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MARS and RNAcmap3:The Master Database of All Possible RNA Sequences Integrated with RNAcmap for RNA Homology Search

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Genomics, Proteomics & Bioinformatics 2024年第1期22卷 143-150页

作者： Ke Chen Thomas Litfin Jaswinder Singh Jian Zhan Yaoqi Zhou Institute of Systems and Physical Biology Shenzhen Bay LaboratoryShenzhen 518055China Peking University shenzhen Graduate School Shenzhen 518055China University of Science and Technology of China Hefei 230026China Suzhou Institute for Advanced Research University of Science and Technology of ChinaSuzhou 215123China Institute for Glycomics Griffith UniversitySouthportQLD 4222Australia

sequences found in the huge,integrated database of protein sequences(Big Fantastic Database).In contrast,the existing nucleotide databases were not consolidated to facilitate wider and deeper homology ***,we built a comprehensive database by incorporating the non-coding RNA(ncRNA)sequences from RNAcentral,the transcriptome assembly and metagenome assembly from metagenomics RAST(MG-RAST),the genomic sequences from Genome Warehouse(GWH),and the genomic sequences from MGnify,in addition to the nucleotide(nt)database and its subsets in National Center of Biotechnology Information(NCBI).The resulting Master database of All possible RNA sequences(MARS)is 20-fold larger than NCBI’s nt database or 60-fold larger than *** new dataset along with a new split-search strategy allows a substantial improvement in homology search over existing state-of-the-art *** also yields more accurate and more sensitive multiple sequence alignments(MSAs)than manually curated MSAs from Rfam for the majority of structured RNAs mapped to *** results indicate that MARS coupled with the fully automatic homology search tool RNAcmap will be useful for improved structural and functional inference of ncRNAs and RNA language models based on *** is accessible at https://***/omix/release/OMIX003037,and RNAcmap3 is accessible at http://***/download/.

关键词： RNA sequence database Homology search Secondary structure MARS RNAcmap3

Src heterodimerically activates Lyn or Fyn to serve as targets for the diagnosis and treatment of esophageal squamous cell carcinoma

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Science China(Life Sciences) 2023年第6期66卷 1245-1263页

作者： Jing Zhang Di Zhao Lingyuan Zhang Yuanfan Xiao Qingnan Wu Yan Wang Jie Chen Qimin Zhan Key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&InstituteBeijing100142China Peking University International Cancer Institute Peking UniversityBeijing100191China Research Unit of Molecular Cancer Research Chinese Academy of Medical SciencesBeijing100142China Institute of Cancer Research Shenzhen Bay LaboratoryShenzhen518107China

Although Src is one of the oldest and most investigated oncoproteins,its function in tumor malignancy remains to be defined *** this study,we demonstrated that the inhibition of Src activity by ponatinib effectively suppressed several malignant phenotypes of esophageal squamous cell carcinoma(ESCC)both in vitro and in vivo,whereas it did not produce growthinhibitory effects on normal esophageal epithelial cells(NEECs).Importantly,we combined phosphoproteomics and several cellular and molecular biologic strategies to identify that Src interacted with the members of Src-family kinases(SFKs),such as Fyn or Lyn,to form *** interactions with Fyn and Lyn phosphorylated the tyrosine sites in SH2(Fyn Tyr^(185)or Lyn Tyr^(183))and kinase domains(Fyn Tyr^(420) or Lyn Tyr^(397)),which critically contributed to ESCC *** contrast,Src could not form heterodimers with Fyn or Lyn in *** used RNA sequencing to comprehensively demonstrate that the inhibition of Src activity effectively blocked several critical tumor-promoting pathways,such as JAK/STAT,mTOR,stemness-related,and metabolism-related *** of the real-time polymerase chain reaction(RT-PCR)assay confirmed that Lyn and Fyn were critical effectors for the Src-mediated expression of tumor growth or metastasis-related ***,results of the clinical ESCC samples showed that the hyperactivation of pSrc Tyr^(419),Fyn Tyr^(185) or Tyr^(420),and Lyn Tyr^(183)or Tyr^(397)could be biomarkers of ESCC *** study illustrates that Src/Fyn and Src/Lyn heterodimers serve as targets for the treatment of ESCC.

