Cell Reports
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2019
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IF 7.815
Dan Chen,Wei Xu,Yu Wang,Yongshen Ye,Yue Wang,Miao Yu,Jinghu Gao,Jielin Wei,Yiming Dong,Honghua Zhang,Xin Fu,Ke Ma,Hui Wang,Zhenrong Yang,Jie Zhou,Wenqing Cheng,Shu Wang,Juan Chen,Barth D. Grant,Chad L. Myers,Anbing Shi,Tian Xia
To systematically explore the genes mediating functional crosstalk between metazoan biological processes, we apply comparative genetic interaction (GI) mapping in Saccharomyces cerevisiae and Caenorhabditis elegans to generate an inter-bioprocess network consisting of 178 C. elegans GIs. The GI network spans six annotated biological processes including aging, intracellular transport, microtubule-based processes, cytokinesis, lipid metabolic processes, and anatomical structure development. By proposing a strategy called “reciprocal functional test” for interacting gene pairs, we discover a group of genes that mediate crosstalk between distinct biological processes. In particular, we identify the ribosomal S6 Kinase/RSKS-1, previously characterized as an mTOR (mechanistic target of rapamycin) effector, as a regulator of DAF-2 endosomal recycling transport, which traces a functional correlation between endocytic recycling and aging processes. Together, our results provide an alternative and effective strategy for identifying genes and pathways that mediate crosstalk between bioprocesses with little prior knowledge.
研究领域:
分子生物学
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遗传学
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细胞生物学
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发育生物学
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代谢调控
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衰老研究
✓ 已验证
DOI
PubMed
高影响因子
Cancer Communications
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2025
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IF 24.9
Fanglin Tian,Jian Huang,Weina Fan,Xin Li,Yuning Zhan,Kexin Zhu,Xiangyu Wang,Xin Hong,Xin Wang,Jin Ren,Ying Xing,Li Cai
Background Eps15 homology domain (EHD) proteins, including EHD1 to EHD4, play vital roles in tumor progression. In this study, we aimed to investigate which specific EHD proteins, if any, are implicated in tumor immune evasion and immunotherapy response. Methods The immunotherapy responses of lung adenocarcinoma (LUAD) patients were predicted using tumor immune dysfunction and exclusion (TIDE) analysis. The T cell killing assay was performed by co-culturing activated T cells with LUAD cells. The function of EHD1 as a regulator of programmed death-ligand 1 (PD-L1) endocytic recycling was determined by receptor internalization assays. Methylated RNA immunoprecipitation (MeRIP) was performed to investigate N6-methyladenosine (m 6 A) modification of EHD1 mRNA. The protein-protein interaction was revealed by the molecular docking analysis and validated by immunofluorescence (IF) and immunoprecipitation (IP) assays. RNA immunoprecipitation (RIP) was used to examine the interaction between YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1) and EHD1 mRNA. The regulatory mechanism of YTHDF1 on EHD1 was investigated through the application of m 6 A-binding site mutation analysis. The murine LUAD cells were employed to establish subcutaneous xenograft models within immunocompetent C57BL/6 mice to assess the immunomodulatory impact of EHD1 in vivo. Results TIDE algorithms and survival analysis identified that EHD1 promoted LUAD immune escape. EHD1 knockdown enhanced T cell cytotoxicity in killing LUAD cells across all effector-to-target (E/T) ratios. EHD1 overexpression exerted the opposite effect. The molecular docking analysis revealed an interaction between EHD1 and the PD-L1 protein, verified by IF and IP. Furthermore, EHD1 knockdown inhibited PD-L1 recycling, thereby promoting its lysosomal degradation. Disruption of the EHD1/PD-L1 interaction impaired the regulatory function of EHD1 in tumor immune evasion. In an immune-competent mouse model, we found that EHD1 silencing impeded tumor immune evasion and enhanced the efficacy of anti‑PD‑1 therapy. MeRIP-qPCR confirmed obvious m 6 A modification of EHD1 . Further, the EHD1 mRNA was found to bind to the YTHDF1 protein, an m 6 A reader. YTHDF1 overexpression up-regulated EHD1 expression by enhancing its mRNA stability in an m 6 A-dependent manner. Conclusion Our study illuminates the role of m 6 A-modified EHD1 in tumor immune evasion and immunotherapy responses, thereby offering a novel avenue to potentially enhance immunotherapeutic sensitivity and improve the prognosis for patients with LUAD.
