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Gli1 promotes epithelial-mesenchymal transition and metastasis of non-small cell lung carcinoma by regulating snail transcriptional activity and stability

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Acta Pharmaceutica Sinica B 2022年第10期12卷 3877-3890页

作者： Xueping Lei Zhan Li Yihang Zhong Songpei Li Jiacong Chen Yuanyu Ke Sha Lv Lijuan Huang Qianrong Pan Lixin Zhao Xiangyu Yang Zisheng Chen Qiudi Deng Xiyong Yu guangzhou municipal and guangdong provincial key laboratory of molecular target&Clinical Pharmacology the NMPA and State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical Sciences and the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China Department of Respiratory and Critical Care Medicine the Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People’s HospitalQingyuan 511518China GMU-GIBH Joint School of Life Sciences Guangzhou Medical UniversityGuangzhou 511436China

Metastasis is crucial for the mortality of non-small cell lung carcinoma(NSCLC) *** epithelial-mesenchymal transition(EMT) plays a critical role in regulating tumor ***-associated oncogene 1(Gli1) is aberrantly active in a series of tumor tissues. However, the molecular regulatory relationships between Gli1 and NSCLC metastasis have not yet been identified. Herein,we reported Gli1 promoted NSCLC metastasis. High Gli1 expression was associated with poor survival of NSCLC patients. Ectopic expression of Gli1 in low metastatic A549 and NCI-H460 cells enhanced their migration, invasion abilities and facilitated EMT process, whereas knock-down of Gli1 in high metastatic NCI-H1299 and NCI-H1703 cells showed an opposite effect. Notably, Gli1 overexpression accelerated the lung and liver metastasis of NSCLC in the intravenously injected metastasis model. Further research showed that Gli1 positively regulated Snail expression by binding to its promoter and enhancing its protein stability, thereby facilitating the migration, invasion and EMT of NSCLC. In addition, administration of GANT-61, a Gli1 inhibitor, obviously suppressed the metastasis of NSCLC. Collectively, our study reveals that Gli1 is a critical regulator for NSCLC metastasis and suggests that targeting Gli1 is a prospective therapy strategy for metastatic NSCLC.

关键词： Non-small cell lung carcinoma Metastasis Epithelialemesenchymal transition Glioma-associated oncogene 1 Promote Snail Protein stability GANT-61

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Acceptor-engineering tailored type-Ⅰ photosensitizer with aggregation-induced NIR-II emission for cancer multimodal phototheranostics

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Science China Chemistry 2024年第8期67卷 2647-2660页

作者： Jiangao Li Niu Niu Deliang Wang Xue Liu Yi Qin Lei Wang Ben Zhong Tang Dong Wang Center for AIE Research Shenzhen Key Laboratory of Polymer Science and TechnologyGuangdong Research Center for Interfacial Engineering of Functional MaterialsCollege of Materials Science and EngineeringShenzhen UniversityShenzhen 518060China guangzhou municipal and guangdong provincial key laboratory of molecular target Clinical Pharmacologythe State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical Sciences and the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China School of Science and Engineering Shenzhen Institute of Aggregate Science and TechnologyThe Chinese University of Hong KongShenzhen(CUHK-Shenzhen)Shenzhen 518172China

Exploration of single molecular species synchronously featured by long excitation/emission wavelength, accurate diagnosis, and effective therapy, remains supremely appealing to implement high-performance cancer phototheranostics. However, those previously established phototheranostic agents are undiversified and stereotyped in terms of structural skeleton, and generally exhibit insufficient phototheranostic outcomes. Herein, we innovatively utilized indanone-condensed thiadiazolo[3,4-g]quinoxaline(ITQ) as electron acceptor to construct novel photosensitizer with second near-infrared(NIR-II) emission. Experimental study and theoretical calculation demonstrated that comparing with the counterparts constituting by widely employed NIR-II building block benzobisthiadiazole(BBTD) and 6,7-diphenylthiadiazoloquinoxaline(DPTQ), ITQ-based photosensitizer(TITQ) showed superior aggregation-induced emission(AIE) characteristics, much stronger type-I reactive oxygen species(ROS) production, and prominent photothermal conversion capacity. Furthermore, TITQ nanoparticles with excellent biocompatibility were capable of effectively accumulating in the tumor site and visualizing tumor through fluorescence-photoacoustic-photothermal trimodal imaging with highly spatiotemporal resolution, and completely eliminating tumor by type-I photodynamic-photothermal therapy.

