Abstract
MiRNA (miR)-206 plays a tumor suppressor role in various cancer types. Here, we investigated whether miR-206 is involved in prostaglandin E2 (PGE2)-induced epithelial–mesenchymal transition (EMT) in colorectal cancer (CRC) cells through the targetting of transmembrane 4 L six family member 1 (TM4SF1).The effect of PGE2 on growth and apoptosis of CRC cells was evaluated using the MTT assay and flow cytometry analysis, respectively. TM4SF1 and miR-206 expression levels were determined with quantitative polymerase chain reaction (qRT-PCR) in CRC tissues and cell lines. The concentration of PGE2 in the serum of CRC patients and healthy controls was measured with an ELISA kit. A miR-206 or TM4SF1 construct was transfected into cells with PGE2. Transwell migration and invasion assays were used to examine cell migration and invasion properties. Additionally, a luciferase assay was performed to determine whether TM4SF1 was directly targetted by miR-206.We found that miR-206 was down-regulated and TM4SF1 was up-regulated in human CRC tissues and cell lines. Moreover, miR-206 was negatively correlated with TM4SF1 expression. Bioinformatics analysis and a luciferase reporter assay revealed that miR-206 directly targetted the 3′-untranslated region (UTR) of TM4SF1, and TM4SF1 expression was reduced by miR-206 overexpression at both the mRNA and protein levels. Additionally, PGE2 significantly suppressed the expression of miR-206 and increased the expression of TM4SF1 in CRC cells. PGE2 induction led to enhanced CRC cell proliferation, migration, and invasion. Moreover, the overexpression of miR-206 decreased CRC cell proliferation, migration, and invasion compared with control group in PGE2-induced cells, and these effects could be recovered by the overexpression of TM4SF1. Overexpression of miR-206 also suppressed the expression of β-catenin, VEGF, MMP-9, Snail, and Vimentin and enhanced E-cadherin expression in PGE2-induced cells. These results could be reversed by the overexpression of TM4SF1. At last, up-regulation of miR-206 suppressed expression of p-AKT and p-ERK by targetting TM4SF1 in PGE2-induced cells.Our results provide further evidence that miR-206 has a protective effect on PGE2-induced colon carcinogenesis.
Highlights
Colorectal cancer (CRC) is one of the most common malignant tumors and one of the major causes of cancer-related deaths, with most CRC patients dying due to metastasis [1,2,3]
We initially examined the expression of cyclooxygenase 2 (COX-2) mRNA in CRC specimens and the adjacent normal tissues by quantitative polymerase chain reaction (qRT-PCR)
We found that the expression levels of EP2 and EP4 receptors mRNAs were significantly increased in prostaglandin E2 (PGE2)-induced cells compared with the untreated groups, which resulted in the c 2018 The Author(s)
Summary
Colorectal cancer (CRC) is one of the most common malignant tumors and one of the major causes of cancer-related deaths, with most CRC patients dying due to metastasis [1,2,3]. Overexpression of COX-2 in tumor-associated macrophages promotes pro-metastatic effects of breast cancer cells by regulating MMP-9 and EMT and Akt pathway, and the COX-2/PGE2 axis mediates cell invasion in EGF-induced ovarian cancer [7,8]. Many molecular pathways have been identified as downstream of PGE2 to promote cell migration and invasion, including the PI3K/Akt, β-catenin/TCF-4, and JAK2/STAT3 signaling pathways [11,12,13,14]. These results have shown that PGE2 may act as an important factor in the development, migration, and invasion of CRC cells. Its essential role in regulating the migration and invasion of CRC cells remains unclear
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