Publications by authors named "George A Calin"

395 Publications

RNAi-based therapeutics and tumor targeted delivery in cancer.

Adv Drug Deliv Rev 2022 Jan 18:114113. Epub 2022 Jan 18.

Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, Texas, 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas, MD Anderson Cancer Center, Houston, Texas, 77030, USA. Electronic address:

Over the past decade, non-coding RNA-based therapeutics have proven as a great potential for the development of targeted therapies for cancer and other diseases. The discovery of the critical function of microRNAs (miRNAs) has generated great excitement in developing miRNA-based therapies. The dysregulation of miRNAs contributes to the pathogenesis of various human diseases and cancers by modulating genes that are involved in critical cellular processes, including cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, drug resistance, and tumorigenesis. miRNA (miRNA mimic, anti-miRNA/antagomir) and small interfering RNA (siRNA) can inhibit the expression of any cancer-related genes/mRNAs with high specificity through RNA interference (RNAi), thus representing a remarkable therapeutic tool for targeted therapies and precision medicine. siRNA and miRNA-based therapies have entered clinical trials and recently three novel siRNA-based therapeutics were approved by the Food and Drug Administration (FDA), indicating the beginning of a new era of targeted therapeutics. The successful clinical applications of miRNA and siRNA therapeutics rely on safe and effective nanodelivery strategies for targeting tumor cells or tumor microenvironment. For this purpose, promising nanodelivery/nanoparticle-based approaches have been developed using a variety of molecules for systemic administration and improved tumor targeted delivery with reduced side effects. In this review, we present an overview of RNAi-based therapeutics, the major pharmaceutical challenges, and the perspectives for the development of promising delivery systems for clinical translation. We also highlight the passive and active tumor targeting nanodelivery strategies and primarily focus on the current applications of nanoparticle-based delivery formulations for tumor targeted RNAi molecules and their recent advances in clinical trials in human cancers.
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http://dx.doi.org/10.1016/j.addr.2022.114113DOI Listing
January 2022

Analysis of the circRNA and T-UCR populations identifies convergent pathways in mouse and human models of Rett syndrome.

Mol Ther Nucleic Acids 2022 Mar 22;27:621-644. Epub 2021 Dec 22.

Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, 08916 Catalonia, Spain.

Noncoding RNAs play regulatory roles in physiopathology, but their involvement in neurodevelopmental diseases is poorly understood. Rett syndrome is a severe, progressive neurodevelopmental disorder linked to loss-of-function mutations of the gene for which no cure is yet available. Analysis of the noncoding RNA profile corresponding to the brain-abundant circular RNA (circRNA) and transcribed-ultraconserved region (T-UCR) populations in a mouse model of the disease reveals widespread dysregulation and enrichment in glutamatergic excitatory signaling and microtubule cytoskeleton pathways of the corresponding host genes. Proteomic analysis of hippocampal samples from affected individuals confirms abnormal levels of several cytoskeleton-related proteins together with key alterations in neurotransmission. Importantly, the glutamate receptor gene displays altered biogenesis in affected individuals and human cells and is influenced by expression of two ultraconserved RNAs. We also describe post-transcriptional regulation of SIRT2 by circRNAs, which modulates acetylation and total protein levels of GluR-1. As a consequence, both regulatory mechanisms converge on the biogenesis of AMPA receptors, with an effect on neuronal differentiation. In both cases, the noncoding RNAs antagonize MeCP2-directed regulation. Our findings indicate that noncoding transcripts may contribute to key alterations in Rett syndrome and are not only useful tools for revealing dysregulated processes but also molecules of biomarker value.
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http://dx.doi.org/10.1016/j.omtn.2021.12.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749388PMC
March 2022

Standardisation of protocols can be crucial in long non-coding RNA research.

Br J Cancer 2021 Dec 15. Epub 2021 Dec 15.

Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

In this issue, Traversa et al. [1] reviewed our current knowledge about the role of circular and linear forms of PVT1 non-coding RNA in cancer and human diseases. They highlighted the technical challenges of these studies and raised a potential bias in the publications, which require more attention from researchers.
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http://dx.doi.org/10.1038/s41416-021-01656-8DOI Listing
December 2021

CORRIGENDUM: GATA3 as a master regulator for interactions of tumor-associated macrophages with high-grade serous ovarian carcinoma.

Cell Signal 2022 Jan 9;89:110147. Epub 2021 Nov 9.

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.

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http://dx.doi.org/10.1016/j.cellsig.2021.110147DOI Listing
January 2022

APPLE and translation: When a small peptideproduced from a "non-coding RNA" matters!

