Abstract

   Background: Previous studies demonstrated that microRNA-92a (miR-92a)
   may serve as a novel promising biomarker in colorectal cancer (CRC)
   patients. However, a comprehensive analysis of the contribution of
   miR-92a in CRC is lacking. We aimed to systematically summarize the
   diagnostic and prognostic values of miR-92a in CRC.

   Methods: The diagnostic and prognostic roles of individual miR-92a and
   the combination biomarkers based on miR-92a were evaluated through
   comprehensive meta-analyses. Meanwhile, the function and potential
   mechanisms of miR-92a were assessed by an integrative bioinformatics
   analysis.

   Results: According to the results, we found that miR-92a yielded a
   pooled area under ROC curve (AUC) of 0.82 (sensitivity: 76%,
   specificity: 75%) in discriminating CRC from controls. Notably, the
   combination biomarkers based on miR-92a increased the diagnostic
   performance, yielding an AUC of 0.91, with a sensitivity of 83% and a
   specificity of 87%. For the prognostic meta-analysis, patients with
   higher expression of miR-92a had significant shorter overall survival
   (pooled HR: 2.30; 95% CI: 1.03-5.12). In addition, the regulated genes
   of miR-92a were retrieved and enriched through gene ontology and
   pathway analysis, indicating their correlations with the initiation and
   progression of CRC. Furthermore, protein-protein interaction network
   was set up with miR-92a targets and screened for hub nodes and
   significant modules, which were confirmed strongly involved in the
   occurrence and development of CRC again.

   Conclusions: Current evidences suggest miR-92a is a promising biomarker
   for early detection and prognosis of CRC while miRNA combination
   biomarkers may be considered as the right way for clinical practice.
   However, more prospective studies are required to highlight the
   theoretical strengths.

   Keywords: Colorectal cancer, Biomarker, Meta-analysis, System
   biological analysis

Background

   Colorectal cancer (CRC) is one of the most commonly diagnosed
   malignancies and leading causes of cancer related deaths all over the
   world [35]^1. CRC with an early stage of development is more likely to
   be treated successfully with better prognosis than those locally
   advanced stages [36]^2. Currently, the gold standard method for early
   detection of CRC is mainly based on colonoscopy and biopsy; however,
   the wide application of this method has been limited because of its
   invasive nature and the high cost. Other strategies employed to early
   detect CRC including computed tomography imaging techniques, fecal
   occult-blood testing (FOBT) and some molecular markers such as
   carcinoembryonic antigen (CEA) have not been widely used due to their
   wide detectable range, low sensitivity and specificity [37]^3^, [38]^4.
   As a result, the majority of patients could only be diagnosed
   accurately in locally advanced stages of CRC when the survival outcomes
   are poor. Consequently, an urgent need exists to identify simple and
   more reliable biomarkers for the early diagnosis of CRC. In addition,
   new prognostic methods for CRC are also in urgent need to improve
   treatment strategies.

   Promisingly, the discovery of microRNAs has opened new opportunities of
   a non-invasive test for the early detection and survival prediction of
   cancer. MicroRNAs (miRNAs), which are a class of small noncoding RNA
   molecules (18-25 nucleotides), have a great regulatory role over the
   expression of most human protein-coding genes at the
   post-transcriptional level [39]^5. During the past decades,
   accumulating evidences have demonstrated that miRNAs play vital roles
   in the regulation of developmental, physiological and oncogenic
   processes of various cancers including cell growth, differentiation,
   apoptosis, invasion, and metastasis [40]^6. A number of studies have
   shown that profiles of miRNA expression differ between tumor-associated
   samples and normal controls. Meanwhile, miRNAs exhibited an outstanding
   stability in body fluids and resistance against boiling, pH changes,
   extended storage time, and repeated freeze-thaw cycles [41]^7. Those
   studies have revealed that miRNAs may be sensitive and informative
   biomarkers for cancer diagnosis, prognosis and therapeutic efficacy
   [42]^8.

   Emerging as one of the most promising miRNA biomarkers, microRNA-92a
   (miR-92a) has been extensively explored by plenty studies in a variety
   of cancers. Previously, there have been an increasing number of studies
   regarding the correlation of miR-92a with colorectal tumorigenesis and
   the modulation of the clinical course of the disease [43]^9. Meanwhile,
   several groups of researches have studied the diagnostic power of
   miR-92a in CRC, suggesting it may be a promising biomarker for
   distinguishing CRC patients from healthy controls [44]^10. In addition,
   recent evidence has indicated that high miR-92a expression promotes CRC
   progression and predicts poor prognosis of CRC patients [45]^11.
   Therefore, miR-92a may be the promising substrate in not only early
   detection of CRC but also predicting patients' outcome. However, the
   clinical applicability of the identified miR-92a as biomarkers of CRC
   is still limited due to the inconsistent results among different
   studies. Moreover, the potential molecular mechanism of miR-92a in the
   initiation and progression of CRC is still not very clear for the
   current insufficient knowledge.

   Therefore, in the present study, we first carried out a comprehensive
   meta-analysis to overcome the limitation of single study and to obtain
   a better understanding of the clinical feasibility of miR-92a as
   excellent biomarker in the diagnosis, recurrence and prognosis of CRC.
   In contrast to traditional biomarker studies with an isolated and
   static mode addicted to single molecule, we also investigated the role
   of combination biomarkers based on miR-92a in CRC. Moreover, we
   performed an integrative bioinformatics analysis to assess the
   biological roles of miR-92a at the systems biology level.

Materials and Methods

Publication search strategy

   All relevant articles were searched via several electronic databases
   including PMC database, Embase, Cochrane Library, and Web of Science
   databases (up to August 03, 2018) by using the following search terms:
   (“microRNA-92” OR “miR-92” OR “miRNA-92”), (“rectal” OR “rectum” OR
   “colon” OR “colorectal” OR “CRC”) and (“cancer” OR “tumor” OR
   “neoplasm” OR “carcinoma”). Meanwhile, the references of included