关键词： phototheranostics aggregation-induced emission NIR-Ⅱfluorescence acceptor engineering photodynamic-photothermal therapy

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Transferrin receptor-targeted immunostimulant for photodynamic immunotherapy against metastatic tumors through β-catenin/CREB interruption

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4118-4133页

作者： Mengyi Yan Xiayun Chen Xiaotong Li Qianqian Liu Baixue Yu Yi Cen Wei Zhang Yibin Liu Xinxuan Li Ying Chen Tao Wang Shiying Li The Fifth Affiliated Hospital Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacologythe NMPA and State Key Laboratory of Respiratory Diseasethe School of Pharmaceutical SciencesGuangzhou Medical UniversityGuangzhou 511436China Department of Anesthesiology the Second Clinical School of Guangzhou Medical UniversityGuangzhou 511436China State key laboratory of Respiratory Diseases Guangdong Key Laboratory of Vascular DiseasesGuangzhou Institute of Respiratory Healththe first Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510120China Department of Pulmonary and Critical Care Medicine Zhujiang HospitalSouthern Medical UniversityGuangzhou 510280China

The immunosuppressive phenotype of tumor cells extensively attenuates the immune activation effects of traditional *** this work,a transferrin receptor(TfR)targeted immunostimulant(PTI)is fabricated for photodynamic immunotherapy against metastatic tumors by interrupting β-catenin signal *** synthesize PTI,the photosensitizer conjugated TfR targeting peptide moiety(Palmitic-K(PpIX)-HAIYPRH)is unitized to encapsulate the transcription interrupter of *** the one hand,the recognition of PTI and TfR can promote drug delivery into tumor cells to destruct primary tumors through photodynamic therapy and initiate an immunogenic cell death with the release of tumorassociated *** the other hand,PTI will interrupt the binding between b-catenin andcAMP response element-binding protein(CREB),regulating the gene transcription to downregulate programmed death ligand 1(PD-L1)while upregulating CeC motif chemokine ligand 4(CCL4).Furthermore,the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration,and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung *** work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.

关键词： Transferrin receptor β-Catenin signal pathway Tumor targeting Photodynamic therapy Immunotherapy Immunogenic cell death Programmed death ligand 1 C-C motif chemokine ligand 4

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Biomimetic Phosphohydrolase Nanozyme Based on Defect-Engineered Metal-Organic Framework

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CCS Chemistry 2024年第7期6卷 1821-1835页

作者： Xiaoxue Kou Yuhong Lin Yong Shen Linjing Tong Rui Gao Suya Liu Siming Huang Fang Zhu Guosheng Chen Gangfeng Ouyang MOE key laboratory of Bioinorganic and Synthetic Chemistry School of ChemistrySun Yat-sen UniversityGuangzhou 510006 Shanghai NanoPort Thermo Fisher ScientificPudong DistrictShanghai 200120 guangzhou municipal and guangdong provincial key laboratory of molecular target and Clinical Pharmacology The NMPA and State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical Sciences and The Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436

Phosphodiester bonds are the backbone linkages of all the nucleic acids which store and transfer biological *** hydrolysis of phosphodiester bonds is of great importance to the replication,recombination,and damage repair of DNA as well as the maturation and processing of ***,the spontaneous scission of individual phosphodiester linkages is kinetically challenging under physiological conditions,with an estimated half-life of 30 million ***,we discover a defect-engineered Zr-metal-organic framework(Zr-MOF)nanozyme containing cluster-missing reo defects,named UiO-66 REO,that possesses intrinsic phosphodiesterase-like activity that allows for the cleavage of the phosphodiester bond in physiological condition(pH=7.4 and 37℃),outperforming the activityrecording *** atomic-level structure of the UiO-66 REO nanozyme has been directly identified by the synchrotron radiation absorption spectrum and integrated differential phase contrast-scanning transmission electron *** find that both the defective boundary regions and unusual Zr6-clusters formed in the reo phase of the UiO-66 REO nanozyme contribute to the improvement in efficiency of phosphodiesterase-like hydrolysis,which realizes the cleavage of DNA in mild *** work offers a new insight into biomimetic enzymology using crystal and defect engineering and opens up new possibilities for the development of low-cost,structurally stable and sustainable phosphodiesterase nanozymes for different biological applications.