Mol Cell 2021 11;81(21):4349-4351

Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Sun et al. (2021) identified a novel translation initiation mechanism mediated through a new type of regulator named APPLE, a small peptide produced from a non-coding RNA transcript in acute myeloid leukemia, providing unforeseen opportunities for targeting the translation machinery in cancer cells.
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http://dx.doi.org/10.1016/j.molcel.2021.10.012DOI Listing
November 2021

Classical and noncanonical functions of miRNAs in cancers.

Trends Genet 2021 Oct 30. Epub 2021 Oct 30.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Alterations in microRNAs (miRNAs) expression are causative in the initiation and progression of human cancers. The molecular events responsible for the widespread differential expression of miRNAs in malignancy are exemplified by their location in cancer-associated genomic regions, epigenetic mechanisms, transcriptional dysregulation, chemical modifications and editing, and alterations in miRNA biogenesis proteins. The classical miRNA function is synonymous with post-transcriptional repression of target protein genes. However, several studies have reported miRNAs functioning outside this paradigm and some of these novel modes of regulation of gene expression have been implicated in cancers. Here, we summarize key aspects of miRNA involvement in cancer, with a special focus on these lesser-studied mechanisms of action.
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http://dx.doi.org/10.1016/j.tig.2021.10.002DOI Listing
October 2021

Selection of a Nuclease-Resistant RNA Aptamer Targeting CD19.

Cancers (Basel) 2021 Oct 18;13(20). Epub 2021 Oct 18.

IEOS-Istituto per l'endocrinologia e l'oncologia "Gaetano Salvatore", CNR, 80131 Naples, Italy.

The transmembrane glycoprotein cluster of differentiation 19 (CD19) is a B cell-specific surface marker, expressed on the majority of neoplastic B cells, and has recently emerged as a very attractive biomarker and therapeutic target for B-cell malignancies. The development of safe and effective ligands for CD19 has become an important need for the development of targeted conventional and immunotherapies. In this regard, aptamers represent a very interesting class of molecules. Additionally referred to as 'chemical antibodies', they show many advantages as therapeutics, including low toxicity and immunogenicity. Here, we isolated a nuclease-resistant RNA aptamer binding to the human CD19 glycoprotein. In order to develop an aptamer also useful as a carrier for secondary reagents, we adopted a cell-based SELEX (Systematic Evolution of Ligands by EXponential Enrichment) protocol adapted to isolate aptamers able to internalise upon binding to their cell surface target. We describe a 2'-fluoro pyrimidine modified aptamer, named B85.T2, which specifically binds to CD19 and shows an exquisite stability in human serum. The aptamer showed an estimated dissociation constant (K) of 49.9 ± 13 nM on purified human recombinant CD19 (rhCD19) glycoprotein, a good binding activity on human B-cell chronic lymphocytic leukaemia cells expressing CD19, and also an effective and rapid cell internalisation, thus representing a promising molecule for CD19 targeting, as well as for the development of new B-cell malignancy-targeted therapies.
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http://dx.doi.org/10.3390/cancers13205220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533794PMC
October 2021

Immune Modulatory Short Noncoding RNAs Targeting the Glioblastoma Microenvironment.

Front Oncol 2021 31;11:682129. Epub 2021 Aug 31.

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.

Glioblastomas are heterogeneous and have a poor prognosis. Glioblastoma cells interact with their neighbors to form a tumor-permissive and immunosuppressive microenvironment. Short noncoding RNAs are relevant mediators of the dynamic crosstalk among cancer, stromal, and immune cells in establishing the glioblastoma microenvironment. In addition to the ease of combinatorial strategies that are capable of multimodal modulation for both reversing immune suppression and enhancing antitumor immunity, their small size provides an opportunity to overcome the limitations of blood-brain-barrier (BBB) permeability. To enhance glioblastoma delivery, these RNAs have been conjugated with various molecules or packed within delivery vehicles for enhanced tissue-specific delivery and increased payload. Here, we focus on the role of RNA therapeutics by appraising which types of nucleotides are most effective in immune modulation, lead therapeutic candidates, and clarify how to optimize delivery of the therapeutic RNAs and their conjugates specifically to the glioblastoma microenvironment.
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http://dx.doi.org/10.3389/fonc.2021.682129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438301PMC
August 2021

Profiling Long Non-coding RNA expression Using Custom-Designed Microarray.

Methods Mol Biol 2021 ;2372:43-51

Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Long non-coding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. The abnormal expression of lncRNAs has been implicated in a range of many human diseases, including cancer. To date, a small number of functional lncRNAs have been well characterized. lncRNA expression profiling may help to identify useful molecular biomarkers and targets for novel therapeutic approaches. In this chapter, we describe a highly efficient lncRNA expression profiling method using a custom-designed microarray.
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http://dx.doi.org/10.1007/978-1-0716-1697-0_6DOI Listing
January 2022

A noncoding RNA modulator potentiates phenylalanine metabolism in mice.

Science 2021 08;373(6555):662-673

Division of Metabolism, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland.

