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Exosomal microRNAs as potential circulating biomarkers in gastrointestinal tract cancers: a systematic… Gheytanchi, Elmira; Madjd, Zahra; Janani, Leila; Rasti, Arezoo; Ghods, Roya; Atyabi, Fatemeh; Asadi-Lari, Mohammad H; Babashah, Sadegh Nov 17, 2017

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PROTOCOL Open AccessExosomal microRNAs as potentialcirculating biomarkers in gastrointestinaltract cancers: a systematic review protocolElmira Gheytanchi1, Zahra Madjd2*, Leila Janani3*, Arezoo Rasti1, Roya Ghods4, Fatemeh Atyabi5,Mohammad Hossein Asadi-Lari6 and Sadegh Babashah7AbstractBackground: Metastasis is the most frequent type of recurrence in gastrointestinal (GI) cancers, and there isan emerging potential for new diagnostic and therapeutic approaches, especially in the cases of metastatic GIcarcinomas. The expression profiles of circulating exosomal microRNAs are of particular interest as novel non-invasivediagnostic and prognostic biomarkers for improved detection of GI cancers in body fluids, especially in the serum ofpatients with recurrent cancers. The aim of this study is to systematically review primary studies and identify the miRNAprofiles of serum exosomes of GI cancers.Methods and design: This systematic review will be reported in line with the Preferred Reporting Items for SystematicReviews and Meta-analyses (PRISMA) guidance. Relevant studies will be identified through a comprehensive search ofthe following main electronic databases: PubMed, Web of Science, Embase, Scopus, and Google Scholar, withno language restrictions (up to July 2017). Full copies of articles will be identified by a defined search strategy and willbe considered for inclusion against pre-defined criteria. The quality assessment of the included studies will be performedby the Newcastle-Ottawa Scale (NOS). Data will be analyzed using Stata software V.12. Publication bias will be assessed byfunnel plots, Beggs’ and Eggers’ tests. The levels of evidence for primary outcomes will be evaluated usingthe GRADE criteria.Discussion: The analysis of circulating exosomal miRNA profiles provides attractive screening and non-invasivediagnostic tools for the majority of solid tumors including GI cancers. There is limited information regardingthe relationship between serum exosomal miRNA profiles and the pathological condition of patients withdifferent GI cancers. Since there is no specific biomarker for GI cancers, we aim to suggest a number ofcirculating exosomal miRNA candidates as potential multifaceted GI cancer biomarkers for clinical utility.Systematic review registration: PROSPERO CRD42017057129Keywords: Circulating, Exosomal microRNAs, Gastrointestinal tract, CancerBackgroundGastrointestinal tract (GI) cancers represent a majorchallenge to healthcare systems given that they consti-tute 25% of cancer-related mortalities [1]. The incidencerate of GI cancers varies between developed anddeveloping countries [2]. Among the 15 most frequentmalignancies worldwide, one out of four new cancercases and one out of three annual cancer-related deathsare attributed to GI cancers [3].miRNAs are small non-coding RNA molecules con-sisting of approximately 22 nucleotides that control geneexpression through targeting specific mRNAs bearingpartially complementary target sequences for degrad-ation and/or translational repression. miRNAs have beenshown to be involved in regulating several cellular pro-cesses including cell differentiation, proliferation, and* Correspondence: Zahra.madjd@yahoo.com; Leila_janani@yahoo.com2Oncopathology Research Center, Department of Molecular Medicine,Faculty of Advanced Technologies in Medicine, Iran University of MedicalSciences, Tehran, Iran3Department of Biostatistics, School of Public Health, Iran University ofMedical Sciences, Tehran, IranFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Gheytanchi et al. Systematic Reviews  (2017) 6:228 DOI 10.1186/s13643-017-0624-2apoptosis in both normal and pathological conditions [4,5]. miRNAs can act as either oncogenes or tumor sup-pressor genes in the networks specifically altered duringcancer development and progression [4, 6, 7]. They arepresent as mobile genetic components for cell to cellcommunication