关键词： esophageal squamous cell carcinoma heterodimer Src-family kinase Src tyrosine phosphorylation

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Tumor-associated macrophage(TAM)-derived CCL22 induces FAK addiction in esophageal squamous cell carcinoma(ESCC)

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Cellular & Molecular Immunology 2022年第9期19卷 1054-1066页

作者： Jie Chen Di Zhao Lingyuan Zhang Jing Zhang Yuanfan Xiao Qingnan Wu Yan Wang Qimin Zhan Key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&InstituteBeijing100142China Peking University International Cancer Institute Peking UniversityBeijing100191China Research Unit of Molecular Cancer Research Chinese Academy of Medical SciencesBeijingChina Institute of Cancer Research Shenzhen Bay LaboratoryShenzhen518107China

Tumor cell dependence on activated oncogenes is considered a therapeutic target,but protumorigenic microenvironment-mediated cellular addiction to specific oncogenic signaling molecules remains to be further ***,we showed that tumor-associated macrophages(TAMs)produced an abundance of C-C motif chemokine 22(CCL22),whose expression in the tumor stroma was positively associated with the level of intratumoral phospho-focal adhesion kinase(pFAK Tyr^(397)),tumor metastasis and reduced patient ***,CCL22-stimulated hyperactivation of FAK was correlated with increased malignant progression of cancer ***22-induced addiction to FAK was demonstrated by the persistent suppression of tumor progression upon FAK-specific ***,we identified that diacylglycerol kinaseα(DGKα)acted as a signaling adaptor to link the CCL22 receptor C-C motif chemokine receptor 4(CCR4)and FAK and promoted CCL22-induced activation of the FAK/AKT ***22/CCR4 signaling activated the intracellular Ca^(2+)/phospholipase C-γ1(PLC-γ1)axis to stimulate the phosphorylation of DGKαat a tyrosine residue(Tyr^(335))and promoted the translocation of DGKαto the plasma membrane to assemble the DGKα/FAK signalosome,which critically contributed to regulating sensitivity to FAK inhibitors in cancer *** identification of TAM-driven intratumoral FAK addiction provides opportunities for utilizing the tumor-promoting microenvironment to achieve striking anticancer effects.

关键词： Tumor-associated macrophages Esophageal squamous cell carcinoma FAK Oncogene addiction

Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma

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National Science Review 2024年第5期11卷 170-185页

作者： Yong Zhou Shanlan Mo Heyang Cui Ruifang Sun Weimin Zhang Xiaofei Zhuang Enwei Xu Hongyi Li Yikun Cheng Yongsheng Meng Meilin Liu Ting Yan Huijuan Liu Ling Zhang Bin Yang Yanfeng Xi Shubin Wang Xiaolong Cheng Shuai Cheng Li Zhihua Liu Qimin Zhan Zheng Hu Yongping Cui Cancer Institute Department of Pathology Peking University Shenzhen Hospital Shenzhen Peking University-the Hong Kong University of Science and Technology(PKU-HKUST) Medical Center Institute of Cancer ResearchShenzhen Bay Laboratory Key laboratory of Cellular Physiology of the Ministry of Education Department of Pathology Shanxi Medical University City University of Hong Kong shenzhen Research Institute CAS Key laboratory of Quantitative Engineering Biology Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of Sciences Department of Surgery Faculty of Medicine The Chinese University of Hong Kong Department of Tumor Biobank Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University Key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute Research Unit of Molecular Cancer Research Chinese Academy of Medical Sciences Department of Thoracic Surgery Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University Department of Pathology Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University College of Letters & Science University of California Berkeley State Key laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College

Esophageal squamous cell carcinoma（ESCC） is a poor-prognostic cancer type with extensive intra-and inter-patient heterogeneity in both genomic variations and tumor microenvironment（TME）. However, the patterns and drivers of spatial genomic and microenvironmental heterogeneity of ESCC remain largely unknown. Here, we generated a spatial multi-omic atlas by whole-exome, transcriptome, and methylome sequencing of 507 tumor samples from 103 patients. We identified a novel tumor suppressor PREX2,accounting for 22% of ESCCs with frequent somatic mutations or hyper-methylation, which promoted migration and invasion of ESCC cells in vitro. Analysis of the TME and quantification of subclonal expansion indicated that ESCCs undergo spatially directed evolution, where subclones mostly originated from the tumor center but had a biased clonal expansion to the upper direction of the ***, we found upper regions of ESCCs often underwent stronger immunoediting with increased selective fitness, suggesting more stringent immune selection. In addition, distinct TMEs were associated with variable genomic and clinical outcomes. Among them, hot TME was associated with high immune evasion and subclonal heterogeneity. We also found that immunoediting, instead of CD8+T cell abundance, acts as an independent prognostic factor of ESCCs. Importantly, we found significant heterogeneity in previously considered potential therapeutic targets, as well as BRCAness characteristics in a subset of patients, emphasizing the importance of focusing on heterogeneity in ESCC targeted ***, these findings provide novel insights into the mechanisms of the spatial evolution of ESCC and inform precision therapeutic strategies.

