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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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Targeting Micrornas With Small Molecules: From Dream to Reality

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CLINICAL PHARMACOLOGY & THERAPEUTICS 2010年第6期87卷 754-758页

作者： Zhang, S. Chen, L. Jung, E. J. Calin, G. A. Univ Texas MD Anderson Canc Ctr Dept Expt Therapeut Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Ctr RNA Interference & Non Coding RNAs Houston TX 77030 USA

Currently, one out of four deaths in the United States is due to cancer; therefore, every major therapeutic advance in cancer has the potential to save many lives. One of the most fascinating discoveries in the area of molecular oncology in the past decade is that, in cancer, alterations in both protein-coding genes and noncoding rnas, known as micrornas (mirnas), complement each other. In this article, we focus on a novel idea involving the use of small molecules to target overexpressed mirnas as a new therapy for diseases, particularly cancer, in humans. Clinical Pharmacology & Therapeutics (2010) 87 6, 754–758. doi: 10.1038/clpt.2010.46

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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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Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer

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NATURE COMMUNICATIONS 2016年第1期7卷 10798-10812页

作者： Zhang, Dingxiao Park, Daechan Zhong, Yi Lu, Yue Rycaj, Kiera Gong, Shuai Chen, Xin Liu, Xin Chao, Hsueh-Ping Whitney, Pamela Calhoun-Davis, Tammy Takata, Yoko Shen, Jianjun Iyer, Vishwanath R. Tang, Dean G. Univ Texas MD Anderson Canc Ctr Dept Epigenet & Mol Carcinogenesis Smithville TX 78957 USA Univ Texas Austin Ctr Syst & Synthet Biol Inst Cellular & Mol Biol Dept Mol Biosci Austin TX 78712 USA Tongji Univ Sch Med East Hosp Res Ctr Translat MedCanc Stem Cell Inst Shanghai 2001120 Peoples R China Univ Texas MD Anderson Canc Ctr RNA Interference & Non Coding RNAs & Mol Carcinog Ctr Canc Epigenet Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr RNA Interference & Non Coding RNAs & Mol Carcinog Ctr Stem Cell Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr RNA Interference & Non Coding RNAs & Mol Carcinog Ctr Dev Biol Houston TX 77030 USA Univ Texas Austin Dept Chem Engn Austin TX 78712 USA

The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here we describe a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep rna sequencing. Through molecular and biological characterizations, we show that the differential gene-expression profiles account for their distinct functional properties. Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal rna (rrna) biogenesis. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rrna transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers. Therefore, we link the cell-type-specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features.

关键词： Gene expression Prostate cancer

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Corrigendum to Exosomal mirna confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer

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EBioMedicine 2025年 111卷 105486页

作者： Pinar Kanlikilicer Recep Bayraktar Merve Denizli Mohammed H Rashed Cristina Ivan Burcu Aslan Rahul Mitra Kubra Karagoz Emine Bayraktar Xinna Zhang Cristian Rodriguez-Aguayo Amr Ahmed El-Arabey Nermin Kahraman Seyda Baydogan Ozgur Ozkayar Michael L Gatza Bulent Ozpolat George A Calin Anil K Sood Gabriel Lopez-Berestein Department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center Houston TX USA Center for RNA Interference and Non-Coding RNA The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center Houston TX USA. Center for RNA Interference and Non-Coding RNA The University of Texas MD Anderson Cancer Center Houston TX USA Department of Gynecologic Oncology and Reproductive Medicine The University of Texas MD Anderson Cancer Center Houston TX USA. Rutgers Cancer Institute of New Jersey New Brunswick NJ USA. Hacettepe University Ankara Turkey. Department of Cancer Biology The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Cancer Biology The University of Texas MD Anderson Cancer Center Houston TX USA Department of Cancer Biology The University of Texas MD Anderson Cancer Center Houston TX USA. Electronic address: glopez@***.

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Unraveling the therapeutic potential of the Lncrna-dependent noncanonical Hedgehog pathway in cancer

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MOLECULAR & CELLULAR ONCOLOGY 2015年第4期2卷 Article: e998900页

作者： Xing, Zhen Lin, Chunru Yang, Liuqing Univ Texas MD Anderson Canc Ctr Dept Mol & Cellular Oncol Houston TX 77030 USA Univ Texas Houston Cancer Biol Program Houston TX 77004 USA Univ Texas MD Anderson Canc Ctr Ctr RNA Interference & Non Coding RNAs Houston TX 77030 USA

Acquired resistance to Hedgehog pathway inhibitors has been reported in the clinical setting and upregulation of noncanonical Hedgehog signaling is one of the major underlying mechanisms behind this resistance. As demonstrated in our recent study, greater clinical efficacy might be achieved by focusing on downstream targets of the chemokine activated noncanonical Hedgehog signaling pathway such as BCAR4 and phospho-GLI2 (Ser149).

