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Transcription factor EHF interacting with coactivator AJUBA aggravates malignancy and acts as a therapeutic target for gastroesophageal adenocarcinoma

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2119-2136页

作者： Li Peng Yanyi Jiang Hengxing Chen Yongqiang Wang Qiusheng Lan Shuiqin Chen Zhanwang Huang Jingyuan Zhang Duanqing Tian Yuntan Qiu Diankui Cai Jiangyun Peng Daning Lu Xiaoqing Yuan Xianzhu Yang Dong Yin Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong-Hong Kong Joint Laboratory for RNA MedicineSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Medical Research Center Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Hefei Institutes of Physical Science Chinese Academy of SciencesHefei 230031China Department of Gastrointestinal Surgery Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Hepatobiliary Surgery Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China School of Biomedical Sciences and Engineering South China University of TechnologyGuangzhou International CampusGuangzhou 511442China

Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug ***,it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors(TFs)except for the nuclear receptor family of *** is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma(GEA)or the therapeutic effects of targeting TF and transcription cofactor *** this study,we found that ETS homologous factor(EHF)expression is promoted by a core transcriptional regulatory circuitry(CRC),specifically ELF3-KLF5-GATA6,and interference with its expression suppressed the malignant biological behavior of GEA ***,we identified Ajuba LIM protein(AJUBA)as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in ***,we identified KRAS signaling as a common pathway downstream of EHF and ***,dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in *** conclusion,EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS *** of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.

关键词： EHF AJUBA KRAS pathway Enhancer Core transcriptional regulatory circuitry Gastroesophageal adenocarcinoma Gastric adenocarcinoma Esophageal adenocarcinoma Transcription factor Coactivator Lipid nanoparticles

Nanomedicine targeting ferroptosis to overcome anticancer therapeutic resistance

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Science China(Life Sciences) 2024年第1期67卷 19-40页

作者： Jing Cai Xiaoding Xu Phei Er Saw Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong-Hong Kong Joint Laboratory for RNA MedicineMedical Research CenterSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Nanhai Translational Innovation Center of Precision Immunology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityFoshan 528200China

A potential reason for the failure of tumor therapies is treatment *** to chemotherapy,radiotherapy,and immunotherapy continues to be a major obstacle in clinic,resulting in tumor recurrence and *** major mechanisms of therapy resistance are inhibitions of cell deaths,like apoptosis and necrosis,through drug inactivation and excretion,repair of DNA damage,tumor heterogeneity,or changes in tumor microenvironment,*** studies have shown that ferroptosis play a major role in therapies resistance by inducing phospholipid peroxidation and iron-dependent cell *** ferroptosis inducers in combination with clinical treatment techniques have been used to enhance the effect in tumor ***,versatile ferroptosis nanoinducers exhibit an extensive range of functions in reversing therapy resistance,including directly triggering ferroptosis and feedback ***,we provide a detailed description of the design,mechanism,and therapeutic application of ferroptosis-mediated synergistic tumor *** also discuss the prospect and challenge of nanomedicine in tumor therapy resistance by regulating ferroptosis and combination therapy.

关键词： ferroptosis cancer therapy therapy resistance nanoinducers

Poly(ferulic acid)nanocarrier enhances chemotherapy sensitivity of acute myeloid leukemia by selectively targeting inflammatory macrophages

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Chinese Chemical Letters 2024年第9期35卷 289-295页

作者： Weijian Zhang Xianyu Deng Liying Wang Jian Wang Xiuting Guo Lianggui Huang Xinyi Wang Jun Wu Linjia Jiang Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Otolaryngology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Hematology The Seventh Affiliated HospitalSun Yat-sen UniversityShenzhen 518107China Department of Pediatrics Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Bioscience and Biomedical Engineering Thrust The Hong Kong University of Science and Technology(Guangzhou)NanshaGuangzhou 511400China Division of Life Science The Hong Kong University of Science and TechnologyHong Kong SAR 999077China

Macrophages,as a subset of innate immune cells,play a pivotal role in the initiation,maintenance,and resolution of inflammatory responses during tissue damage repair,defense against infections,and tumor ***,the mechanisms by which macrophages regulate inflammation in acute myeloid leukemia(AML)and their involvement in the chemotherapeutic effect remain *** this study,we have identified that AML cells stimulate macrophage expansion by activating the colony-stimulating factor 1 receptor(CSF1R)*** expanded macrophages activate nuclear factor kappa-B(NFκB)to induce the expression of inflammatory factors,thereby maintaining leukemic cell quiescence and promoting cell survival following ***,we have successfully utilized a poly(ferulic acid)nanocarrier to selectively target macrophages for inhibiting the NFκB-mediated inflammation,ultimately enhancing chemotherapy efficacy against *** together,our findings highlight the crucial role of macrophage-induced inflammation in conferring chemoresistance to AML,and demonstrate the potential of a targeted nanocarrier specifically designed for inflammatory macrophages to improve the AML chemotherapeutic outcomes.