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA and human associate with phenylalanine hydroxylase (PAH). -knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically, modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc- mimics reduced excessive Phe in and mice and improved the Phe tolerance of these mice.
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http://dx.doi.org/10.1126/science.aba4991DOI Listing
August 2021

Viral Micro-RNAs Are Detected in the Early Systemic Response to Injury and Are Associated With Outcomes in Polytrauma Patients.

Crit Care Med 2021 Jul 2. Epub 2021 Jul 2.

1 Surgical Critical Care Initiative (SC2i), Bethesda, MD. 2 Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD. 3 Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD. 4 Translational Molecular Pathology, Houston, TX. 5 DecisionQ, Arlington, VA. 6 Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD. 7 Department of Surgery, Emory University, Atlanta, GA. 8 Department of Surgery, Duke University, Durham, NC.

Objectives: To evaluate early activation of latent viruses in polytrauma patients and consider prognostic value of viral micro-RNAs in these patients.

Design: This was a subset analysis from a prospectively collected multicenter trauma database. Blood samples were obtained upon admission to the trauma bay (T0), and trauma metrics and recovery data were collected.

Setting: Two civilian Level 1 Trauma Centers and one Military Treatment Facility.

Patients: Adult polytrauma patients with Injury Severity Scores greater than or equal to 16 and available T0 plasma samples were included in this study. Patients with ICU admission greater than 14 days, mechanical ventilation greater than 7 days, or mortality within 28 days were considered to have a complicated recovery.

Interventions: None.

Measurements And Main Results: Polytrauma patients (n = 180) were identified, and complicated recovery was noted in 33%. Plasma samples from T0 underwent reverse transcriptase-quantitative polymerase chain reaction analysis for Kaposi's sarcoma-associated herpesvirus micro-RNAs (miR-K12_10b and miRK-12-12) and Epstein-Barr virus-associated micro-RNA (miR-BHRF-1), as well as Luminex multiplex array analysis for established mediators of inflammation. Ninety-eight percent of polytrauma patients were found to have detectable Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus micro-RNAs at T0, whereas healthy controls demonstrated 0% and 100% detection rate for Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, respectively. Univariate analysis revealed associations between viral micro-RNAs and polytrauma patients' age, race, and postinjury complications. Multivariate least absolute shrinkage and selection operator analysis of clinical variables and systemic biomarkers at T0 revealed that interleukin-10 was the strongest predictor of all viral micro-RNAs. Multivariate least absolute shrinkage and selection operator analysis of systemic biomarkers as predictors of complicated recovery at T0 demonstrated that miR-BHRF-1, miR-K12-12, monocyte chemoattractant protein-1, and hepatocyte growth factor were independent predictors of complicated recovery with a model complicated recovery prediction area under the curve of 0.81.

Conclusions: Viral micro-RNAs were detected within hours of injury and correlated with poor outcomes in polytrauma patients. Our findings suggest that transcription of viral micro-RNAs occurs early in the response to trauma and may be associated with the biological processes involved in polytrauma-induced complicated recovery.
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http://dx.doi.org/10.1097/CCM.0000000000005181DOI Listing
July 2021

Construction and validation of prognostic nomogram for metaplastic breast cancer.

Bosn J Basic Med Sci 2021 Jun 10. Epub 2021 Jun 10.

Laboratory of Cancer Biology, Key Lab of Zhejiang Biotherapy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

In this study we aimed to develop nomogram models for predicting the overall survival (OS) and cancer-specific survival (CSS) of patients with metaplastic breast cancer (MBC). Data of patients diagnosed with MBC from 1973 to 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses were performed to identify independent prognostic factors for OS and CSS of MBC patients. The obtained prognostic variables were combined to construct nomogram models for predicting OS and CSS in patients with MBC. Model performance was evaluated using concordance index (C-index) and calibration plots. Data from 1125 patients were collected and divided into a training (750) and a validation (375) cohort. The multivariate Cox model identified age, TNM stage, tumor size, and radiotherapy as independent covariates associated with OS and CSS. The nomogram constructed based on these covariates demonstrated excellent accuracy in estimating 3-, and 5-year OS and CSS, with a C-index of 0.769 (95% CI, 0.731-0.808) for OS and 0.761 (95% CI, 0.713-0.809) for CSS in the training cohort. In the validation cohort, the nomogram-predicted C-index was 0.738 (95%CI, 0.676-0.800) for OS and 0.747 (95%CI, 0.667-0.827) for CSS. All calibration curves exhibited good consistency between predicted and actual survival. The nomogram models established in this study may enhance the accuracy of prognosis prediction and therefore may improve individualized assessment of survival risks and enable constructive therapeutic suggestions.
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http://dx.doi.org/10.17305/bjbms.2021.5911DOI Listing
June 2021

CRISPR/Cas9 to Silence Long Non-Coding RNAs.