关键词： nanozyme metal-organic framework biomimetic catalysis hydrolase-like activity defective engineering

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Bromodomain-containing proteins BRD1, BRD2, and BRD13 are core subunits of SWI/SNF complexes and vital for their genomic targeting in Arabidopsis

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molecular Plant 2021年第6期14卷 888-904页

作者： Yaoguang Yu Wei Fu Jianqu Xu Yawen Lei Xin Song Zhenwei Liang Tao Zhu Yuhui Liang Yuanhao Hao Liangbing Yuan Chenlong Li State key laboratory of Biocontrol Guangdong Provincial Key Laboratory of Plant ResourcesSchool of Life SciencesSun Yat-Sen UniversityGuangzhouChina

Switch defective/sucrose non-fermentable(SWI/SNF)chromatin remodeling complexes are multi-subunit machines that play vital roles in the regulation of chromatin structure and gene ***,the mechanisms by which SWI/SNF complexes recognize their target loci in plants are not fully ***,we show that the Arabidopsis thaliana bromodomain-containing proteins BRD1,BRD2,and BRD13 are core subunits of SWI/SNF complexes and critical for SWI/SNF genomic *** three BRDs interact directly with multiple SWI/SNF subunits,including the BRAHMA(BRM)catalytic *** and transcriptomic analyses of the brd1 brd2 brd13 triple mutant revealed that these BRDs act largely redundantly to control gene expression and developmental processes that are also regulated by ***-wide occupancy profiling demonstrated that these three BRDs extensively colocalize with BRM on *** loss of function of three BRD genes results in reduced BRM protein levels and decreased occupancy of BRM on chromatin across the ***,we demonstrated that the bromodomains of BRDs are essential for genomic targeting of the BRD subunits of SWI/SNF complexes to their target ***,these results demonstrate that BRD1,BRD2,and BRD13 are core subunits of SWI/SNF complexes and reveal their biological roles in facilitating genomic targeting of BRM-containing SWI/SNF complexes in plants.

关键词： SWI/SNF complexes chromatin remodeling bromodomain BRAHMA Arabidopsis

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Advances in targeted therapy for esophageal cancer

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Signal Transduction and targeted Therapy 2020年第1期5卷 585-595页

作者： Yan-Ming Yang Pan Hong Wen Wen Xu Qing-Yu He Bin Li MOE key laboratory of Tumor molecular Biology and key laboratory of Functional Protein Research of guangdong Higher Education Institutes Institute of Life and Health EngineeringJinan UniversityGuangzhouChina MOE key laboratory of Tumor molecular Biology and guangdong provincial key laboratory of Bioengineering Medicine National Engineering Research Center of Genetic MedicineInstitute of BiomedicineCollege of Life Science and TechnologyJinan UniversityGuangzhouChina

Esophageal cancer(EC)is one of the most lethal cancers in the world,and its morbidity and mortality rates rank among the top ten in ***,surgical resection,radiotherapy and chemotherapy are the primary clinical treatments for esophageal ***,outcomes are still unsatisfactory due to the limited efficacy and severe adverse effects of conventional *** a new type of approach,targeted therapies have been confirmed to play an important role in the treatment of esophageal cancer;these include cetuximab and bevacizumab,which target epidermal growth factor receptor(EGFR)and vascular endothelial growth factor(VEGF),*** addition,other drugs targeting surface antigens and signaling pathways or acting on immune checkpoints have been continuously *** example,trastuzumab,a monoclonal antibody targeting human epidermal growth factor receptor 2(HER-2),has been approved by the Food and Drug Administration(FDA)as a first-line treatment of HER-2-positive ***,the PD-L1 inhibitor pembrolizumab has been approved as a highly efficient drug for patients with PD-L1-positive or advanced esophageal squamous cell carcinoma(ESCC).These novel drugs can be used alone or in combination with other treatment strategies to further improve the treatment efficacy and prognosis of cancer ***,adverse events,optimal dosages and effective combinations still need further *** this review,we expound an outline of the latest advances in targeted therapies of esophageal cancer and the mechanisms of relevant drugs,discuss their efficacy and safety,and provide a clinical rationale for precision medicine in esophageal cancer.

