucan-induced DCs significantly attenuated IFN-γ production by co-cultured CD4 + T cells and inhibited the proliferation and differentiation of CD4 + T cells. Thus, these data indicate that autophagy in β-glucan-induced DCs is a crucial mechanism for the maturation of DCs, and it drives innate cytokine production, thereby facilitating adaptive immune responses.
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http://dx.doi.org/10.1007/s00430-018-0556-zDOI Listing
February 2019

Tumor exosomes block dendritic cells maturation to decrease the T cell immune response.

Immunol Lett 2018 07 22;199:36-43. Epub 2018 May 22.

Medical Research Center, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China; Oncology Institute, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, 213003, China. Electronic address:

Tumors can induce the generation and accumulation of immunosuppression in a tumor microenvironment, contributing to the tumor's escape from immunological surveillance. Although tumor antigen-pulsed dendritic cell can improve anti-tumor immune responses, tumor associated regulatory dendritic cells are involved in the induction of immune tolerance. The current study sought to investigate whether exosomes produced by tumor cells had any effect on DCs in immune suppression. In this study, we examined the effect of tumor exosomes on DCs and found that exosomes from LLC Lewis lung carcinoma or 4T1 breast cancer cell blocked the differentiation of myeloid precursor cells into CD11c DCs and induced cell apoptosis. Tumor exosome treatment inhibited the maturation and migration of DCs and promoted the immune suppression of DCs. The treatment of tumor exosomes drastically decreased CD4IFN-γ Th1 differentiation but increased the rates of regulatory T (Treg) cells. The immunosuppressive ability of tumor exosome-treated DCs were partially restored with PD-L1 blockage. These data suggested that PD-L1 played a role in tumor exosome-induced DC-associated immune suppression.
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http://dx.doi.org/10.1016/j.imlet.2018.05.002DOI Listing
July 2018

[Whole glucan particle promotes the maturation of tumor-educated mouse dendritic cells to suppress regulatory T cell differentiation].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2017 Sep;33(9):1171-1176

Medical Research Center, Changzhou Second People's Hospital, Nanjing Medical University, Changzhou 213164, China. *Corresponding authors, E-mail:

Objective To investigate the maturation and immune responses of tumor-educated dendritic cells (TEDCs) stimulated by whole glucan particle (WGP). Methods Mouse bone marrow-derived dendritic cells were generated by Flt3 ligand and co-cultured with interleukin 10 (IL-10) and transforming growth factor β (TGF-β) in vitro to induce TEDCs, and then stimulated by WGP for 2 days. CD4 FOXP3 T cells from the lymph nodes and spleens of OT-II mice were purified by magnetic-activated cell sorting, and then co-cultured with TEDCs in the presence of ovalbumin (OVA). Expressions of cell surface markers (CD11c, CD86, CD40, CD80, MHC-II) and CD4 FOXP3T cell differentiation and proliferation were detected by flow cytometry. real-time quantitative PCR was used to detect the mRNA levels of TNF-α, IL-12p40, IL-10, IL-6, IL-4, TGF-β1 and ELISA was used to detect the levels of TNF-α, IL-23, IL-12p70, IL-4 in culture supernatant. Results WGP up-regulated MHC-II and co-stimulation molecules CD86, CD80, CD40 on TEDCs, increased the levels of TNF-α, IL-12p40, IL-6 in TEDCs, decreased the production of TGF-β1. Furthermore, WGP also suppressed CD4FOXP3 T cell differentiation and proliferation in vitro. Conclusion WGP improves TEDC maturation and inhibits immunosuppressive functions.
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September 2017

[Guanylate-binding protein 2 regulates the maturation of mouse dendritic cells induced by β-glucan].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2017 Sep;33(9):1153-1159

Medical Research Center, Changzhou Second People's Hospital, Nanjing Medical University, Changzhou 213000, China. *Corresponding author, E-mail:

Objective To investigate the effect of guanylate-binding protein 2 (GBP2) on β-glucan-induced maturation and immune response of dendritic cells (DCs). Methods RNA-microarray and real time quantitative PCR were used to investigate the change of genes in DCs induced by β-glucan. Thereafter, DCs were transfected with GBP2 siRNA to knock down the expression of GBP2. Flow cytometry was used to detect the surface markers (CD11c, MHC-II, CD80) on DCs as well as the proliferation of T cells. Cytokines (IL-6, IL-12p70, TNF-α, IL-10) were tested by ELISA. Results The expressions of DC surface markers, including CD11c, MHC- II, CD80, were significantly down-regulated after the cells were transfected with GBP2 siRNA. Moreover, the production of IL-6, IL-12 and TNF-α were also depressed. OVA specific T-cell proliferation decreased when OT-II T cells were co-cultured with GBP2-siRNA transfected-DCs. Conclusion GBP2 can effectively regulate β-glucan-induced maturation of DCs, thus suppressing the proliferation of T cells.
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September 2017

β-glucan restores tumor-educated dendritic cell maturation to enhance antitumor immune responses.

Int J Cancer 2016 Jun 8;138(11):2713-23. Epub 2016 Feb 8.

Medical Research Center, The Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People's Hospital, Changzhou, 213003, China.