Methods Mol Biol 2021 ;2348:175-187

Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway.

Knockout (KO) of long non-coding RNAs (lncRNAs) enables functional characterization of this still poorly described group of transcripts. One of the most efficient and simplest methods to achieve complete KO of a lncRNA is by employing CRISPR/Cas gene editing. As most lncRNAs are not well annotated, their individual functional regions are often not defined, and the majority of the transcripts are not affected by single nucleotide mutations. Therefore, CRISPR/Cas KO is more challenging for lncRNAs as compared to KO of protein coding genes. Strategies for lncRNAs KO include complete removal of the entire gene, removal of the promoter and transcriptional start site, abolishing exon-exon junctions, or removing the transcriptional termination site. Here, we describe the methodology to perform CRISPR/Cas9 KO of lncRNAs in vitro using electroporation as the method of transfection of presynthesized single guide RNAs (sgRNAs) and Cas9 enzyme.
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http://dx.doi.org/10.1007/978-1-0716-1581-2_12DOI Listing
September 2021

Noncoding RNA therapeutics - challenges and potential solutions.

Nat Rev Drug Discov 2021 08 18;20(8):629-651. Epub 2021 Jun 18.

Translational Molecular Pathology, MD Anderson Cancer Center, Texas State University, Houston, TX, USA.

Therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), represents an attractive approach for the treatment of cancers, as well as many other diseases. Over the past decade, substantial effort has been made towards the clinical application of RNA-based therapeutics, employing mostly antisense oligonucleotides and small interfering RNAs, with several gaining FDA approval. However, trial results have so far been ambivalent, with some studies reporting potent effects whereas others demonstrated limited efficacy or toxicity. Alternative entities such as antimiRNAs are undergoing clinical testing, and lncRNA-based therapeutics are gaining interest. In this Perspective, we discuss key challenges facing ncRNA therapeutics - including issues associated with specificity, delivery and tolerability - and focus on promising emerging approaches that aim to boost their success.
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http://dx.doi.org/10.1038/s41573-021-00219-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212082PMC
August 2021

MicroRNA-138 suppresses glioblastoma proliferation through downregulation of CD44.

Sci Rep 2021 04 28;11(1):9219. Epub 2021 Apr 28.

Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin St., MSE R117B, Houston, TX, 77030, USA.

Tumor suppressive microRNAs (miRNAs) are increasingly implicated in the development of anti-tumor therapy by reprogramming gene network that are aberrantly regulated in cancer cells. This study aimed to determine the therapeutic potential of putative tumor suppressive miRNA, miR-138, against glioblastoma (GBM). Whole transcriptome and miRNA expression profiling analyses on human GBM patient tissues identified miR-138 as one of the significantly downregulated miRNAs with an inverse correlation with CD44 expression. Transient overexpression of miR-138 in GBM cells inhibited cell proliferation, cell cycle, migration, and wound healing capability. We unveiled that miR-138 negatively regulates the expression of CD44 by directly binding to the 3' UTR of CD44. CD44 inhibition by miR-138 resulted in an inhibition of glioblastoma cell proliferation in vitro through cell cycle arrest as evidenced by a significant induction of p27 and its translocation into nucleus. Ectopic expression of miR-138 also increased survival rates in mice that had an intracranial xenograft tumor derived from human patient-derived primary GBM cells. In conclusion, we demonstrated a therapeutic potential of tumor suppressive miR-138 through direct downregulation of CD44 for the treatment of primary GBM.
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http://dx.doi.org/10.1038/s41598-021-88615-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080729PMC
April 2021

Being Small and Intronic: miRNAs That Count!

Authors:
George A Calin

Cancer Res 2021 03;81(5):1212-1213

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

The roles of intronic miRNAs and their functional interaction with host coding genes represent a topic that is poorly explored. The study by Kwok and colleagues in this issue of presents solid evidence that the FTX locus at chromosome Xq13.2 contains multiple noncoding RNAs (ncRNA) with coordinated expression and concordant functional effects in colorectal cancer cells. The long ncRNA, FTX, and its intronic miRNAs, miR-374a, -374b, -421, and -545, are all interconnected in a functional network, including the downstream protein coding targets , and These data prove that multigenic loci in the human genome have a complex functional landscape that modulates key signaling pathways for cancer progression and that much knowledge with potential clinical utility remains to be revealed from the largest, noncoding portion of the genome..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-4172DOI Listing
March 2021

Quicker and digital: the way on protein biomarkers?

Authors:
George A Calin

Blood 2021 03;137(12):1564-1565

University of Texas MD Anderson Cancer Center.

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http://dx.doi.org/10.1182/blood.2020010235DOI Listing
March 2021

Effects of long non-coding RNAs on androgen signaling pathways in genitourinary malignancies.