关键词： Acute myeloid leukemia Chemoresistance Macrophage Inflammation NFκB

Maximizing conditional independence for unsupervised domain adaptation

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Science China(Information Sciences) 2024年第5期67卷 136-149页

作者： Yiming ZHAI Chuanxian REN Youwei LUO Daoqing DAI School of Mathematics Sun Yat-Sen University

Unsupervised domain adaptation(UDA) studies how to transfer a learner from a labeled source domain to an unlabeled target domain with different distributions. Existing methods mainly focus on matching marginal distributions of the source and target domains, which probably leads to a misalignment of samples from the same class but different domains. In this paper, we tackle this misalignment issue by achieving the class-conditioned transferring from a new perspective. Specifically, we propose a method named maximizing conditional independence(MCI) for UDA, which maximizes the conditional independence of feature and domain given class in the reproducing kernel Hilbert spaces. The optimization of conditional independence can be viewed as a surrogate for minimizing class-wise mutual information between feature and domain. An interpretable empirical estimation of the conditional dependence measure is deduced and connected with the unconditional case. Besides, we provide an upper bound on the target error by taking the class-conditional distribution into account, which provides a new theoretical insight for class-conditioned transferring. Extensive experiments on six benchmark datasets and various ablation studies validate the effectiveness of the proposed model in dealing with UDA.

关键词： conditional independence kernel method domain adaptation class-conditioned transferring

LncRNA ZFPM2-AS1 promotes phyllodes tumor progression by binding to CDC42 and inhibiting STAT1 activation

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2942-2958页

作者： Shishi He Guowei Huang Rong Lei Rurong Jia Zhanghai He Jiewen Chen Hongyan Huang Zixian Huang Ailifeire Yilihamu Xun Li Zilin Zhuang Mengjia Han Xueman Chen Di Huang Yan Nie Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong-Hong Kong Joint Laboratory for RNA MedicineMedical Research CenterSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Breast Tumor Center Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Pathology Shantou University Medical CollegeShantou 515041China School of Basic Medical Science Southern Medical UniversityGuangzhou 510515China Department of Pathology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Breast Medicine Affiliated Foshan Maternity and Child Healthcare HospitalSouthern Medical UniversityFoshan 528000China Department of Breast Surgery Zhujiang HospitalSouthern Medical UniversityGuangzhou 510282China Department of Oral and Maxillofacial Surgery Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China

Breast phyllodes tumor(PT)is a rare fibroepithelial neoplasm with potential malignant *** non-coding RNAs(lncRNAs)play multifaceted roles in various cancers,but their involvement in breast PT remains largely *** this study,microarray was leveraged for the first time to investigate the role of lncRNA in *** identified lncRNA ZFPM2-AS1 was significantly upregulated in malignant PT,and its overexpression endowed PT with high tumor grade and adverse ***,we elucidated that ZFPM2-AS1 promotes the proliferation,migration,and invasion of malignant PT in *** ZFPM2-AS1 through nanomaterial-mediated siRNA delivery in patient-derived xenograft(PDX)model could effectively inhibit tumor progression in ***,our findings showed that ZFPM2-AS1 is competitively bound to CDC42,inhibiting ACK1 and STAT1 activation,thereby launching the transcription of *** conclusion,our study provides evidence that ZFPM2-AS1 plays a pivotal role in the pathogenesis of breast PT,and suggests that ZFPM2-AS1 could serve as a prognostic indicator for patients with PT as well as a promising novel therapeutic target.

