PLOS BIOLOGY
·
2018
·Vol. 16
·期 7
·e2005869
·
IF 9.163
Weilong Chen,Yuanyuan Qin,Dong Wang,Lei Zhou,Yin Liu,Sheng Chen,Liang Yin,Yaoxing Xiao,Xiao-Hong Yao,Xiaoli Yang,Wei Ma,Weifeng Chen,Xueyan He,Lixing Zhang,Qifeng Yang,Xiuwu Bian,Zhi-ming Shao,Suling Liu
Chemotherapeutic resistance in triple-negative breast cancer (TNBC) has brought great challenges to the improvement of patient survival. The mechanisms of taxane chemoresistance in TNBC have not been well investigated. Our results illustrated C-C motif chemokine ligand 20 (CCL20) was significantly elevated during taxane-containing chemotherapy in breast cancer patients with nonpathologic complete response. Furthermore, CCL20 promoted the self-renewal and maintenance of breast cancer stem cells (BCSCs) or breast cancer stem-like cells through protein kinase Cζ (PKCζ) or p38 mitogen-activated protein kinase (MAPK)-mediated activation of p65 nuclear factor kappa B (NF-κB) pathway, significantly increasing the frequency and taxane resistance of BCSCs. Moreover, CCL20-promoted NF-κB activation increased ATP-binding cassette subfamily B member 1 (ABCB1)/multidrug resistance 1 (MDR1) expression, leading to the extracellular efflux of taxane. These results suggested that chemotherapy-induced CCL20 mediated chemoresistance via up-regulating ABCB1. In addition, NF-κB activation increased CCL20 expression, forming a positive feedback loop between NF-κB and CCL20 pathways, which provides sustained impetus for chemoresistance in breast cancer cells. Our results suggest that CCL20 can be a novel predictive marker for taxane response, and the blockade of CCL20 or its downstream pathway might reverse the taxane resistance in breast cancer patients.
Breast cancers are divided into several different subtypes according to the expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal receptor 2 (HER2). One subtype of breast cancer is known as triple-negative breast cancer (TNBC) because of lack of expression of all three receptors. TNBC is highly malignant and susceptible to developing drug resistance during chemotherapy. However, the reasons for resistance have not been well explained. We found that a secretory protein called C-C motif chemokine ligand 20 (CCL20) responds to taxane chemotherapy in TNBC and promotes the expression of a drug efflux pump through a specific signaling pathway (CCL20-protein kinase Cζ [PKCζ]/p38 mitogen-activated protein kinase [MAPK]-nuclear factor kappa B [NF-κB]-ATP-binding cassette subfamily B member 1 [ABCB1]). Increasing levels of CCL20 result in expanding breast cancer stem-like cell population and chemotherapeutic resistance in breast cancer cells. Breast cancer stem-like cells are a special population of cells with self-renewal and differentiation potential within the tumor, which are often the culprit of tumor reoccurrence, drug resistance, and metastasis. Our results suggest that blocking CCL20 or its downstream signal can significantly improve the therapeutic efficacy of TNBC.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
CANCER LETTERS
·
2026
·
IF 11.8
Ling-Dong Meng,Lu-Yang Jiang,Yang-Yang Liang,Zhan-Zhong Zheng,Qun Chen,Dan-Rui Li,Shuang Wang,Hao Yuan,Xu Feng,Kui-Rong Jiang
Pancreatic cancer has a dismal prognosis, largely due to resistance to all current therapeutic modalities, including prevailing immunotherapy. Deciphering the mechanisms underlying the immunosuppressive tumor microenvironment is pivotal for developing effective therapeutic strategies. In this study, we found that the expression of CCL20 is negatively correlated with the infiltration of CD8 + T cells, and consistently, patients with higher CCL20 expression have a worse prognosis. CCL20, as a secreted ligand protein regulated by SP5, can bind to its cognate receptor CCR6 in the tumor microenvironment and is mainly produced by tumor cells, as confirmed by single-cell RNA sequencing and immunofluorescence staining of tumor tissues. Compared with CCL20 wild-type tumors, CCL20 knockout tumors exhibited impaired growth, decreased infiltration of CCR6 + Tregs, and concomitantly increased infiltration of CD8 + T cells. Importantly, this altered immune infiltration phenotype was abolished in Treg-specific CCR6 knockout mice. Furthermore, CCR6 inhibition potentiated the efficacy of anti-PD1 immune checkpoint blockade. Taken together, our data demonstrate that tumor cell-derived CCL20 shapes an immunosuppressive microenvironment in pancreatic cancer by recruiting CCR6 + Tregs, suggesting that targeting the CCL20-CCR6 axis offers a promising therapeutic strategy, particularly when combined with immune checkpoint blockade.
