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Key questions about the checkpoint blockade-are micrornas an answer?

Cancer Biology & Medicine 2018年第2期15卷 103-115页

作者： Mihnea Dragomir Baoqing Chen Xiao Fu George A.Calin department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center Research center for Functional Genomics Biomedicine and Translational MedicineIuliu Hatieganu University of Medicine and Pharmacy department of Surgery Fundeni Clinical HospitalCarol Davila University of Medicine and Pharmacy center for rna interference and non-coding rnas The University of Texas MD Anderson Cancer Center

The introduction of immune-checkpoint blockade in the cancer therapy led to a paradigm change of the management of late stage cancers. There are already multiple FDA approved checkpoint inhibitors and many other agents are undergoing phase 2 and early phase 3 clinical trials. The therapeutic indication of immune checkpoint inhibitors expanded in the last years, but still remains unclear who can benefit. Micro rnas are small rnas with no coding potential. By complementary pairing to the 3' untranslated region of messenger rna, micrornas exert posttranscriptional control of protein expression. A network of micrornas directly and indirectly controls the expression of checkpoint receptors and several micrornas can target multiple checkpoint molecules,mimicking the therapeutic effect of a combined immune checkpoint blockade. In this review, we will describe the micrornas that control the expression of immune checkpoints and we will present four specific issues of the immune checkpoint therapy in cancer:(1) imprecise therapeutic indication,(2) difficult response evaluation,(3) numerous immunologic adverse-events, and(4)the absence of response to immune therapy. Finally, we propose micrornas as possible solutions for these pitfalls. We consider that in the near future micrornas could become important therapeutic partners of the immune checkpoint therapy.

关键词： Microrna PD-1 PD-L1 CTLA-4 checkpoint inhibitors

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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

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Gut microbiota:a new player in regulating immune-and chemo-therapy efficacy

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Cancer Drug Resistance 2020年第3期3卷 356-370页

作者： Simone Anfossi George A.Calin department of Experimental Therapeutics The University of Texas MD Anderson Cancer CenterHoustonTX 77054USA. center for rna interference and non-coding rnas The University of Texas MD Anderson Cancer CenterHoustonTX 77054USA.

Development of drug resistance represents the major cause of cancer therapy failure,determines disease progression and results in poor prognosis for cancer *** mechanisms are responsible for drug *** genetic modifications of cancer cells induce the alteration of expression of gene controlling specific pathways that regulate drug resistance:drug transport and metabolism;alteration of drug targets;DNA damage repair;and deregulation of apoptosis,autophagy,and pro-survival *** the other hand,a complex signaling network among the entire cell component characterizes tumor microenvironment and regulates the pathways involved in the development of drug *** microbiota represents a new player in the regulation of a patient’s response to cancer therapies,including chemotherapy and *** particular,commensal bacteria can regulate the efficacy of immune checkpoint inhibitor therapy by modulating the activation of immune responses to *** bacteria can also regulate the efficacy of chemotherapeutic drugs,such as oxaliplatin,gemcitabine,and ***,it has been shown that such bacteria can produce extracellular vesicles(EVs)that can mediate intercellular communication with human host ***,bacterial EVs carry rna molecules with gene expression regulatory ability that can be delivered to recipient cells of the host and potentially regulate the expression of genes involved in controlling the resistance to cancer *** the other hand,host cells can also deliver human EVs to commensal bacteria and similarly,regulate gene *** intercellular communication between commensal bacteria and host cells may thus represent a novel research area into potential mechanisms regulating the efficacy of cancer therapy.