关键词： LncRNA Phyllodes tumor ZFPM2-AS1 Cell division cycle 42 Activated cdc42 kinase 1 Signal transducer and activator of transcription 1 TNF receptor superfamily member 19 Nano particles

ILF3 safeguards telomeres from aberrant homologous recombination as a telomeric R-loop reader

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Protein & Cell 2024年第7期15卷 493-511页

作者： Chuanle Wang Yan Huang Yue Yang Ruofei Li Yingying Li Hongxin Qiu Jiali Wu Guang Shi Wenbin Ma Zhou Songyang MOE Key Laboratory of Gene Function and Regulation State Key Laboratory of Biocontrol and Guangzhou Key Laboratory of Healthy AgingSchool of LifesciencesSun Yat-sen UniversityGuangzhou 510275China Department of Oncology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510275China Department of Nephrology The First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China

Telomeres are specialized structures at the ends of linear chromosomes that protect genome *** telomeric repeat-containing RNA(TERRA)that is transcribed from subtelomeric regions can invade into double-stranded DNA regions and form RNA:DNA hybrid-containing structure called *** tumor cells,R-loop formation is closely linked to gene expression and the alternative lengthening of telomeres(ALT)*** R-loops can cause stalled replication forks and telomere ***,how R-loops are recognized and regulated,particularly at telomeres,is not well *** discovered that ILF3 selectively associates with telomeric R-loops and safeguards telomeres from abnormal homologous *** out ILF3 results in excessive R-loops at telomeres and triggers telomeric DNA damage *** addition,ILF3 deficiency disrupts telomere homeostasis and causes abnormalities in the ALT *** the proximity-dependent biotin identification(BioID)technology,we mapped the ILF3 interactome and discovered that ILF3 could interact with several DNA/RNA helicases,including ***,ILF3 may aid in the resolution of telomeric R-loops through its interaction with *** findings suggest that ILF3 may function as a reader of telomeric R-loops,helping to prevent abnormal homologous recombination and maintain telomere homeostasis.

关键词： ILF3 RNA:DNA hybrids telomeric R-loops homologous recombination telomeric DNA damage responses

TP53-specific mutations serve as a potential biomarker for homologous recombination deficiency in breast cancer:a clinical next-generation sequencing study

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Precision Clinical Medicine 2024年第2期7卷 122-131页

作者： Yongsheng Huang Shuwei Ren Linxiaoxiao Ding Yuanling jiang Jiahuan Luo Jjinghua Huang Xinke Yin Jianli Zhao Sha Fu Jianwei Liao Cellular&Molecular Diagnostics Center Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Clinical Laboratory The Sixth Affliated HospitalSun Yat-sen UniversityGuangzhou 510655China Breast Tumor Center Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Guangzhou Regenerative Medicine and Health Guangdong LaboratorySun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China

Background:TP53 mutations and homologous recombination deficiency(HRD)occur frequently in breast ***,the characteristics of TP53 pathogenic mutations in breast cancer patients with/without HRD are not ***:Clinical next-generation sequencing(NGS)of both tumor and paired blood DNA from 119 breast cancer patients(BRCA-119 cohort)was performed with a 520-gene ***,tumor mutation burden(TMB),and genomic HRD scores were assessed from NGS *** data from 47 breast cancer patients in the HRD test cohort were analyzed for further ***:All TP53 pathogenic mutations in patients had somatic origin,which was associated with the protein expression of estrogen receptor and progestogen *** to patients without TP53 pathologic mutations,patients with TP53 pathologic mutations had higher levels of HRD scores and different genomic *** frequency of TP53 pathologic mutation was higher in the HRDhigh group(HRD score≥42)relative to that in the HRD-low group(HRD score<42).TP53 has different mutational characteristics between the HRD-low and HRD-high ***53-specific mutation subgroups had diverse genomic features and ***,TP53 pathogenic mutations predicted the HRD status of breast cancer patients with an area under the curve(AUC)of ***53-specific mutations,namely HRD-low mutation,HRD-high mutation,and HRD common mutation,predicted the HRD status of breast cancer patients with AUC values of 0.32,0.72,and 0.58,***,TP53 HRD-high mutation and HRD common mutation combinations showed the highest AUC values(0.80)in predicting HRD ***:TP53-specific mutation combinations predict the HRD status of patients,indicating that TP53 pathogenic mutations could serve as a potential biomarker for poly-ADP-ribose polymerase(PARP)inhibitors in breast cancer patients.