研究领域:
癌症生物学
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免疫学
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分子生物学
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生物化学
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RNA生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanomedicine-Nanotechnology Biology and Medicine
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2020
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IF 5.182
Zitong Qi,Cuiping Jiang,Hai Gao,Yanyan Wang,Qiqi Zhang,Wenli Zhang,Jianping Liu
Reconstituted high-density lipoproteins (rHDLs) hold promise as nanocarriers for atherosclerosis-targeted delivery, with biofunctions typified by mediating cholesterol efflux. The paradox is how rHDL offloads the delivered drugs into atherosclerotic foam cells , while simultaneously transferring cholesterol out of cells. Herein, simvastatin-loaded discoidal rHDL (ST-d-rHDL), constructed based on established paradigms, was employed to investigate its basic trafficking mechanism in foam cells. As proved, ST-d-rHDL was resecreted via lysosomal and Golgi apparatus-recycling endosome-mediated pathways following clathrin-mediated endocytosis . And the resecretion ratio reached 60% within 6-h chase with excessive ST-d-rHDLs. During the rHDL resecretion, 39% of cellular cholesterol efflux was detected, accompanied by 85% of the encapsulated cargo released intracellularly. Furthermore, the recycling rate was demonstrated to be promoted by smaller rHDL size and higher cellular lipid contents. Collectively, endocytic recycling confers the synergism in ST-d-rHDL to coordinate cholesterol efflux and intracellular drug release, providing new insights into design of biofunctional rHDL.
研究领域:
药理学
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细胞生物学
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纳米技术
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心血管疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2015
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IF 7.705
HongYan Zhu,ShengYu Zhang,Yong Ling,GuoLiang Meng,Yu Yang,Wei Zhang
Hypoxia is a characteristic of cancer and plays a key role in tumorigenesis, angiogenesis and resistance to cancer therapies. SiRNA treatment is effective against hypoxic tumors by gene silencing. However, siRNA delivery to the hypoxic regions of solid tumors still presents a challenge due to the distance from blood vessels and the increased presence of efflux transporters. Therefore, tumor therapies would be improved through the immediate development of an effective siRNA delivery system to hypoxic regions. To this end, we synthesized a system to deliver HIF-1α siRNA into hypoxic tumor cells. The system consists of a functional shell composed of 2-deoxyglucose (DG)-polyethylene glycol (PEG) connected with the compound of lipoic acid , lysine and 9-poly- d -arginine (LA–Lys–9R) by a hydrazone bond and a core of CdTe quantum dots (QDs). The molecular structure of DG–PEG–LA–Lys–9R was confirmed by liquid chromatography–mass spectrometry (LC–MS), nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy (FTIR), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The multifunctional CdTe QDs measured approximately 200 nm and showed excellent biocompatibility , perfect siRNA binding capability and enhanced hypoxic tumor targeting. Importantly, the system described here is pH-responsive with a hydrazone bond; therefore, it avoids GLUT1 receptor-mediated endocytic recycling, resulting in irreversible delivery of the siRNA. We used Western blots to confirm the superior gene silencing efficiency induced by the DG–PEG–LA–Lys–9R with hydrazone modified CdTe QDs. Here, we demonstrate high efficacy of the siRNA tumor delivery system using in vitro and in vivo experiments. In addition, these studies demonstrate that pH-responsive hybrid quantum dots show improved antitumor efficacy with decreased organ toxicity , indicating a promising siRNA delivery system for hypoxic cancer therapy.
研究领域:
癌症治疗
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纳米技术
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分子生物学
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药学
✓ 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）