关键词： esophageal drugs targeted

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A Robust CRISPR/Cas9 System for Convenient, High-Efficiency Multiplex Genome Editing in Monocot and Dicot Plants

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molecular Plant 2015年第8期8卷 1274-1284页

作者： Xingliang Ma Qunyu Zhang Qinlong Zhu Wei Liu Yan Chen Rong Qiu Bin Wang Zhongfang Yang Heying Li Yuru Lin Yongyao Xie Rongxin Shen Shuifu Chen Zhi Wang Yuanling Chen Jingxin Guo Letian Chen Xiucai Zhao Zhicheng Dong Yao-Guang Liu State key laboratory for Conservation and Utilization of Subtropical Agro-Bioresources Guangzhou 510642 China key laboratory of Plant Functional Genomics and Biotechnology of guangdong provincial Higher Education Institutions Guangzhou 510642 China guangdong provincial key laboratory of Protein Function and Regulation in Agricultural Organisms Guangzhou 510642 China College of Life Sciences South China Agricultural University Guangzhou 510642 China key laboratory of South China Agriculture Plant molecular Analysis and Genetic Improvement South China Botanical Garden Chinese Academy of SciencesGuangzhou 510650 China

CRISPR/Cas9 genome targeting systems have been applied to a variety of species. However, most CRISPR/Cas9 systems reported for plants can only modify one or a few target sites. Here, we report a robust CRISPR/Cas9 vector system, utilizing a plant codon optimized Cas9 gene, for convenient and high- efficiency multiplex genome editing in monocot and dicot plants. We designed PCR-based procedures to rapidly generate multiple sgRNA expression cassettes, which can be assembled into the binary CRISPR/ Cas9 vectors in one round of cloning by Golden Gate ligation or Gibson Assembly. With this system, we edi- ted 46 target sites in rice with an average 85.4% rate of mutation, mostly in biallelic and homozygous status. We reasoned that about 16% of the homozygous mutations in rice were generated through the non-homol- ogous end-joining mechanism followed by homologous recombination-based repair. We also obtained uni- form biallelic, heterozygous, homozygous, and chimeric mutations in Arabidopsis T1 plants. The targeted mutations in both rice and Arabidopsis were heritable. We provide examples of loss-of-function gene mu- tations in To rice and T1Arabidopsis plants by simultaneous targeting of multiple （up to eight） members of a gene family, multiple genes in a biosynthetic pathway, or multiple sites in a single gene. This system has provided a versatile toolbox for studying functions of multiple genes and gene families in plants for basic research and genetic improvement.

关键词： sequence-specific nucleases genome editing CRISPR/Cas9 rice Arabidopsis

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Dt1 inhibits SWEET-mediated sucrose transport to regulate photoperiod-dependent seed weight in soybean

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molecular Plant 2024年第3期17卷 496-508页

作者： Xiaoming Li Zhonghui Chen Haiyang Li Lin Yue Cuirong Tan Hongjie Liu Yilong Hu Yuhua Yang Xiani Yao Lingping Kong Xiang Huangi Bin Yu Chunyu Zhang Yuefeng Guan Baohui Liu Fanjiang Kong Xingliang Hou guangdong provincial key laboratory of Applied Botany&State key laboratory of Plant Diversity and Specialty Crops South China Botanical GardenChinese Academyof SciencesGuangzhou510650China guangdong provincial key laboratory of Plant Adaptation and molecular Design Guangzhou Key Laboratory of Crop Gene EditingInnovative Center of Molecular Genetics and EvolutionSchool of Life SciencesGuangzhou UniversityGuangzhou 510006China University of Chinese Academy of Sciences Beijing 100049China College of Agronomy and Biotechnology China Agricultural UniversityBeijing 100193China

Soybean is a photoperiod-sensitive short-day crop whose reproductive period and yield are markedly affected by day-length *** weight is one of the key traits determining the soybean yield;how-ever,the prominent genes that control the final seed weight of soybean and the mechanisms underlying the photoperiod's effect on this trait remain poorly *** this study,we identify SwW19 as a major locus controlling soybean seed weight by QTL mapping and determine Dt1,an orthologous gene of Arabidopsis TFL1 that is known to govern the soybean growth habit,as the causal gene of the SW19 *** showed that Dt1 is highly expressed in developing seeds and regulates photoperiod-dependent seed weight in *** analyses revealed that the Dt1 protein physically interacts with the sucrose transporter GmSWEET10a to negatively regulate the import of sucrose from seed coat to the embryo,thus modulating seed weight under long ***,Dt1 does not function in seed development under short days due to its very low ***,we discovered a novel natural allelic variant of Dt1(H4 haplotype)that decouples its pleiotropic effects on seed size and growth habit;i.e.,this variant remains functional in seed development but fails to regulate the stem growth habit of ***,our findings provide new insights into how soybean seed development responds to photoperiod at different latitudes,offering an ideal genetic component for improving soybean's yield by manipulating its seed weightandgrowth habit.