Mol Cell Endocrinol 2021 04 9;526:111197. Epub 2021 Feb 9.

Institute of Genetics and Biophysics "A. Buzzati Traverso", National Research Council (CNR), Naples, Italy. Electronic address:

The non-coding RNA (ncRNA) are generally classified, based on length, into small ncRNAs less than 200 nucleotides, such as miRNA, and long ncRNA (lnRNA) with more than 200 nucleotides. The transcription of ncRNAs, similarly to genes that code for proteins, is highly deregulated in cancer. Their expression level can influence physiological processes, e.g. epigenetic regulation of gene expression, regulation of cell cycle and modification of chromatin. Recent studies on androgen receptor in oncology revealed that it exerts a pivotal role in genitourinary malignancies, in particular in prostate tumor was demonstrated that its deregulation takes part in all stages of carcinogenesis. Here, we discuss present learning of the main lnRNAs involvement on androgen signaling pathways in genitourinary neoplasms, highlighting lnRNAs potential in the regulating network comfortable to cancer onset and progression, and discuss the lnRNAs prognostic and diagnostic value in cancer management.
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http://dx.doi.org/10.1016/j.mce.2021.111197DOI Listing
April 2021

Subcellular Localization of uc.8+ as a Prognostic Biomarker in Bladder Cancer Tissue.

Cancers (Basel) 2021 Feb 8;13(4). Epub 2021 Feb 8.

Institute of Genetics and Biophysics "A. Buzzati Traverso", National Research Council (CNR), 80131 Naples, Italy.

Non-coding RNA transcripts originating from Ultraconserved Regions (UCRs) have tissue-specific expression and play relevant roles in the pathophysiology of multiple cancer types. Among them, we recently identified and characterized the ultra-conserved-transcript-8+ (uc.8+), whose levels correlate with grading and staging of bladder cancer. Here, to validate uc.8+ as a potential biomarker in bladder cancer, we assessed its expression and subcellular localization by using tissue microarray on 73 human bladder cancer specimens. We quantified uc.8+ by in-situ hybridization and correlated its expression levels with clinical characteristics and patient survival. The analysis of subcellular localization indicated the simultaneous presence of uc.8+ in the cytoplasm and nucleus of cells from the Low-Grade group, whereas a prevalent cytoplasmic localization was observed in samples from the High-Grade group, supporting the hypothesis of uc.8+ nuclear-to-cytoplasmic translocation in most malignant tumor forms. Moreover, analysis of uc.8+ expression and subcellular localization in tumor-surrounding stroma revealed a marked down-regulation of uc.8+ levels compared to the paired (adjacent) tumor region. Finally, deep machine-learning approaches identified nucleotide sequences associated with uc.8+ localization in nucleus and/or cytoplasm, allowing to predict possible RNA binding proteins associated with uc.8+, recognizing also sequences involved in mRNA cytoplasm-translocation. Our model suggests uc.8+ subcellular localization as a potential prognostic biomarker for bladder cancer.
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http://dx.doi.org/10.3390/cancers13040681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914980PMC
February 2021

Non-coding RNAs regulation of macrophage polarization in cancer.

Mol Cancer 2021 02 1;20(1):24. Epub 2021 Feb 1.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Noncoding RNA (ncRNA) transcripts that did not code proteins but regulate their functions were extensively studied for the last two decades and the plethora of discoveries have instigated scientists to investigate their dynamic roles in several diseases especially in cancer. However, there is much more to learn about the role of ncRNAs as drivers of malignant cell evolution in relation to macrophage polarization in the tumor microenvironment. At the initial stage of tumor development, macrophages have an important role in directing Go/No-go decisions to the promotion of tumor growth, immunosuppression, and angiogenesis. Tumor-associated macrophages behave differently as they are predominantly induced to be polarized into M2, a pro-tumorigenic type when recruited with the tumor tissue and thereby favoring the tumorigenesis. Polarization of macrophages into M1 or M2 subtypes plays a vital role in regulating tumor progression, metastasis, and clinical outcome, highlighting the importance of studying the factors driving this process. A substantial number of studies have demonstrated that ncRNAs are involved in the macrophage polarization based on their ability to drive M1 or M2 polarization and in this review we have described their functions and categorized them into oncogenes, tumor suppressors, Juggling tumor suppressors, and Juggling oncogenes.
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http://dx.doi.org/10.1186/s12943-021-01313-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849140PMC
February 2021

Editing and Chemical Modifications on Non-Coding RNAs in Cancer: A New Tale with Clinical Significance.