关键词： squamous cell carcinoma heterogeneity multi-omics evolution tumor microenvironment

AKT2^(S128)/CCTα^(S315/319/323)-positive cancer-associated fibroblasts (CAFs) mediate focal adhesion kinase (FAK) inhibitors resistance via secreting phosphatidylcholines (PCs)

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Signal Transduction and Targeted Therapy 2024年第2期9卷 782-796页

作者： Jie Chen Lingyuan Zhang Yuheng Zhu Di Zhao Jing Zhang Yanmeng Zhu Jingyuan Pang Yuanfan Xiao Qingnan Wu Yan Wang Qimin Zhan Key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&Institute100142 BeijingChina Peking University International Cancer Institute Peking University100191 BeijingChina Research Unit of Molecular Cancer Research Chinese Academy of Medical SciencesBeijingChina Soochow University Cancer Institute Suzhou 215000China Institute of Cancer Research Shenzhen Bay LaboratoryShenzhen 518107China

Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic *** study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to demonstrate that the pAKT2 Ser128 and pCCTαSer315/319/323-positive cancer-associated fibroblasts(CAFs)substantially release phosphatidylcholines(PCs),contributing to the resistance of focal adhesion kinase(FAK)inhibitors in esophageal squamous cell carcinoma(ESCC)***,we observed extremely low levels of FAK Tyr397 expression in CAFs,potentially offering no available target for FAK inhibitors playing their anti-growth role in ***,FAK inhibitor increased the intracellular concentration of Ca2+in CAFs,promoting the formation of AKT2/CCTαcomplex,leading to phosphorylation of CCTαSer315/319/323 sites and eventually enhancing stromal PC *** activation could stimulate the intratumoral Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3(STAT3)pathway,triggering resistance to FAK *** of clinical samples demonstrated that stromal pAKT2 Ser128 and pCCTαSer315/319/323 are related to the tumor malignancy and reduced patient ***-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC *** conclusion,inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.

关键词： CAFs metabolism resistance

Nuclear genome-derived circular RNA circPUMl localizes in mitochondria and regulates oxidative phosphorylation in esophageal squamous cell carcinoma

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Signal Transduction and Targeted Therapy 2022年第3期7卷 816-828页

作者： Wei Gong Jiancheng Xu Yan Wang Qingjie Min Xu Chen Weimin Zhang Jie Chen Qimin Zhan Key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&Institute100142 BeijingChina institute of Systems Biomedicine School of Basic Medical SciencesPeking University Health Science Center100191 BeijingChina Peking University International Cancer Institute 100191 BeijingChina shenzhen bay laboratory Shenzhen 518132China Research Unit of Molecular Cancer Research Chinese Academy of Medical Sciences100021 BeijingChina

Circular RNAs(circRNAs)were shown to play an important role in the occurrence and progression of ***,the functions of nuclear genome-derived circRNAs localized in mitochondria of tumor cells remain largely ***,we report that circPUMl,a circular RNA derived from back-splicing of pre-mRNAs of nuclear genome PUM1,localizes in mitochondria.

关键词： esophageal circular squamous

Dendritic cell maturation in the tumor microenvironment

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National Science Open 2023年第6期2卷 42-64页

作者： Yuhui Miao Yuning Liu Haidong Tang Zemin Zhang Institute of Cancer Research Shenzhen Bay LaboratoryShenzhen 518132China School of Pharmaceutical Sciences Tsinghua UniversityBeijing 100084China BIOPIC and School of Life Sciences Peking UniversityBeijing 100871China

Maturation is essential for dendritic cells(DCs)to function as a bridge between innate and adaptive *** plastic maturation states correspond to the multifaceted roles of DCs in the initiation of protective,tolerogenic and pathogenic immune *** formation of a distinct maturation state of DCs involves the complex crosstalk between the intrinsic differences in their ontogeny and the immune *** studies have defined a universal mature DC population in the tumor microenvironment(TME),but their ontogenesis and functions remain ***,we summarize recent advances in DC maturation and attempt to dissect the complex functions of mature DCs in the *** highlighted that there is a distinct similarity and heterogeneity of mature DCs in the TME,in which the environment and development are both *** help us revisit the diversity of DC maturation and to better dissect the complex functions of DCs in the TME.