关键词： Gut microbiota resistance chemotherapy immunotherapy immune checkpoint inhibitor extracellular vesicles mirnas cell-to-cell communication

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Microrna therapeutics:principles,expectations,and challenges

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Chinese Journal of Cancer 2011年第6期30卷 368-370页

作者： Rajesha Rupaimoole Hee-Dong Han Gabriel Lopez-Berestein Anil K.Sood department of Gynecologic Oncology The University of Texas M.D.Anderson Cancer Center department of center for rna interference and non-coding rna The University of Texas M.D.Anderson Cancer Center department of Experimental Therapeutics The University of Texas M.D.Anderson Cancer Center department of department of Cancer Biology The University of Texas M.D.Anderson Cancer Center

Micrornas(mirnas) are a class of highly abundant non-coding rna molecules that are involved in several biological *** mirnas are often deregulated in several diseases including *** is substantial interest in exploiting mirnas for therapeutic *** this editorial,we briefly review current advances in the use of mirnas or antisense oligonucleotides(antagomirs) for such *** of the key issues related to therapy using mirnas is degradation of naked particles in *** overcome this limitation,delivery systems for mirna-based therapeutic agents have been developed,which hold tremendous potential for improving therapeutic outcome of cancer patients.

关键词：微rna 疗法 mirnas 小分子rna 治疗药物期望非编码rna 反义寡核苷酸

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PTMD: A Database of Human Disease-associated Post-translational Modifications

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Genomics, Proteomics & Bioinformatics 2018年第4期16卷 244-251页

作者： Haodong Xu Yongbo Wang Shaofeng Lin Wankun Deng Di Peng Qinghua Cui Yu Xue department of Bioinformatics & Systems Biology MOE Key Laboratory of Molecular Biophysics College of Life Science and Technology and the Collaborative Innovation Center for Biomedical Engineering Huazhong University of Science and Technology department of Biomedical Informatics School of Basic Medical Sciences MOE Key Laboratory of Molecular Cardiovascular Sciences Center for Non-coding RNA Medicine Peking University

Various posttranslational modifications （PTMs） participate in nearly all aspects of biological processes by regulating protein functions, and aberrant states of PTMs are frequently implicated in human diseases. Therefore, an integral resource of PTM–disease associations （PDAs）would be a great help for both academic research and clinical use. In this work, we reported PTMD,a well-curated database containing PTMs that are associated with human diseases. We manually collected 1950 known PDAs in 749 proteins for 23 types of PTMs and 275 types of diseases from the literature. Database analyses show that phosphorylation has the largest number of disease associations, whereas neurologic diseases have the largest number of PTM associations. We classified all known PDAs into six classes according to the PTM status in diseases and demonstrated that the upregulation and presence of PTM events account for a predominant proportion of diseaseassociated PTM events. By reconstructing a disease–gene network, we observed that breast cancers have the largest number of associated PTMs and AKT1 has the largest number of PTMs connected to diseases. Finally, the PTMD database was developed with detailed annotations and can be a useful resource for further analyzing the relations between PTMs and human diseases. PTMD is freely accessible at http：//***.

关键词： Posttranslational modification Phosphorylation PTM-disease association Disease-gene network AKT1

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Rice Bran-derived Peptide KF-8 Attenuates Dexamethasone-induced Myopathy in Caenorhabditis elegans by Regulating Locomotion-related Genes

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Food Science and Human Wellness 2024年

作者： Yixin Wu Jianqiang Wang Fang Huang Yajuan Chen Qinlu Lin Zhongxu Chen Zhigang Liu Yao Jiang Wenqing Xie Hengzhen Li Yusheng Li Ying Liang National Clinical Research center for Geriatric Disorders， Xiangya Hospital， Central South University Molecular Nutrition Branch， National Engineering Research center of Rice and By-product Deep Processing， College of Food Science and Engineering， Central South University of Forestry and Technology Laboratory of Functional Chemistry and Nutrition of Food， College of Food Science and Engineering， Northwest A&F University The Key Lab of non-wood Forest Cultivation and Protection of Education Ministry， The Key Lab of non-wood Forest Products of Forestry Ministry， Forestry Institute， Central South University of Forestry & Technology department of Orthopedics， Xiangya Hospital， Central South University