or through the systemic circulation sys-tem within the body [4, 8].Exosomes are nano-sized membrane vesicles, rangingfrom 30 to 100 nm in size, that are secreted by several celltypes, including cancer cells, by exocytosis and can be iso-lated from different body fluids and malignant ascites [1,4, 9]. Exosome content is composed of unique miRNAs,mRNA, DNA, lipids, and proteins that indicate the geneticinformation of their parental cells [10]. Exosomes play animportant role in transferring bioactive oncogenic cargoto non-transformed recipient cells which cause tumor in-vasion, drug resistance, metastasis, and modulation ofcancer metabolism [1, 11]. Findings have shown that thediscovery of specific exosomal content and markers mayrepresent a novel diagnostic tool [12, 13]. Since the major-ity of serum miRNAs are encapsulated in exosomes inorder to be more stable, the exosomal miRNAs could beapplied as promising non-invasive biomarkers and poten-tial targetable factors in cancer diagnosis and treatment[9, 14, 15]. Recent studies have focused on “tumor-spe-cific” or “tumor-enriched” miRNAs which are specificallypackaged into exosomes [16–19].Exosomal miRNA profiling of serum from different can-cer patients versus healthy controls has revealed signifi-cant differences in relation to cancer development andmetastasis, indicating a possible use of these miRNAs asprognostic biomarkers [20].The role of specific exosomalmiRNAs as biomarkers in cancer diagnosis, prognosis,and screening have been studied in several types of can-cers, including GI cancers [15–17, 21–32].Some of the serum exosomal miRNAs can be used asbiomarkers to predict the recurrence of GI carcinomassuch as hepatocellular cancer and esophageal squamouscell carcinoma [33, 34]. The diagnostic and prognosticroles of exosomal miRNA profiles of colorectal cancer(CRC), as the most common malignancy of the GI system,have been evaluated in several studies [15, 31, 35–40].Previous studies had been developed to investigate thepreclinical and clinical characteristics of GI cancers andhave led to improved overall and progression-free sur-vival rates. However, there is an emerging potential forscreening, diagnosis, or surveillance of cancer and thedesigning of new therapeutic approaches, especially inthe cases of metastatic GI carcinomas. The identificationand validation of biomarkers that can be measured rou-tinely in easily accessible samples, including plasma, andthat are able to diagnose cancer and predict treatmentefficacy and the risk of progression or relapse is a majorchallenge in cancer research. To date, many researchershave published their data on the clinical relevance ofmicoRNAs and exosomal miRNA expression and circu-lating exosomal miRNAs in different clinical and non-clinical samples including tissue, stool, serum, and celllines of GI cancers [15, 31, 35, 40–44].Recently, a published review showed that the exosomalmiRNAs could be detected and isolated from body fluidssuch as saliva. This review primarily provided an overviewon exosomal miRNAs as diagnostic markers of GI cancerswith a focus on the origin and trafficking of exosomes be-tween cells and techniques to isolate exosomal miRNAs,micoRNAs, and exosomal miRNAs expression [44]. How-ever, there is currently no systematic review on circulatingexosomal miRNAs as promising non-invasive biomarkersfor GI cancers. In the current systematic review, we focuson studies that have evaluated circulating exosomal miR-NAs as non-invasive biomarkers in serum of patients withprimary GI tumors. We also aim to carry out a systematicreview of published exosomal miRNAs, profiling studiesthat were performed by microarray and real-time PCRmethods and then compare the exosomal miRNA expres-sion profiles between primary and metastatic tumors inthe serum or plasma of GI cancer patients. Additionally,we intend to identify the most consistently downregulatedand upregulated circulating exosomal microRNAs in GIcancers and introduce some of them as diagnostic andprognostic biomarkers for non-invasive clinical applica-tions. Although identification of exosomal miRNAs inother clinical specimen may be significant, in practice, it isdifficult to apply invasive methods on patients. On theother hand, it would be challenging