Tumors can induce the generation and accumulation of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) in a tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell-based cancer vaccines can initiate antitumor immune responses, tumor-educated dendritic cells (TEDCs) involved in the tolerance induction have attracted much attention recently. In this study, we investigated the effect of β-glucan on TEDCs and found that β-glucan treatment could promote the maturation and migration of TEDCs and that the suppressive function of TEDCs was significantly decreased. Treatment with β-glucan drastically decreased the levels of regulatory T (Treg) cells but increased the infiltration of macrophages, granulocytes and DCs in tumor masses, thus elicited Th1 differentiation and cytotoxic T-lymphocyte responses and led to a delay in tumor progression. These findings reveal that β-glucan can inhibit the regulatory function of TEDCs, therefore revealing a novel function for β-glucan in immunotherapy and suggesting its potential clinical benefit. β-Glucan directly abrogated tumor-educated dendritic cells-associated immune suppression, promoted Th1 differentiation and cytotoxic T-lymphocyte priming and improved antitumor responses.
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http://dx.doi.org/10.1002/ijc.30002DOI Listing
June 2016

[β-Glucan promotes the maturation and migration of bone marrow-derived dendritic cells].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2016 Jan;32(1):10-4

Medical Research Center, Changzhou Second People's Hospital, Nanjing Medical University, Changzhou 213000, China. *Corresponding author, E-mail:

Objective: To investigate the effects of β-glucan on the maturation and migration of bone marrow-derived dendritic cells (BMDCs).

Methods: BMDCs were isolated from mouse bone marrow cells in vitro and induced by β-glucan for maturation. The expressions of cell surface markers were detected by flow cytometry (FCM). The cytokines (IL-6, IL-12p40, tumor necrosis factor α) in the supernatants were measured by ELISA, and the expressions of intracellular CC chemokine receptor 1 (CCR1), CCR2, CCR5, CCR7 were determined by real-time quantitative PCR. Furthermore, the chemotactic response to CC chemokine ligand 19 (CCLl9) and CCL21, i.e. CCR7-1igands, was measured by Transwell(TM) migration assay. Moreover, the number of migrated cells in the draining lymph nodes was analyzed by FCM.

Results: Compared with the control group, the expressions of co-stimulation molecules (MHC II, CD40, CD80, CD86) on BMDCs were up-regulated in the presence of β-glucan. Furthermore, β-glucan could prompt BMDCs to secret high levels of IL-6, TNF-α, IL-12 p40 and increase the production of CCR7 mRNA. After β-glucan treatment, BMDCs were more sensitive to CCL19/CCL21. The number of BMDCs migrated from subcutaneous injection site into the draining lymph nodes significantly increased in β-glucan group.

Conclusion: β-glucan can promote the maturation of BMDCs and enhance the migration ability of BMDCs in vitro and in vivo.
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January 2016

MiR-124 inhibits cell proliferation in breast cancer through downregulation of CDK4.

Tumour Biol 2015 Aug 3;36(8):5987-97. Epub 2015 Mar 3.

Oncology Institute, The Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People's Hospital, Changzhou, 213003, China.

Studies have shown that microRNAs (miRNAs) are involved in the malignant progression of human cancer. However, little is known about the potential role of miRNAs in breast carcinogenesis. miR-124 expression in breast cancer tissue was measured by quantitative real-time PCR (qRT-PCR). Target prediction algorithms and luciferase reporter gene assays were used to investigate the target of miR-124. Breast cancer cells growth was regulated by overexpression or knockdown miR-124. At the end of the study, tumor-bearing mice were tested to confirm the function of miR-124 in breast cancer. In this study, we demonstrated that the expression of miR-124 was significantly downregulated in breast cancer tissues compared with matched adjacent non-neoplastic tissues. We identified and confirmed that cyclin-dependent kinase 4 (CDK4) was a direct target of miR-124. Overexpression of miR-124 suppressed CDK4 protein expression and attenuated cell viability, proliferation, and cell cycle progression in MCF-7 and MDA-MB-435S breast cancer cells in vitro. Overexpression of CDK4 partially rescued the inhibitory effect of miR-124 in the breast cancer cells. Moreover, we found that miR-124 overexpression effectively repressed tumor growth in xenograft animal experiments. Our results demonstrate that miR-124 functions as a growth-suppressive miRNA and plays an important role in inhibiting tumorigenesis by targeting CDK4.
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http://dx.doi.org/10.1007/s13277-015-3275-8DOI Listing
August 2015

β-Glucan enhances cytotoxic T lymphocyte responses by activation of human monocyte-derived dendritic cells via the PI3K/AKT pathway.

Hum Immunol 2015 Mar 27;76(2-3):146-54. Epub 2015 Jan 27.

Oncology Institute, The Affiliated Hospital of Nanjing Medical University, Changzhou No. 2 People's Hospital, Changzhou 213003, China. Electronic address:

Purpose: To investigate the effects of β-(1,3/1,6)-d-glucan on dendritic cells (DCs) maturation, cytotoxic T lymphocyte responses and the molecular mechanisms of its transition.

Methods And Results: Human monocyte-derived DCs were matured using yeast-derived particulate β-glucan (WGP) or a mix of TNF-α, IL-1β and IL-6 ("Conv mix"). Multicolor flow cytometry was used to study the DCs phenotype and cytotoxic T-lymphocyte priming and differentiation. ELISA and RT-PCR assays were used to evaluate cytokine production. Western blot was used to investigate the signal pathways. WGP-matured DCs functions were compared with those of Conv mix-matured DCs. WGP-matured DCs expressed higher levels of CD11c, CD86, CD40 and HLA-DR; produced higher levels of pro-inflammatory cytokines; and elicited more CTL priming and differentiation than Conv mix-matured DCs. The PI3K/AKT signaling pathway was involved in WGP-induced dendritic cell maturation. Furthermore, WGP-matured DCs significantly increased tumor-specific CTL responses.

Conclusion: Excellent ability of yeast-derived particulate β-glucan to induce DCs maturation and tumor-specific CTL responses explains, in part, its clinical benefits and emphasizes its utility in ex vivo maturation of DCs generated for therapy.
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http://dx.doi.org/10.1016/j.humimm.2015.01.009DOI Listing
March 2015
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