关键词： next-generation sequencing homologous recombination deficiency TP53 breast cancer

Imide-pillared covalent organic framework protective films as stable zinc ion-conducting interphases for dendrite-free Zn metal anodes

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Journal of Energy Chemistry 2024年第10期97卷 470-477页

作者： Xiaoman Ye Xuemei Xiao Zhijing Wu Xin Wu Lin Gu Sheng Liu School of Chemical Engineering and Technology Sun Yat-sen University The Key Lab of Low-Carbon Chemistry & Energy Conservation of Guangdong Province Sun Yat-sen University

The notorious growth of zinc dendrite and the water-induced corrosion of zinc metal anodes（ZMAs）restrict the practical development of aqueous zinc ion batteries（AZIBs）.In this work,a zinc metallized,imide-pillared covalent organic framework（ZPC） protective film has been engineered as a stable Zn2+ion-conducting interphase to modulate interfacial kinetics and suppress side reactions for *** to bare Zn,ZPC@Zn exhibits a higher Zn2+ionic conductivity,a larger Zn2+transference number,a lower electronic conductivity,a smaller desolvation activation energy and correspondingly a significant suppression of corrosion,hydrogen evolution and Zn ***,the ZPC@Zn||ZPC@Zn symmetric cell obtains a cycling lifespan over 3000 h under 5 mA cm-2for 1 mA h *** ZPC@Zn||NH4V4O10coin-type full battery delivers a specific capacity of 195.8 mA h g-1with a retention rate of78.5% at 2 A g-1after 1100 cycles,and the ZPC@Zn||NH4V4O10pouch full cell shows a retention of70.1% in reversible capacity at 3 A g-1after 1100 *** present incorporation of imide-linked covalent organic frameworks in the surface modification of ZMAs will offer fresh perspectives in the search for ideal protective films for the practicality of AZIBs.

关键词： Aqueous zinc ion batteries Covalent organic frameworks Imide linkage Surface modification Zinc metal anodes

Changes of nutrients and microbial communities in recovery process of abandoned rare earth tailings

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Pedosphere 2024年第4期34卷 826-836页

作者： Bing ZHANG Junli WU Mengyuan HUANG Yan ZHANG Jin ZHAO Chuntao HE Zhongyi YANG School of Environmental Science and Engineering Sun Yat-sen UniversityGuangzhou 510006China School of Life Sciences Sun Yat-sen UniversityGuangzhou 510275China School of Agriculture State Key Laboratory for BiocontrolShenzhen Campus of Sun Yat-sen UniversitySun Yat-sen UniversityShenzhen 518107China

Rare earth element(REE)mining has wrought severe ecosystem destruction,particularly in the loss of carbon(C),nitrogen(N),and phosphorus(P).Furthermore,its effects on nutrient recovery characteristics and associated microbial abundance are still poorly *** this study,an investigation was conducted to determine C,N,and P recovery patterns and microbial communities in abandoned REE mining tailings with different abandoned durations of 1.5(1.5-Y),7(7-Y),10(10-Y),and 14(14-Y)years and at an unmined site(the control group)in Jiangxi Province,*** tailing delamination at each site was investigated in 0–15(layer 1)and 15–30(layer 2)cm tailing *** the abandoned duration of REE tailings,C and P in layer 1 continued to recover from 1.62 to 8.51 g kg^(-1) and from 0.71 to 1.94 g kg^(-1),respectively;N losses of 0.60 and 0.22 g kg^(-1) occurred at the 1.5-Y and 10-Y sites,while N in layer 1 slightly increased at the 14-Y ***,Methylosinus,Bradyrhizobium,Pseudomonas,and Azospirillum were dominant bacteria at the 14-Y site and in the *** relative abundances of N-fixing bacteria Mesorhizobium(32.94%),Sinorhizobium(0.24%),Frankia(0.71%),and Burkholderia(2.38%)at the 14-Y site were 1.33–3.97 times those in the control(24.19%,0.18%,0.32%and 0.60%,respectively),which was helpful for tailing N *** the 14-Y site,Tylospora(50.24%),Luellia(11.02%),Tomentella(6.94%),and Chaetomium(4.34%)were the dominant fungal genera,while Tylospora(56.93%),Suillus(11.45%),and Penicillium(6.78%)predominated in the *** relative abundance of the P-dissolving fungus Aspergillus at the 14-Y site(0.42%)was 4.2 times that in the control(0.1%),which may lead to the improved tailing P *** the 14-Y site,woody plants such as Pinus massoniana and native pioneering herbs and ferns such as Dicranopteris dichotoma and Nephrolepis auriculata probably invaded from adjacent *** study unraveled the natural restoration of plant and micro

关键词： abandoned duration mining tailing N-fixing bacteria nutrient recovery P-solubilizing fungi rare earth element