to apply findingsabout exosomal miRNAs expression in non-clinical sam-ples into clinical contexts. Therefore, this systematic re-view aims to evaluate the circulating exosomal miRNAs aspromising non-invasive biomarkers of GI cancers, for thefirst time.Methods/DesignAim of the studyThe primary objective of this review is to provide a sys-tematic review of primary studies to estimate the fre-quency of exosome-encapsulated miRNAs in thecirculating blood of patients with GI cancers. The sec-ondary objectives are to identify the expression pattern(up- and downregulation) of exosomal miRNAs in pa-tients with different gastrointestinal tract cancers and toidentify the specific circulating exosomal miRNAs in-volved in the diagnosis and prognosis of GI cancers.This review will complement the findings of an existingreview published in 2016 [44].Review questionsThis review of studies should address the following points:Gheytanchi et al. Systematic Reviews  (2017) 6:228 Page 2 of 61. To establish the frequency of circulating exosomalmiRNAs in GI cancers.2. To establish the up- and downregulated circulatingexosomal miRNAs in GI cancers.3. To identify the specific circulating exosomal miRNAsinvolved in the diagnosis and prognosis of GI cancers.Study designThis review protocol has been published in the PROS-PERO International prospective register of systematic re-views (http://www.crd.york.ac.uk/PROSPERO), with theregistration number CRD 42017057129. In addition, thecompleted review will be reported in line with the Pre-ferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance [45] (Additional file 1).Criteria for considering studies for the reviewInclusion criteriaObservational studies (cross-sectional, case-control, andcohort studies) investigating circulating exosomal miR-NAs in diagnosis and prognosis of GI malignancies, in-cluding upper and lower GI, and hepatopancreato-biliarywill be included.ParticipantsThe participants are patients with GI cancers.Types of studies to be excludedStudies assessing in vitro and in vivo models, reviews,letters, editorials, case reports, and case series studieswill be excluded.Search methods for identification of studiesElectronic searchesThe search strategy for identification of relevant studieswill comprise the following main electronic databases:PubMed, Web of Science, Embase, and Scopus, as wellas Google Scholar search engines with no language re-strictions (up to July 2017). An example of the PubMedsearch strategy is shown in Table 1. The search syntaxwill be modified in other databases accordingly.Other resourcesReference lists of relevant primary studies, reviews, andkey journals will be searched for additional studies.Screening of the studiesDuplicate studies will be removed. All databases will besearched, and the titles and abstracts will be extracted(EGh). All the retrieved titles and abstracts from theelectronic search will be screened, and the relevant datawill be independently extracted (EGh and AR) accordingto the previously described inclusion criteria. The ex-tracted data will then be cross-checked to rule out anydiscrepancies. Unresolved discrepancies will be referredto a third author to solve (LJ). All the reasons for exclu-sion of ineligible studies will be recorded.Data extraction (selection and coding)Data for each of the included studies will be extracted asfollows:1. Study characteristics (first author’s surname,publication year, publication language, country,study design, setting, locations, criteria forsample selection and sample size, diagnosticcriteria, outcomes measured, patient enrolmentstrategies, exosome isolation and identificationmethods, miRNA profiling, real-time PCR resultsof serum samples)2. Participants’ characteristics (age, gender)3. Frequency estimates of expression of circulatingexosomal miRNAsDiscrepancies between two reviewers will be resolvedby consensus. An independent investigator will be con-sulted through discussion to reach consensus wherethere is uncertainty or disagreement between reviewers.Table 1 Search strategy for PubMedQuary Search syntaxRelated terms/synonyms#1 (mesentery[Mesh] OR stomach[Mesh] OR Pancreas[Mesh] OR rectum[Mesh] OR duodenum[Mesh] OR jejunum[Mesh] OR ileum[Mesh] ORcecum[Mesh] OR colon[Mesh] OR mouth[Mesh] OR