Background and aims: Dexamethasone is a common glucocorticoid medication with adverse effects that can cause muscle atrophy， but no drug intervention has been approved or recommended for this condition. KF-8 is a rice bran-derived anti-oxidant peptide that extends the life span of Caenorhabditis elegans. Methods: We established a C. elegans model of dexamethasone-induced myopathy to evaluate the potential therapeutic effects of KF-8 in this model. C. elegans muscle function was assessed in terms of locomotory behaviors including crawling， swimming， burrowing， pharyngeal pumping， and head swing. Muscle actin filament integrity was evaluated using fluorescence imaging. The molecular mechanisms of KF-8 were investigated using transcriptome sequencing， qRT-PCR， rna interference， and western blot analysis. Results: Dexamethasone disrupted actin filaments in the striated muscles of the body wall and inhibited C. elegans crawling， swimming， burrowing， pharyngeal pumping， and head swing. KF-8 reversed the actin filament disruption and locomotor dysfunction induced by dexamethasone. Transcriptome sequencing， pathway enrichment， and qRT-PCR analyses revealed that KF-8 regulated the locomotion-related genes W04G5.10， vha-12， and ddr-1， as well as age-1 (the catalytic subunit ortholog of PI3K)， and akt1. rna interference， conducted using a genetically engineered E. coli HT115 strain as a food source， confirmed age-1 as a key regulator of locomotor function of C. elegans. Further mechanistic studies with C2C12 myotubes showed that KF-8 regulated the IRS-PI3K-Akt pathway， the master regulator of protein synthesis and degradation. Conclusion: Together， these findings suggest that KF-8 protects against dexamethasone-induced myopathy in C. elegans by regulating locomotion-related genes and the IRS-PI3K-Akt pathway.

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The role of exosomal long non-coding rnas in cancer drug resistance

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Cancer Drug Resistance 2019年第4期2卷 1178-1192页

作者： Mireia Cruz De los Santos Mihnea P.Dragomir George A.Calin department of Experimental Therapeutics The University of Texas MD Anderson Cancer CenterHoustonTX 77054USA Research center for Functional Genomics Biomedicine and Translational MedicineIuliu Hatieganu University of Medicine and PharmacyCluj-Napoca 40015Romania department of Surgery Fundeni Clinical HospitalCarol Davila University of Medicine and PharmacyBucharest 022328Romania center for rna interference and non-coding rnas The University of Texas MD Anderson Cancer CenterHoustonTX 77054USA

One of the major challenges in oncology is drug resistance,which triggers relapse and shortens patients’*** order to promote drug desensitization,cancer cells require the establishment of an ideal tumor microenvironment that accomplishes specific *** achieve this objective,cellular communication is a key ***,cells were believed to restrictively communicate by ligand-receptor binding,physical cell-to-cell interactions and ***,the crosstalk between tumor cells and stroma cells has also been recently reported to be mediated through exosomes,the smallest extracellular vesicles,which transport a plethora of functionally active molecules,such as:proteins,lipids,messenger rna,DNA,microrna or long non-coding rna(lncrnas).Lncrnas are rna molecules greater than 200 base pairs that are deregulated in cancer and other *** lncrnas are highly stable and can be found in several body fluids,being considered potential biomarkers for tumor liquid *** lncrnas promote angiogenesis,cell proliferation and drug *** role of exosomal lncrnas in drug resistance affects the main treatment strategies in oncology:chemotherapy,targeted therapy,hormone therapy and ***,knowing the molecular mechanisms by which exosomal lncrna induce pharmacologic resistance could improve further drug development and identify drug resistance biomarkers.

关键词： Tumor microenvironment extracellular vesicles exosomes non-coding rna long non-coding rna drug resistance

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OUGENE： a disease associated over-expressed and under-expressed gene database

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Science Bulletin 2016年第10期61卷 752-754页

作者： Xiaoyong Pan Hong-Bin Shen Section for Animal Genetics Bioinformatics and Breeding Center for Non-Coding RNA in Technology and Health University of Copenhagen 1870 Frederiksberg Denmark department of Disease Systems Biology Novo NordiskFoundation Center for Protein Research University ofCopenhagen 1870 Frederiksberg Denmark Institute of Image Processing and Pattern Recognition Shanghai Jiao Tong University and Key Laboratory of System Control and Information Processing Ministry of Education of China Shanghai 200240 China

Gene over-expression or under-expression is closely associated with human diseases, which contributes to phenotypic variations and diversity. To our best knowledge, there is no single open specific resource available to provide the association information between gene over- or under-expression and various diseases. In this study, we presented a comprehensive disease-associated over- and under-expressed gene database （OUGene） based on our proposed text mining pipeline and several open curated databases. It contains total 41,269 unique associa- tions between 7,238 over- or under-expressed genes and 1,480 diseases, which are supported by 81,974 evidence sentences from 56,442 articles. The OUGene is compre- hensive and covers most important therapeutic areas. Meanwhile a new scoring system is designed to rank the associations based on benchmarking against hand-curated data. OUGene provides an easy-of-use web interface for researchers to analyze these data and visualize the associ- ated networks, which can give insights to the complex relationships between over- and under-expressed genes and diseases at a system level. It is available at ***. ***/bioinf/OUGene/.