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Hao Kan,Yuan Liu,Ka Zhang,Aiqin Mao,Li Geng,Fan Yu,Lei Feng
Background Endothelial dysfunction induced by lipotoxicity is a critical initiating factor in atherosclerosis. Sweroside, a bioactive iridoid glycoside, possesses significant anti-inflammatory activities; however, its therapeutic potential in regulating vascular endothelial inflammation and dysfunction remains unexplored. This study aimed to investigate the protective effects of Sweroside against endothelial injury and to elucidate the underlying molecular mechanisms, specifically focusing on the transcriptional regulation of inflammatory cascades. Methods Human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs) stimulated with palmitic acid (PA), along with C57BL/6J mice fed a high-fat diet (HFD), served as the in vitro and in vivo models, respectively. Transcriptome sequencing (RNA-seq) was employed to screen for potential therapeutic targets. Molecular mechanisms were validated using small interfering RNA (siRNA) knockdown, Western blotting, and dual-luciferase reporter assays. Vascular function was evaluated via wire myograph to assess endothelium-dependent relaxation and pulse wave velocity (PWV) to measure arterial stiffness. Results Sweroside treatment significantly attenuated PA-induced cytotoxicity, oxidative stress, inflammation, and cytoskeletal disruption in ECs. RNA-seq identified Krüppel-like Factor 2 ( KLF2 ) as a core target up-regulated by Sweroside. Mechanistically, Sweroside restored KLF2 expression, which subsequently functioned as a transcriptional repressor by directly binding to the promoter of Fatty Acid Binding Protein 4 ( FABP4 ). This repression reduced FABP4 levels, thereby alleviating the suppression of PPAR-γ and blocking the NF-κB-dependent induction of the downstream chemokine CCL20. In vivo, Sweroside administration effectively improved endothelium-dependent relaxation, and reduced aortic stiffness and vascular inflammation in HFD-fed mice. Conclusions Sweroside ameliorates endothelial dysfunction and vascular remodeling by activating the KLF2-mediated signaling axis to repress FABP4 and the downstream CCL20 inflammatory cascade. These findings highlight Sweroside as a promising therapeutic candidate for the treatment of atherosclerosis and cardiovascular diseases associated with metabolic inflammation.
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Xiaoming Su,Xinyu Liu,Yuzhen Ouyang,Yangcenzi Xie,Mingyang Chen,Pan Chen,Jia Liu,Minghua Wu,Chien-hong Lin,Hong Zhong,Ming Li
Operative microwave ablation (MWA) has become a superior curative treatment modality for unresectable hepatocellular carcinoma (HCC). However, rapid noninvasive assessment of the MWA outcomes of HCC patients remains technically challenging. Herein, a surface-enhanced Raman spectroscopy (SERS)-lateral flow strip (LFS) immunosensor is reported for simultaneous quantification of two serum protein biomarkers – (C-C motif chemokine ligand 20) CCL20 and epidermal growth factor (EGF) proteins, which enables rapid noninvasive assessment of operative MWA outcomes of HCC patients. This biosensor is built with two test lines for CCL20 and EGF proteins using the encoded SERS probes, respectively. The integration of the SERS detection and the lateral flow immunoassay detection format yields high sensitivity, robust anti-interference ability, and ease-to-use. This biosensor achieves a limit of detection down to 0.064 ng/mL for CCL20 protein and 0.090 ng/mL for EGF protein with a wide dynamic detection range. Moreover, the SERS-LFS immunosensor is demonstrated with exceptional performance for quantitative detection of CCL20 and EGF proteins in clinical serum samples in a single test strip. The results reveal the discriminative levels of CCL20 and EGF proteins in serum samples of HCC patients undergoing complete and incomplete MWA, verifying the capability of our developed biosensor for rapid assessment of MWA outcomes. We believe that the developed SERS-LFS immunosensor could be applied to support medical professionals in clinical settings for improvement of MWA outcomes of HCC patients.
研究领域:
医学工程
·
肿瘤学
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Hongping Wan,Kai Deng,Zhengqun Huang,Yunhan Yang,Bo Jing,Yumei Feng,Yuanfeng Li,Yong Liu,Mingqin Lu,Xinghong Zhao
Despite the safety profile of subunit vaccines, the inferior immunogenicity hinders their application in the nasal cavity. This study introduces a novel antigen delivery and adjuvant system utilizing mucoadhesive chitosan–catechol (Chic) on silica spiky nanoparticles (Ssp) to enhance immunity through multiple mechanisms. The Chic functionalizes the Ssp surface and incorporates with SARS-CoV-2 spike protein receptor-binding domain (RBD) and toll-like receptor (TLR)9 agonist unmethylated cytosine-guanine (CpG) motif, forming uniform virus-like nanoparticles (Ssp-Chic-RBD-CpG) via electrostatic and covalent interactions. Ssp-Chic-RBD-CpG, mimicking the morphology and function of inactive virions, effectively prolongs the retention time of RBD in the nasal mucosa by 3.92-fold compared to RBD alone, enhances the maturation of dendritic cells (DCs), and facilitates the antigen trafficking to the draining lymph nodes, which subsequently induces a stronger mucosal immunity. Mechanistically, the enhanced chemokine chemokine (C-C motif) ligand 20 (CCL20)-driven DCs recruitment and maturation by Ssp-Chic-RBD-CpG are evidenced by a cell co-culture model. In addition, the overexpression of TLR4/9 and activation of MYD88/NF-κB signaling pathway in activation of DCs are observed. Proof of principle is obtained for RBD, but similar delivery mechanisms can be applied in other protein-based subunit vaccines as well when intranasal administration is needed.
研究领域:
纳米技术
·
免疫学
·
疫苗开发
·
分子生物学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）