esophagus[Mesh] OR Gastrointestinal Tracts[Mesh] OR “Gastrointestinal Tracts”[tiab] OR“GI Tract”[tiab] OR “GI Tracts”[tiab] OR “gastrointestinal tract”[tiab] OR “Gastrointestinal Cancer”[tiab] OR “Digestive Tract”[tiab] OR “DigestiveTracts”[tiab] OR “Lower GI Tract”[tiab] OR GI[tiab] OR oral[tiab] OR mouth[tiab] OR esophagus[tiab] OR gullet[tiab] OR gastric[tiab] ORduodenum[tiab] OR jejunum[tiab] OR ileum[tiab] OR cecum[tiab] OR colon[tiab] OR colorectal[tiab] OR sigmoid[tiab] OR rectum[tiab] ORanus[tiab] OR mesentery[tiab] OR hepatic[tiab] OR liver[tiab] OR hepatocellular[tiab] OR stomach[tiab] OR Pancrea*[tiab])#2 (Neoplasms [Mesh] OR Cancer*[tiab] OR Neoplasm*[tiab] OR Carcinoma[tiab] OR Tumo*[tiab])#3 (extracellular vesicles[Mesh] OR exosomes[Mesh] OR exosome*[tiab] OR “extracellular vesicle”[tiab] OR “extracellular vesicles”[tiab] ORmicrovesicle[tiab] OR “Shedding Microvesicles”[tiab])#4 #1 AND #2 AND #3The asterisk (*) is used to signify truncationGheytanchi et al. Systematic Reviews  (2017) 6:228 Page 3 of 6Corresponding authors will be contacted if further in-formation is needed. If no response is received aftersending a reminder, studies will be excluded.Risk of bias (quality) assessmentQuality assessment of observational studies is challengingdue to their methodological complexities and the subject-ive nature of quality evaluations [46]. The Cochrane Col-laboration endorsed the use of the Newcastle-OttawaScale (NOS) to assess the quality of observational studiesin its 2011 handbook [47, 48]. The final risk of bias of in-cluded studies will be performed by the above mentionedtool. Two reviewers will independently assess the meth-odological quality of primary studies by the NOS. Thistool is used for assessing the quality of non-randomizedstudies included in a systematic review and/or meta-analyses. The method was developed as a collaborationbetween the University of Newcastle, Australia, and theUniversity of Ottawa, Canada, using a Delphi process todefine variables for data extraction. Using the tool, eachstudy is judged on eight items, categorized into threegroups: the selection of the study groups, the comparabil-ity of the groups, and the ascertainment of either the ex-posure or outcome of interest for case-control or cohortstudies respectively [49]. Separate tools were developedfor cohort and case-control studies. It has also beenadapted for cross-sectional studies [50–52]. For more de-tails, see three appendix scales for evaluating the qualityassessment of the above mentioned observational studies(Additional files 2, 3, and 4).Strategy for data synthesisGiven the considerable variability among cancers andthe difficulty in detecting common exosomal miRNAsand characteristics of the studies, the extracted out-comes will be summarized and reported using descrip-tive statistics without conducting any meta-analyses.Two separate tables will be used in all included studies.The first table will provide details on study quality ac-cording to the mentioned tool, and the other one will in-clude study design, participants, and frequency ofexosomal miRNAs in patients with GI cancers. The pub-lication bias will be assessed by funnel plots (i.e., plots ofstudy results against precision) and Beggs’ and Eggers’tests. We will assess the overall quality of the evidencefor each main outcome based on the GRADE (Gradingof Recommendations Assessment, Development andEvaluation) system [53, 54]. GRADE provides explicitcriteria that address study design, risk of bias, impreci-sion, inconsistency, indirectness, and magnitude of theeffect to rate the quality of evidence across studies. Thismethod rates the quality of the evidence from high (veryconfident that the true effect lies close to that of theestimated effect) to very low (very little confidence inthe effect estimate).Sensitivity analysisGiven the diversity of cancer types and different re-ported exosomal miRNAs across the studies, we antici-pate that we cannot perform a meta-analysis; therefore,no sensitivity analysis will be applicable to this study.Analysis of subgroups or subsetsIf the data is determined to be heterogeneous, we willconduct a narrative synthesis of the findings from the in-cluded studies; therefore, a subgroup analysis will not beapplicable