关键词： Long non-coding rna BCAR4 signaling pathway Hedgehog Gli2 breast cancer lung metastasis cancer treatment locked nucleic acid

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Fundamental Principles of Cancer Biology: Does It Have Relevance to the Perioperative Period?

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Current Anesthesiology Reports 2015年第3期5卷 250-256页

作者： Jiang, Li Nick, Alpa M. Sood, Anil K. Department of Gynecologic Oncology & Reproductive Medicine The University of Texas MD Anderson Cancer Center Houston 77584 TX United States Department of Cancer Biology The University of Texas MD Anderson Cancer Center Houston 77584 TX United States Center for RNA Interference and Non-Coding RNA The University of Texas MD Anderson Cancer Center Houston 77584 TX United States

Malignant tumors are characterized by their ability to metastasize, which is the main cause of cancer-related mortality. Besides intrinsic alternations in cancer cells, the tumor microenvironment plays a pivotal role in tumor growth and metastasis. Ample evidence suggests that the perioperative period and the excision of the primary tumor can promote the development of metastases and can influence long-term cancer patient outcomes. The role of cancer biology and its impact on the perioperative period are of increasing interest. This review will present evidence regarding fundamental principles of cancer biology, especially tumor microenvironment, and discuss new therapeutic opportunities in the perioperative timeframe. We will also discuss the regulatory signaling that could be relevant to various aspects of surgery and surgical responses, which could facilitate the metastatic process by directly or indirectly affecting malignant tissues and the tumor microenvironment. We address the influences of surgery-related stress, anesthetic and analgesic agents, blood transfusion, hypothermia, and β-adrenergic blockade administration on tumor growth and metastasis. Through an improved understanding of these processes, we will provide suggestions for potential new perioperative approaches aimed at improving treatment outcomes of cancer patients. © 2015, Springer Science + Business Media New York.

关键词： Cancer biology Perioperative Therapeutics

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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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The rna-Binding Protein DDX1 Promotes Primary Microrna Maturation and Inhibits Ovarian Tumor Progression

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CELL REPORTS 2014年第5期8卷 1447-1460页

作者： Han, Cecil Liu, Yunhua Wan, Guohui Choi, Hyun Jin Zhao, Luqing Ivan, Cristina He, Xiaoming Sood, Anil K. Zhang, Xinna Lu, Xiongbin Univ Texas MD Anderson Canc Ctr Dept Canc Biol Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Gynecol Oncol & Reprod Med Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Ctr RNA Interference & Non Coding RNAs Houston TX 77030 USA Ohio State Univ Dept Biomed Engn Columbus OH 43210 USA

Posttranscriptional maturation is a critical step in microrna (mirna) biogenesis that determines mature mirna levels. In addition to core components (Drosha and DGCR8 [DiGeorge syndrome critical region gene 8]) in the microprocessor, regulatory rna-binding proteins may confer the specificity for recruiting and processing of individual primary mirnas (primirnas). Here, we identify DDX1 as a regulatory protein that promotes the expression of a subset of mirnas, including five members in the microrna-200 (miR-200) family and four mirnas in an eight-mirna signature of a mesenchymal ovarian cancer subtype. A majority of DDX1-dependent mirnas are induced after DNA damage. This induction is facilitated by the ataxia telangiectasia mutated (ATM)-mediated phosphorylation of DDX1. Inhibiting DDX1 promotes ovarian tumor growth and metastasis in a syngeneic mouse model. Analysis of The Cancer Genome Atlas (TCGA) reveals that low DDX1 levels are associated with poor clinical outcome in patients with serous ovarian cancer. These findings suggest that DDX1 is a key modulator in mirna maturation and ovarian tumor suppression.

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Targeting non-coding rnas to overcome cancer therapy resistance

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Signal Transduction and Targeted Therapy 2022年第5期7卷 1447-1466页

作者： BaoQing Chen Mihnea P.Dragomir Chen Yang Qiaoqiao Li David Horst George A.Calin Department of Radiation Oncology State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouGuangdong 510060China Institute of Pathology Charité-Universitätsmedizin Berlincorporate member of Freie Universität BerlinHumboldt-Universität zu Berlin and Berlin Institute of HealthBerlin 10117Germany Berlin Institute of Health Anna-Louisa-Karsch-Straße 210178 BerlinGermany German Cancer Consortium(DKTK) Partner Site BerlinGerman Cancer Research Center(DKFZ)69210 HeidelbergGermany Department of Translational Molecular Pathology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Center for RNA Interference and Non-Coding RNAs The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA

It is now well known that non-coding rnas(ncrnas),rather than protein-coding transcripts,are the preponderant rna ***,particularly micrornas(mirnas),long non-coding rnas(lncrnas),and circular rnas(circrnas),are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation,apoptosis,invasion,metastasis,and genomic *** recent discoveries in cancer therapy,resistance to chemotherapy,radiotherapy,targeted therapy.

关键词： chemotherapy metastasis rnas

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