br INTRODUCTION br Pancreatic cancer is a major threat
Pancreatic cancer is a major threat to human health with very few effective therapies and prognoses.1–3 As the fourth primary death cause of all different cancers, the survival rate of pancreatic cancer is incredibly low.4 Despite improvements made to pancreatic cancer therapies, the mortality of the disease has remained more or less the same over the past several decades, largely due to the lack of adequate screening methods and biomarkers for early diagnosis.5 Four decades
ago, bone marrow mesenchymal stem 1448440-52-5 (BMSCs) were found in bone and cartilage comprised of approximately 0.001%–0.01% of the marrow nuclear cells. BMSCs can be defined as a family of non-hematopoietic cells similar to fibroblast and first used as multipotent progenitor cells.6,7 That being said, reports have suggested that BMSCs could promote the development of cancer,8–10 while existing literature has emphasized the potential of BMSCs from a therapeutic perspective for patients suffering from amyotrophic lateral sclerosis due to its safety and effectiveness.11 Remarkably, BMSCs have been shown to be capable of migrating to tumor tissues, while studies have speculated their potential for gene therapy in cases of pancreatic cancer.12
Exosomes are small, membrane-enclosed vesicles (30–150 nm) that can deliver cargo (proteins, lipids, and nucleic acids) from the origi-nating cells to the recipient cells.13 Recently, a type of small vesicle released from marrow mesenchymal stem cell (MSC)-derived exo-somes has been shown to transfer functional RNAs to recipient cells, indicating their promise as an alternative for cell-based therapy.14 Especially, it was reported that exosomes could carry microRNAs (miRNAs), which are involved in cancer cell proliferation, differenti-ation, and apoptosis.15,16 Moreover, as tumor suppressors or onco-genes, miRNAs regulate gene expression post-transcriptionally.17
Correspondence: Jun Lu, Key Laboratory for Biotechnology on Medicinal Plants of
Jiangsu Province, School of Life Science, College of Health Sciences, Jiangsu Normal
Correspondence: Yuan-Lin Zheng, Key Laboratory for Biotechnology on Medic-
inal Plants of Jiangsu Province, School of Life Science, College of Health Sciences,
Jiangsu Normal University, No. 101, Shanghai Road, Tongshan District, Xuzhou
E-mail: [email protected]
Correspondence: Gui-Quan Chen, State Key Laboratory of Pharmaceutical
Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model
Animal Research Center, Nanjing University, No. 12, Xuefu Road, Pukou District,
E-mail: [email protected]
Molecular Therapy: Nucleic Acids Vol. 16 June 2019 ª 2019 The Authors. 229 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Molecular Therapy: Nucleic Acids
For instance, miR-126-3p, a subtype miRNA, has been shown to act as a tumor suppressor, while reports have suggested that it may be capable of suppressing the progression of cancer.18,19 Besides, miR-126-3p has been found to exhibit downregulated levels in esophageal squamous cell carcinoma (ESCC), especially in cases with poor prog-nosis.20 Additionally, miR-126-3p has been reported to be capable of inhibiting cellular metastasis, invasion, and dysregulation within the plasm of pancreatic cancer patients.21 Based on the exploration of literature, it was asserted that miR-126-3p could serve as a therapeutic target. Interestingly, miR-126-3p was previously reported to nega-tively regulate a disintegrin and a metalloproteinase-9 (ADAM9).22 ADAM9 is a type I membrane-anchored protein that has been corre-lated with the development of cancers because of its high expression levels in metastatic cancer.23 Growing evidence continues to suggest that the miR-126/ADAM9 axis could suppress the progression of pancreatic cells.24 Hence the hypothesis was asserted that overex-pressed miR-126-3p derived from BMSCs exosomes could suppress the progression of pancreatic cancer via the downregulation of ADAM9. Hence the aim of the current study was to explore the effects of miR-126-3p transferred by BMSC-derived exosomes in pancreatic cancer.
miR-126 Targets ADAM9 in Pancreatic Cancer
Initially, R language was employed to screen for differentially ex-pressed genes from four gene expression chips of pancreatic cancer (GEO: GSE16515, GSE32676, GSE71989, and GSE101448) with jlog2 fold change (FC)j > 1.0 and adj.P.Val < 0.05 set as the screening threshold. The first 400 differentially expressed genes of each chip were compared and plotted in Venn diagram. As illustrated in Fig-ure 1A, ADAM9 was determined to be the exclusive intersection gene. The detailed results of the initial 400 differentially expressed genes of each chip are depicted in Table S1. The expression of the thermal map of the first 60 differentially expressed genes from the GEO: GSE101448 and GSE32676 chips were plotted, respectively (Figures 1B and 1C). The expression of ADAM9 in pancreatic cancer tissues was found to be higher than that of the normal tissues. Simi-larly, our results revealed that ADAM9 was highly expressed in the pancreatic cancer tissues from the GEO: GSE16515 and GSE71989 chips when compared with the normal tissue (Figures 1D and 1E). In order to verify the expression of ADAM9 and analyze the correla-tion between gene expression and survival conditions, the Gene Expression Profiling Interactive Analysis (GEPIA) database was explored to determine and retrieve the expression of ADAM9 in both pancreatic cancer tissues and normal tissues. The expression of ADAM9 in the pancreatic cancer tissues was higher than normal tissues (Figure 1F). Notably, the survival analysis (Figure 1G) revealed that the higher the expression of ADAM9, the lower the total survival rate of patients with pancreatic cancer.