Int J Mol Sci 2021 Jan 8;22(2). Epub 2021 Jan 8.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Currently, for seemingly every type of cancer, dysregulated levels of non-coding RNAs (ncRNAs) are reported and non-coding transcripts are expected to be the next class of diagnostic and therapeutic tools in oncology. Recently, alterations to the ncRNAs transcriptome have emerged as a novel hallmark of cancer. Historically, ncRNAs were characterized mainly as regulators and little attention was paid to the mechanisms that regulate them. The role of modifications, which can control the function of ncRNAs post-transcriptionally, only recently began to emerge. Typically, these modifications can be divided into reversible (i.e., chemical modifications: mC, hmC, mA, mA, and pseudouridine) and non-reversible (i.e., editing: ADAR dependent, APOBEC dependent and ADAR/APOBEC independent). The first research papers showed that levels of these modifications are altered in cancer and can be part of the tumorigenic process. Hence, the aim of this review paper is to describe the most common regulatory modifications (editing and chemical modifications) of the traditionally considered "non-functional" ncRNAs (i.e., microRNAs, long non-coding RNAs and circular RNAs) in the context of malignant disease. We consider that only by understanding this extra regulatory layer is it possible to translate the knowledge about ncRNAs and their modifications into clinical practice.
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http://dx.doi.org/10.3390/ijms22020581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827606PMC
January 2021

Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma.

Nat Med 2021 01 4;27(1):141-151. Epub 2021 Jan 4.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Intratumoral heterogeneity (ITH) is a fundamental property of cancer; however, the origins of ITH remain poorly understood. We performed single-cell transcriptome profiling of peritoneal carcinomatosis (PC) from 15 patients with gastric adenocarcinoma (GAC), constructed a map of 45,048 PC cells, profiled the transcriptome states of tumor cell populations, incisively explored ITH of malignant PC cells and identified significant correlates with patient survival. The links between tumor cell lineage/state compositions and ITH were illustrated at transcriptomic, genotypic, molecular and phenotypic levels. We uncovered the diversity in tumor cell lineage/state compositions in PC specimens and defined it as a key contributor to ITH. Single-cell analysis of ITH classified PC specimens into two subtypes that were prognostically independent of clinical variables, and a 12-gene prognostic signature was derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis and progression and could be practical for patient stratification.
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http://dx.doi.org/10.1038/s41591-020-1125-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074162PMC
January 2021

A mathematical model for the quantification of a patient's sensitivity to checkpoint inhibitors and long-term tumour burden.

Nat Biomed Eng 2021 04 4;5(4):297-308. Epub 2021 Jan 4.

Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX, USA.

A large proportion of patients with cancer are unresponsive to treatment with immune checkpoint blockade and other immunotherapies. Here, we report a mathematical model of the time course of tumour responses to immune checkpoint inhibitors. The model takes into account intrinsic tumour growth rates, the rates of immune activation and of tumour-immune cell interactions, and the efficacy of immune-mediated tumour killing. For 124 patients, four cancer types and two immunotherapy agents, the model reliably described the immune responses and final tumour burden across all different cancers and drug combinations examined. In validation cohorts from four clinical trials of checkpoint inhibitors (with a total of 177 patients), the model accurately stratified the patients according to reduced or increased long-term tumour burden. We also provide model-derived quantitative measures of treatment sensitivity for specific drug-cancer combinations. The model can be used to predict responses to therapy and to quantify specific drug-cancer sensitivities in individual patients.
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http://dx.doi.org/10.1038/s41551-020-00662-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669771PMC
April 2021

Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk.

Cancer Res 2021 03 17;81(6):1431-1440. Epub 2020 Dec 17.

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

In this review, we highlight recent discoveries regarding mechanisms contributing to nerve-cancer cross-talk and the effects of nerve-cancer cross-talk on tumor progression and dissemination. High intratumoral nerve density correlates with poor prognosis and high recurrence across multiple solid tumor types. Recent research has shown that cancer cells express neurotrophic markers such as nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor and release axon-guidance molecules such as ephrin B1 to promote axonogenesis. Tumor cells recruit new neural progenitors to the tumor milieu and facilitate their maturation into adrenergic infiltrating nerves. Tumors also rewire established nerves to adrenergic phenotypes via exosome-induced neural reprogramming by p53-deficient tumors. In turn, infiltrating sympathetic nerves facilitate cancer progression. Intratumoral adrenergic nerves release noradrenaline to stimulate angiogenesis via VEGF signaling and enhance the rate of tumor growth. Intratumoral parasympathetic nerves may have a dichotomous role in cancer progression and may induce Wnt-β-catenin signals that expand cancer stem cells. Importantly, infiltrating nerves not only influence the tumor cells themselves but also impact other cells of the tumor stroma. This leads to enhanced sympathetic signaling and glucocorticoid production, which influences neutrophil and macrophage differentiation, lymphocyte phenotype, and potentially lymphocyte function. Although much remains unexplored within this field, fundamental discoveries underscore the importance of nerve-cancer cross-talk to tumor progression and may provide the foundation for developing effective targets for the inhibition of tumor-induced neurogenesis and tumor progression.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969424PMC
March 2021

Interrupting Neuron-Tumor Interactions to Overcome Treatment Resistance.