关键词： Text mining Gene over- and under-expression Disease Database

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Identification and Analysis of Human Sex-biased Micrornas

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Genomics, Proteomics & Bioinformatics 2018年第3期16卷 200-211页

作者： Chunmei Cui Weili Yang Jiangcheng Shi Yong Zhou Jichun Yang Qinghua Cui Yuan Zhou department of Biomedical Informatics Department of Physiology and Pathophysiology Center for Noncoding RNA Medicine MOE Key Laboratory of Cardiovascular Sciences School of Basic Medical Sciences Peking University department of Physiology and Pathophysiology Center for Noncoding RNA Medicine School of Basic Medical SciencesPeking University Beijing Institute of Heart Lung and Blood Vessel Diseases Beijing Anzhen Hospital Capital Medical University

Sex differences are widely observed under various circumstances ranging from physiolog- ical processes to therapeutic responses, and a myriad of sex-biased genes have been identified. In recent years, transcriptomic datasets of micrornas （mirnas）, an important class of non-coding rnas, become increasingly accessible. However, comprehensive analysis of sex difference in mirna expression has not been performed. Here, we identified the differentially-expressed miR- NAs between males and females by examining the transcriptomic datasets available in public data- bases and conducted a systemic analysis of their biological characteristics. Consequently, we identified 73 female-biased mirnas （FmiRs） and 163 male-biased mirnas （MmiRs） across four tissues including brain, colorectal mucosa, peripheral blood, and cord blood. Our results suggest that compared to FmiRs, MmiRs tend to be clustered in the human genome and exhibit higher evolutionary rate, higher expression tissue specificity, and lower disease spectrum width. In *** enrichment analysis of mirnas show that FmiR genes are significantly associated with metabolism process and cell cycle process, whereas MmiR genes tend to be enriched for functions like histone modification and circadian rhythm. In all, the identification and analysis of sex-biased mirnas together could provide new insights into the biological differences between females and males and facilitate the exploration of sex-biased disease susceptibility and therapy.

关键词： Sex bias Micrornas Conservation Disease association Personalized medicine

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Clinical application value of long non-coding rnas signatures of genomic instability in predicting prognosis of hepatocellular carcinoma

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World Journal of Gastrointestinal Surgery 2024年第8期16卷 2386-2392页

作者： Xiao-Wen Xing Xiao Huang Wei-Peng Li Ming-Ke Wang Ji-Shun Yang department of Disease Control and Prevention Naval Medical CenterNaval Medical UniversityShanghai 200052China Medical Care center Naval Medical UniversityShanghai 200052China

Hepatocellular carcinoma(HCC)presents challenges due to its high recurrence and metastasis rates and poor *** current clinical diagnostic and prognostic indicators exist,their accuracy remains imperfect due to their biol-ogical ***,there is a quest to identify improved biomarkers for HCC diagnosis and *** combining long non-coding rna(lncrna)expression and somatic mutations,Duan et al identified five representative lncrnas from 88 lncrnas related to genomic instability(GI),forming a GI-derived lncrna signature(LncSig).This signature outperforms previously re-ported LncSig and TP53 mutations in predicting HCC *** this editorial,we comprehensively evaluate the clinical application value of such prognostic evaluation model based on sequencing technology in terms of cost,time,and ***,we provide an overview of various prognostic models for HCC,aiding in a comprehensive understanding of research progress in pro-gnostic evaluation methods.

关键词： Hepatocellular carcinoma Prognosis Prognostic model Biomarkers Genomic instability long non-coding rna Clinical application value

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