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Abstract
BackgroundAccumulating evidence indicates that microRNA-27a (miR-27a) is involved in carcinogenesis and tumor progression. However, the exact function and molecular mechanism of miR-27a in gastric cancer remain unclear.MethodsQuantitative real-time PCR (qRT-PCR) was used to quantify the expression of miR-27a and its target gene. The function of miR-27a in gastric cancer was investigated through in vitro and in vivo assays (MTT assay, colony formation assay, flow cytometry assay, wound healing assay, migration and invasion assay, immunohistochemistry (IHC), immunofluorescence (IF) and Western blot). A luciferase reporter assay was conducted to confirm the target gene of miR-27a.ResultsWe found that miR-27a was commonly overexpressed in gastric cancer and high expression of miR-27a was associated with distant metastasis, lymph node metastasis, advanced T stage and advanced clinical stage. Functional assays demonstrated that overexpression of miR-27a in AGS cells accelerated cell proliferation, migration and invasion and suppressed apoptosis. Meanwhile, opposite results were observed in SGC-7901 cells when miR-27a was suppressed. Consistently, down-regulation of miR-27a inhibited the growth and metastasis of engrafted tumors in vivo. Furthermore, we found PH domain and leucine-rich repeat protein phosphatase 2 (PHLPP2) to be a new target of miR-27a, and downregulation of PHLPP2 could rescue the effect of anti-miR-27a in gastric cancer cells. In addition, miR-27a-mediated suppression of PHLPP2 led to stimulation of the AKT/GSK3β pathway.ConclusionsOur data suggest that miR-27a functions as a crucial oncogenic miRNA in gastric cancer. It can promote proliferation and metastasis of tumor cells by suppressing PHLPP2 and activating the AKT/GSK3β pathway. Therefore, miR-27a is a potential novel therapeutic target in gastric cancer treatment.
Highlights
Accumulating evidence indicates that microRNA-27a is involved in carcinogenesis and tumor progression
MiR-27a is upregulated in gastric cancer tissues and cell lines Sequencing data downloaded from the The Cancer Genome Atlas (TCGA) database showed altered miRNAs expression in gastric cancer tissues compared to the corresponding normal tissues, miR-27a was marked with green underline (Fig. 1a)
We found that a higher miR-27a level was associated with advanced clinical stage (Fig. 1c), advanced T stage (Fig. 1d), advanced N stage (Fig. 1e) and advanced M stage (Fig. 1f)
Summary
Accumulating evidence indicates that microRNA-27a (miR-27a) is involved in carcinogenesis and tumor progression. The exact function and molecular mechanism of miR-27a in gastric cancer remain unclear. Compelling evidence has suggested that miRNAs are novel modulators of tumor progression and new targets for tumor therapy in GC [15, 16]. The role of miR-27a in tumorigenesis differs in various cells and tissues. It is regarded as an oncogene in several types of tumors, such as osteosarcoma [17], laryngeal carcinoma [18] and breast cancer [19]. MiR-27a is suggested to be a cancer suppressive miRNA in esophageal squamous cell carcinoma [20] and colorectal cancer [21]. Its functions and molecular mechanisms in GC need to be further investigated
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