Cancers (Basel) 2020 Dec 12;12(12). Epub 2020 Dec 12.

Department of Head and Neck Surgery, Division of Surgery, MD Anderson Cancer Center, Houston, TX 77030, USA.

Neurons in the tumor microenvironment release neurotransmitters, neuroligins, chemokines, soluble growth factors, and membrane-bound growth factors that solid tumors leverage to drive their own survival and spread. Tumors express nerve-specific growth factors and microRNAs that support local neurons and guide neuronal growth into tumors. The development of feed-forward relationships between tumors and neurons allows tumors to use the perineural space as a sanctuary from therapy. Tumor denervation slows tumor growth in animal models, demonstrating the innervation dependence of growing tumors. Further in vitro and in vivo experiments have identified many of the secreted signaling molecules (e.g., acetylcholine, nerve growth factor) that are passed between neurons and cancer cells, as well as the major signaling pathways (e.g., MAPK/EGFR) involved in these trophic interactions. The molecules involved in these signaling pathways serve as potential biomarkers of disease. Additionally, new treatment strategies focus on using small molecules, receptor agonists, nerve-specific toxins, and surgical interventions to target tumors, neurons, and immune cells of the tumor microenvironment, thereby severing the interactions between tumors and surrounding neurons. This article discusses the mechanisms underlying the trophic relationships formed between neurons and tumors and explores the emerging therapies stemming from this work.
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http://dx.doi.org/10.3390/cancers12123741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762969PMC
December 2020

Pyknon-Containing Transcripts Are Downregulated in Colorectal Cancer Tumors, and Loss of Is Associated With Worse Patient Outcome.

Front Genet 2020 12;11:581454. Epub 2020 Nov 12.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Pyknons are specific human/primate-specific DNA motifs at least 16 nucleotides long that are repeated in blocks in intergenic and intronic regions of the genome and can be located in a new class of non-coding RNAs of variable length. Recent studies reported that pyknon deregulation could be involved in the carcinogenesis process, including colorectal cancer. We evaluated the expression profile of a set of 12 pyknons in a set of molecularly characterized colorectal cancer (CRC) patients. The pyknons (, , , , , , , , , , , and ) expression was determined by qRT-PCR. A pilot analysis of 20 cases was performed, and consistent results were obtained for , , , , and . Further, the expression of the selected pyknons was evaluated in 73 CRC cases. Moreover, in 52 patients, we compared the expression profile in both tumor and normal tissues. All five pyknons analyzed showed significantly lower expression levels in the tumor compared to normal tissue. It was observed an association between expression of with mutations ( = 0.029), to histologic grade ( = 0.035), and to clinical staging ( = 0.016). Moreover, levels of were significantly associated with the patient's poor overall survival ( = 0.04). We reported the significant downregulation of pyknons motifs in tumor tissue compared with the normal counterpart, and the association of lower expression with worse patient outcome. Further studies are needed to extend and validate these findings and determine the clinical-pathological impact.
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http://dx.doi.org/10.3389/fgene.2020.581454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693444PMC
November 2020

Inhibition of G Protein-Coupled Receptor Kinase 2 Promotes Unbiased Downregulation of IGF1 Receptor and Restrains Malignant Cell Growth.

Cancer Res 2021 01 6;81(2):501-514. Epub 2020 Nov 6.

Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

The ability of a receptor to preferentially activate only a subset of available downstream signal cascades is termed biased signaling. Although comprehensively recognized for the G protein-coupled receptors (GPCR), this process is scarcely explored downstream of receptor tyrosine kinases (RTK), including the cancer-relevant insulin-like growth factor-1 receptor (IGF1R). Successful IGF1R targeting requires receptor downregulation, yet therapy-mediated removal from the cell surface activates cancer-protective β-arrestin-biased signaling (β-arr-BS). As these overlapping processes are initiated by the β-arr/IGF1R interaction and controlled by GPCR-kinases (GRK), we explored GRKs as potential anticancer therapeutic targets to disconnect IGF1R downregulation and β-arr-BS. Transgenic modulation demonstrated that GRK2 inhibition or GRK6 overexpression enhanced degradation of IGF1R, but both scenarios sustained IGF1-induced β-arr-BS. Pharmacologic inhibition of GRK2 by the clinically approved antidepressant, serotonin reuptake inhibitor paroxetine (PX), recapitulated the effects of GRK2 silencing with dose- and time-dependent IGF1R downregulation without associated β-arr-BS. , PX treatment caused substantial downregulation of IGF1R, suppressing the growth of Ewing's sarcoma xenografts. Functional studies reveal that PX exploits the antagonism between β-arrestin isoforms; in low ligand conditions, PX favored β-arrestin1/Mdm2-mediated ubiquitination/degradation of IGF1R, a scenario usually exclusive to ligand abundancy, making PX more effective than antibody-mediated IGF1R downregulation. This study provides the rationale, molecular mechanism, and validation of a clinically feasible concept for "system bias" targeting of the IGF1R to uncouple downregulation from signaling. Demonstrating system bias as an effective anticancer approach, our study reveals a novel strategy for the rational design or repurposing of therapeutics to selectively cross-target the IGF1R or other RTK. SIGNIFICANCE: This work provides insight into the molecular and biological roles of biased signaling downstream RTK and provides a novel "system bias" strategy to increase the efficacy of anti-IGF1R-targeted therapy in cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1662DOI Listing
January 2021

