Abstract

Background

   Emerging evidence has revealed miR-29 family as promising biomarkers
   for colorectal cancer (CRC), but their biomarker potential and
   molecular mechanisms remain poorly understood.

Methods

   We performed a comprehensive meta-analysis to evaluate the biomarker
   performance of individual miR-29 and the related miRNA combination
   biomarkers. Meanwhile, we conducted an integrative bioinformatics
   analysis to unfold the underlying biological function of miR-29 and
   their relationship with CRC.

Results

   Using miR-29 expression to diagnose CRC produced 0.82 area under the
   curve, 70% sensitivity and 81% specificity while the combination
   biomarkers based on miR-29 enhanced the diagnostic power with an AUC of
   0.86, a sensitivity of 78% and a specificity of 91%. For the prognosis
   evaluation, patients with higher expression of miR-29 had better
   survival outcome (pooled HR 0.78; 95% CI 0.56–1.07). In addition,
   miR-29 has also been identified as potential biomarker for predicting
   recurrence and metastasis in CRC. Then the genes regulated by the
   miR-29 family were retrieved and found closely associated with the
   molecular pathogenesis of CRC according to the gene ontology and
   pathway analysis. Furthermore, hub nodes and significant modules were
   identified from the protein–protein interaction network constructed
   with miR-29 family targets, which were also confirmed highly involved
   in the establishment and development of CRC.

Conclusions

   Current evidences suggest miR-29 family may become promising biomarkers
   for risk, recurrence, metastasis and survival outcome of CRC. Meanwhile
   our data highlight the potential clinical use of miRNA combination
   biomarkers. Nevertheless, further prospective studies are warranted
   before the application of the useful biomarkers in the clinical.

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

Background

   Colorectal cancer (CRC) is the third and second most commonly diagnosed
   cancers and the fourth and second most common causes of cancer related
   death respectively in men and women worldwide [[37]1]. The clinical
   outcome strongly depends on tumor stage at presentation and the early
   diagnosis of CRC is associated with improved survival rates [[38]2].
   Nowadays, several early detection procedures of CRC have been
   established and are increasingly applied, including fecal occult-blood
   testing (FOBT), colonoscopy, and stool DNA test [[39]3]. However, none
   of these methods has been developed as a optimal or universally
   accepted strategy due to their low adherence rates, high cost or low
   sensitivity [[40]4]. Therefore, the development of novel non-invasive,
   sensitive, and specific diagnostic and prognostic biomarkers is highly
   demanded.

   MicroRNAs (miRNAs) are a class of highly conserved single-stranded RNAs
   that epigenetically regulate protein expression at the
   post-transcriptional level [[41]5]. Accumulating evidence has indicated
   that miRNAs are aberrantly expressed in various human cancers and
   crucial to tumorigenesis [[42]6]. Acting as potential oncogenes or
   tumor suppressors in cancer initiation and development, miRNAs play
   vital roles in fundamental cellular processes including cell
   proliferation, apoptosis, differentiation, and migration [[43]7].
   Meanwhile, a number of studies in recent years have convincingly
   demonstrated that the expressions of various miRNAs are frequently
   dysregulated in CRC [[44]8]. It is worth pointing out that miRNAs
   exhibit an outstanding stability in serum, plasma, urine, and other
   body fluids [[45]9]. Considering the perfect biomarker features and
   critical involvement in the regulation of developmental, physiological
   and oncogenic processes, miRNAs show great promises to be convenient
   and informative for CRC diagnosis, prognosis and therapeutic efficacy.

   Among all the reported miRNAs, microRNA-29 (miR-29) family, which
   consists of miR-29a, miR-29b, and miR-29c, has been considered to be
   related to aggressiveness and prognosis of malignant neoplasms and
   might function as promising biomarker for predicting the initiation,
   progression and pathogenesis of cancer [[46]10]. Previous researches
   have demonstrated the availability of the members of miR-29 family in
   cancer diagnosis and prognosis [[47]11]. Overwhelming evidence has
   indicated that aberrant expressions of the miR-29 family members are
   involved in the establishment and development of CRC [[48]12].
   Nevertheless, the biomarker applicability of miR-29 family of CRC
   remains controversial because of inconsistent results from different
   studies. Moreover, the molecular mechanism of miR-29 family in the
   tumorigenesis and cancer progression is still not very clear due to the
   present insufficient knowledge.

   Herein, we summarized recent findings and discussed the potential value
   of miR-29 family as diagnostic and prognostic biomarkers for CRC.
   Different from traditional biomarker studies that focused on single
   molecule, we also explored the value of combination miRNA biomarkers
   based on miR-29 in CRC. Furthermore, we attempted to unfold the
   underlying biological function of miR-29 and their relationship with
   CRC through an integrative bioinformatics analysis.

Materials and methods

Publication search strategy

   A comprehensive literature search of PubMed, Embase and Web of Science
   was performed, with the following keywords variably combined:
   “microRNA-29”, “miR-29”, “miRNA-29”, “cancer”, “carcinoma”, “tumor”,
   “neoplasm”, “colorectal”, “colon”, “rectal”, “rectum”, and “CRC”. The
   last search was done on 21 September 2018. We initially reviewed all
   articles by scanning the titles and abstracts to identify the relevant
   studies, and full texts were further perused for potentially eligible
   studies according to our including criteria. We also searched the
   references within the relevant review papers in order to identify other