关键词： soybean seed weight photoperiod dt1 sucrose transport

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Microgels for Cell Delivery in Tissue Engineering and Regenerative Medicine

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Nano-Micro Letters 2024年第10期16卷 576-617页

作者： Leyan Xuan Yingying Hou Lu Liang Jialin Wu Kai Fan Liming Lian Jianhua Qiu Yingling Miao Hossein Ravanbakhsh Mingen Xu Guosheng Tang guangzhou municipal and guangdong provincial key laboratory of molecular target and Clinical Pharmacology the NMPA and State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical Sciences and the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436People's Republic of China School of Automation Hangzhou Dianzi UniversityHangzhou 310018People's Republic of China Department of Biomedical Engineering The University of AkronAkronOH 44325USA Wallace H.Coulter Department of Biomedical Engineering Georgia Institute of TechnologyAtlantaGA 30332USA

Microgels prepared from natural or synthetic hydrogel materials have aroused extensive attention as multifunctional cells or drug carriers,that are promising for tissue engineering and regenerative *** can also be aggregated into microporous scaffolds,promoting cell infiltration and proliferation for tissue *** review gives an overview of recent developments in the fabrication techniques and applications of microgels.A series of conventional and novel strategies including emulsification,microfluidic,lithography,electrospray,centrifugation,gas-shearing,three-dimensional bioprinting,*** discussed in *** characteristics and applications of microgels and microgel-based scaffolds for cell culture and delivery are elaborated with an emphasis on the advantages of these carriers in cell ***,we expound on the ongoing and foreseeable applications and current limitations of microgels and their aggregate in the field of biomedical *** stimulating innovative ideas,the present review paves new avenues for expanding the application of microgels in cell delivery techniques.

关键词： Microgels Cell delivery Scaffolds 3D bioprinting Single-cell microgels

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The construction of drug-resistant cancer cell lines by CRISPR/Cas9 system for drug screening

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Science Bulletin 2018年第21期63卷 1411-1419页

作者： Lingmin Zhang Ying Li Qinghua Chen Yong Xia Wenfu Zheng Xingyu Jiang CAS Center for Excellence in Nanoscience Beijing Engineering Research Center for BioNanotechnologyCAS Key Laboratory for Biological Effects of Nanomaterials and NanosafetyNational Center for NanoScience and TechnologyBeijing 100190China University of Chinese Academy of Sciences Beijing 100049China guangdong provincial key laboratory of molecular target &Clinical Pharmacology School of Pharmaceutical Sciences and the Third &Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China

Cancer therapy is often hampered by the rapid emergence of drug resistance. Drug-resistant cellular models are essential for understanding the drug resistance and developing new therapeutics. The low efficiency and long time required in creating these models are major obstacles hindering drug resistance research and drug screening. Herein, we report an approach that can accelerate(shortening the time from years to 3 weeks) the establishment of cancer cell line-based, inheritable drug resistance models by specific knockout of MED12 gene using CRISPR/Cas9 system. The resultant MED12^(KO) A375(melanoma)cell line was resistant to inhibitors of B-Raf proto-oncogene, serine/threonine kinase(BRAF), whereas the resultant MED12^(KO) PC9(non-small cell lung cancer) cell line was resistant to inhibitors of epidermal growth factor receptor(EGFR). Evaluation of anti-cancer drugs and their combinations shows that certain combinations of BRAF inhibitors and TGF-β receptor(TGF-βR) inhibitors are active in suppressing the growth of MED12^(KO) A375 cells, and a few combinations of EGFR inhibitors and TGF-βR inhibitors were active in suppressing the growth of MED12^(KO) PC9 cells. The drug-resistant models will be useful in screening novel drugs and drug combinations for multi-drug-resistant cancer therapy.

关键词： CRISPR/Cas9 Drug resistance Cancer Cell line Gene editing

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