A Holistic Perspective: Exosomes Shuttle between Nerves and Immune Cells in the Tumor Microenvironment.

J Clin Med 2020 Oct 31;9(11). Epub 2020 Oct 31.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

One of the limitations of cancer research has been the restricted focus on tumor cells and the omission of other non-malignant cells that are constitutive elements of this systemic disease. Current research is focused on the bidirectional communication between tumor cells and other components of the tumor microenvironment (TME), such as immune and endothelial cells, and nerves. A major success of this bidirectional approach has been the development of immunotherapy. Recently, a more complex landscape involving a multi-lateral communication between the non-malignant components of the TME started to emerge. A prime example is the interplay between immune and endothelial cells, which led to the approval of anti-vascular endothelial growth factor-therapy combined with immune checkpoint inhibitors and classical chemotherapy in non-small cell lung cancer. Hence, a paradigm shift approach is to characterize the crosstalk between different non-malignant components of the TME and understand their role in tumorigenesis. In this perspective, we discuss the interplay between nerves and immune cells within the TME. In particular, we focus on exosomes and microRNAs as a systemic, rapid and dynamic communication channel between tumor cells, nerves and immune cells contributing to cancer progression. Finally, we discuss how combinatorial therapies blocking this tumorigenic cross-talk could lead to improved outcomes for cancer patients.
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http://dx.doi.org/10.3390/jcm9113529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693842PMC
October 2020

Epigenetic silencing of miR-342-3p in B cell lymphoma and its impact on autophagy.

Clin Epigenetics 2020 10 19;12(1):150. Epub 2020 Oct 19.

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong.

Background: miR-342-3p, localized to 14q32, is a tumor suppressor miRNA implicated in carcinogenesis. Given the presence of a promotor-associated CpG island for its host gene, EVL, we hypothesized that intronic miR-342-3p is a tumor suppressor co-regulated with host gene by promoter DNA methylation in B cell lymphoma.

Results: By bisulfite pyrosequencing-verified methylation-specific PCR (MSP), EVL/MIR342 methylation was detected in five (50%) lymphoma cell lines but not normal peripheral blood and tonsils. EVL/MIR342 methylation correlated with repression of both miR-342-3p and EVL in cell lines. In completely methylated SU-DHL-16 cells, 5-AzadC treatment resulted in promoter demethylation and re-expression of miR-342-3p and EVL. In 132 primary lymphoma samples, EVL/MIR342 was preferentially methylated in B cell lymphomas (N = 68; 68.7%) than T cell lymphoma (N = 8; 24.2%) by MSP (P < 0.0001). Moreover, EVL/MIR342 methylation was associated with lower miR-342-3p expression in 79 primary NHL (P = 0.0443). In SU-DHL-16 cells, the tumor suppressor function of miR-342-3p was demonstrated by the inhibition of cellular proliferation and increase of cell death upon over-expression of miR-342-3p. Mechanistically, overexpression of miR-342-3p resulted in a decrease of LC3-II, a biomarker of autophagy, which was pro-survival for SU-DHL-16. Pre-treatment with 3-methyladenine, an autophagy inhibitor, abrogated tumor suppression associated with miR-342-3p overexpression. By luciferase assay, MAP1LC3B, a precursor of LC3-II, was confirmed as a direct target of miR-342-3p. Finally, in SU-DHL-16 cells, overexpression of miR-342-3p downregulated the known target DNMT1, with promoter demethylation and re-expression of tumor suppressor E-cadherin.

Conclusions: Intronic miR-342-3p is co-regulated with its host gene EVL by tumor-specific promoter DNA methylation in B cell lymphoma. The tumor suppressor function of miR-342-3p was mediated via inhibition of pro-survival autophagy by targeting MAP1LC3B and downregulation of DNMT1 with demethylation and re-expression of tumor suppressor genes.
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http://dx.doi.org/10.1186/s13148-020-00926-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574348PMC
October 2020
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