to this study.DiscussionEmerging evidence supports the hypothesis that exosomalmicroRNAs can be used as circulating diagnostic bio-markers of several cancers. However, there is currently nocollective view of which circulating exosomal microRNAsare suitable candidates. The distinctive properties of miR-NAs within exosomes can be manipulated to render themsuitable for the development of effective diagnostic andtargetable tools for non-invasive screening and targetingof tumor cells in cancer patients. Reviews showing theserum exosomal microRNAs in different cancers havealready emerged [1, 39, 44], but to date, this will be thefirst systematic review to evaluate the circulating exoso-mal miRNAs in the serum of patients with GI cancers.The findings of this review may be used in clinical settingsand in designing and developing of the novel non-invasivebiomarkers for early diagnosis and pathological conditionof patients with GI cancers.Additional filesAdditional file 1: PRISMA-P (Preferred Reporting Items for SystematicReview and Meta-Analysis Protocols) 2015 checklist [45]. (DOC 85 kb)Additional file 2: Newcastle-Ottawa quality assessment scale for cross-sectional studies. (PDF 189 kb)Additional file 3: Newcastle-Ottawa quality assessment scale for case-control studies. (PDF 17 kb)Additional file 4: Newcastle-Ottawa quality assessment scale for cohortstudies. (PDF 93 kb)AbbreviationsGI: Gastrointestinal; microRNAs: miRNAs, miRs; PRISMA: Preferred ReportingItems for Systematic Reviews and Meta-AnalysesAcknowledgementsNot applicable.FundingNone.Availability of data and materialsAll recorded data from the data extraction process will be available on requestto the extent that they are not included in the systematic review article.Gheytanchi et al. Systematic Reviews  (2017) 6:228 Page 4 of 6Authors’ contributionsZM, LJ, EGh, AR, and RGh contributed to the concept and study design. EGhand AR developed the search strategies. EGh and LJ contributed to theimplementation and analysis of the studies and will also screen potentialstudies and extract data and assess quality, while ZM, RGH, AR, FA, SB, andMhAL will review the work. EGh and AR contributed to the initial draftingand critical revision the manuscript, and all authors gave feedback to thefinal draft of the protocol. EGh approved the manuscript for submission. Allauthors read and approved the final manuscript.Ethics approval and consent to participateAs this systematic review will only be based on published data already in thepublic domain, an ethical approval is not required. The findings of the currentstudy will be disseminated through a publication in a peer-reviewed journaland conference presentations. To the best of our knowledge, there are nosystematic reviews that have specifically looked at the frequency of exosome-encapsulated miRNAs in the circulating blood of patients with GI cancers. Wewill submit the findings of this systematic review for publication and presentationat national and international conferences to update information on the circulatingexosomal miRNAs as candidates of GI cancers. This review will ultimately helpinform and guide future studies in the field.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in publishedmaps and institutional affiliations.Author details1Oncopathology Research Center, Iran University of Medical Sciences, Tehran,Iran. 2Oncopathology Research Center, Department of Molecular Medicine,Faculty of Advanced Technologies in Medicine, Iran University of MedicalSciences, Tehran, Iran. 3Department of Biostatistics, School of Public Health,Iran University of Medical Sciences, Tehran, Iran. 4Department of MolecularMedicine, Faculty of Advanced Technologies in Medicine, OncopathologyResearch Center, Iran University of Medical Sciences, Tehran, Iran.5Department of Pharmaceutics, Nanotechnology Research Center, Faculty ofPharmacy, Tehran University of Medical Sciences, Tehran, Iran. 6Departmentof Cellular and Physiological Sciences, Faculty of Medicine, University ofBritish Columbia (UBC), Vancouver, BC, Canada. 7Department of MolecularGenetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran,Iran.Received: 18 June 2017 Accepted: 8 November 2017References1. 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