Abstract

   Background: Digestive system cancers (DSCs) have been recognized to be
   linked with high morbidity and mortality. Recent studies have reported
   that microRNA-10b (miR-10b) is abnormally expressed in DSCs and
   associated with prognosis. However, the inconclusive results and
   unknown underlying mechanisms promoted us to perform this study.

   Methods: We systematic searched several databases for eligible studies
   and conducted quantitative analysis for evidence regarding the
   associations between miR-10b and survival outcome of DSCs. We also
   performed a series of bioinformatics analyses to uncover the potential
   mechanisms.

   Results: A total of 32 eligible studies with 3392 patients were
   included. Increased miR-10b expression was linked with unfavorable
   overall survival (OS) in DSCs (HR=1.72; 95% CI: 1.30-2.27; P <0.001).
   When stratified by tumor type, the impact of miR-10b overexpression on
   poor prognosis was observed in colorectal cancer, gastric cancer,
   hepatocellular carcinoma, and esophageal carcinoma, but not in
   pancreatic cancer. Subsequently, we predicted the targets of miR-10b
   and conducted functional enrichment analyses. The results disclosed
   that miR-10b targets were predominantly enriched in some vital
   biological terms and pivotal signaling pathways associated with tumor
   progression including cell cycle, FoxO, proteoglycans, central carbon
   metabolism, p53, Notch, HIF-1, focal adhesion, AMPK, and pancreatic
   cancer. Moreover, a protein-protein interaction (PPI) network was also
   constructed to identify the top ten hub genes and significant modules
   and demonstrated the underlying interactions among them.

   Conclusion: Our results indicated that miR-10b could act as a
   significant biomarker in the prognosis DSCs. However, more research
   should be performed to test these findings.

   Keywords: digestive system cancers, microRNA-10b, prognosis prediction,
   biomarker

Introduction

   Digestive system cancers (DSCs) have become a major public health
   threat, including esophageal squamous cell carcinoma, gastric cancer,
   colorectal cancer, hepatocellular carcinoma, gallbladder cancer and
   pancreatic cancer [41]^1. Despite significant advancements in the
   diagnosis and therapy strategies for DSCs in recent decades, these
   types of diseases remain as leading causes of morbidity and mortality
   of patients across the world [42]^2. In recent years, considerable
   efforts were made to identify prognostic factors for improving risk
   stratification and personalized treatment in DSCs. Nevertheless, as the
   complexity and heterogeneity of cancers, DSCs patients at same stages
   of disease could response to the same treatment differently and lead to
   different clinical outcomes [43]^3. Thus, it is necessary to explore
   novel reliable prognostic biomarkers with high sensitivity and
   specificity that provide effective therapeutic strategies to enhance
   life quality and survival outcomes of patients with DSCs.

   MicroRNAs, about 22 nucleotides, are a member of highly conserved and
   single-stranded non-coding RNAs, which function to be mRNA level
   regulators by regulating messenger RNA translation and degradation
   [44]^4. In recent years, deregulated microRNAs have been identified in
   multiple types of human diseases and cancers [45]^5. Moreover, a series
   of studies have already demonstrated that microRNAs also have a
   significant effect on cancer progression and may be used as promising
   biomarkers for cancer diagnosis, prognosis and therapy effects [46]^6.
   Thus, more and more researches concentrate on the microRNAs as the
   promising biomarkers of DSCs [47]^7^,[48]^8.

   Among these well-studied microRNAs, microRNA-10b (miR-10b) may be one
   of the most important members. There are several studies indicating
   that miR-10b high expression is highly related to clinical outcome of
   patients with various types of malignant tumors, especially in breast
   cancer [49]^9^,[50]^10. Recently, miR-10b has been identified as a
   reliable prognostic indicator in DSCs, with a promising role in
   predicting the survival outcomes for these patients [51]^11. Although
   accumulating evidence suggests that miR-10b is aberrantly expressed in
   DSCs, there has been no clear consensus about its role regarding the
   prognostic value in such diseases. To date, it remains unclear why
   miR-10b may be associated with the survival outcome of patients with
   DSCs.

   Therefore, we performed this study to evaluate the prognostic
   significance of miR-10b expression in DSCs by analyzing all the
   available data coming from a comprehensive search. Furthermore, based
   on above results, we applied several bioinformatics analysis methods
   for an integrated characterization of miR-10b regarding the potential
   mechanism associated with tumor progression.

Material and methods

Data sources and searches

   To enroll all associated articles assessing the prognostic value of
   miR-10b overexpression in digestive system cancer, we searched PubMed
   Central, Web of Science, and EMBASE (up to December 12, 2020) with the
   following search terms: (microRNA-10b OR miR-10b OR miRNA-10b) and
   (esophageal OR gastric OR stomach OR hepatocellular OR pancreatic OR
   rectal OR rectum OR colon OR colorectal OR gastrointestinal OR
   digestive) and (cancer OR carcinoma OR tumor OR neoplasm OR
   malignancy). All related studies from the lists of references of