关键词： dendritic cells tumor microenvironment tumor-associated mature DCs tolerogenic DCs tertiary lymphatic structures immunotherapy

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CDK7-YAP-LDHD axis promotes D-lactate elimination and ferroptosis defense to support cancer stem cell-like properties

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Signal Transduction and Targeted Therapy 2023年第9期8卷 4346-4364页

作者： Mengzhu Lv Ying Gong Xuesong Liu Yan Wang Qingnan Wu Jie Chen Qingjie Min Dongyu Zhao Xianfeng Li Dongshao Chen Di Yang Danna Yeerken Rui Liu Jinting Li Weimin Zhang Qimin Zhan Key laboratory of Carcinogenesis and Translational Research(Ministry of Education) Department of Molecular OncologyPeking University Cancer Hospital and InstituteBeijing 100142China Key laboratory of Carcinogenesis and Translational Research(Ministry of Education) Department of Breast OncologyPeking University Cancer Hospital and InstituteBeijing 100142China Research Unit of Molecular Cancer Research Chinese Academy of Medical SciencesBeijing 100021China Peking University International Cancer Institute Beijing 100191China Institute of Cancer Research Shenzhen Bay LaboratoryShenzhen 518107China Department of Oncology Cancer InstitutePeking University Shenzhen HospitalShenzhen Peking University-Hong Kong University of Science and Technology(PKU-HKUST)Medical CenterShenzhen 518036China Soochow University Cancer Institute Suzhou 215127China

Reprogrammed cellular metabolism is essential for maintaining cancer stem cells(CSCs)***,we report that mitochondrial D-lactate catabolism is a necessary initiating oncogenic event during tumorigenesis of esophageal squamous cell carcinoma(ESCC).We discover that cyclin-dependent kinase 7(CDK7)phosphorylates nuclear Yes-associated protein 1(YAP)at S127 and S397 sites and enhances its transcription function,which promotes D-lactate dehydrogenase(LDHD)protein ***,LDHD is enriched significantly in ESCC-CSCs rather than differentiated tumor cells and high LDHD status is connected with poor prognosis in ESCC ***,the CDK7-YAP-LDHD axis helps ESCC-CSCs escape from ferroptosis induced by D-lactate and generates pyruvate to satisfy energetic demands for their elevated self-renewal ***,we conclude that esophageal CSCs adopt a D-lactate elimination and pyruvate accumulation mode dependent on CDK7-YAP-LDHD axis,which drives stemness-associated hallmarks of ***,targeting metabolic checkpoints may serve as an effective strategy for ESCC therapy.

关键词： esophageal metabolism elevated

Characterization of the depsidone gene cluster reveals etherification,decarboxylation and multiple halogenations as tailoring steps in depsidone assembly

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Acta Pharmaceutica Sinica B 2023年第9期13卷 3919-3929页

作者： Jiafan Yang Zhenbin Zhou Yingying Chen Yongxiang Song Jianhua Ju CAS Key laboratory of Tropical Marine Bio-resources and Ecology RNAM Center for Marine MicrobiologyGuangdong Key Laboratory of Marine Materia MedicaSouth China Sea Institute of OceanologyChinese Academy of SciencesGuangzhou 510301China University of Chinese Academy of Sciences Beijing 110039China

Depsides and depsidones have attracted attention for biosynthetic studies due to their broad biological activities and structural *** structure-activity relationships indicated that triple halogenated depsidones display the best anti-pathogenic ***,the gene cluster and the tailoring steps responsible for halogenated depsidone nornidulin(3)remain *** this study,we disclosed the complete biosynthetic pathway of the halogenated depsidone through in vivo gene disruption,heterologous expression and in vitro biochemical *** demonstrated an unusual depside skeleton biosynthesis process mediated by both highly-reducing polyketide synthase and nonreducing polyketide synthase,which is distinct from the common depside skeleton *** skeleton was subsequently modified by two in-cluster enzymes DepG and DepF for the ether bond formation and decarboxylation,*** addition,the decarboxylase DepF exhibited substrate promiscuity for different scaffold ***,and interestingly,we discovered a halogenase encoded remotely from the biosynthetic gene cluster,which catalyzes triple-halogenation to produce the active end product nornidulin(3).These discoveries provide new insights for further understanding the biosynthesis of depsidones and their derivatives.

关键词： Depside and depsidone Polyketide synthase Tailoring enzymes Multiple-halogenated Antibacterial activity

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