Abstract
BackgroundTumor metastasis is one of the leading causes of poor prognosis for colorectal cancer (CRC) patients. Loss of Smad4 contributes to aggression process in many human cancers. However, the underlying precise mechanism of aberrant Smad4 expression in CRC development is still little known.ResultsmiR-20a-5p negatively regulated Smad4 by directly targeting its 3′UTR in human colorectal cancer cells. miR-20a-5p not only promoted CRC cells aggression capacity in vitro and liver metastasis in vivo, but also promoted the epithelial-to-mesenchymal transition process by downregulating Smad4 expression. In addition, tissue microarray analysis obtained from 544 CRC patients’ clinical characters showed that miR-20a-5p was upregulated in human CRC tissues, especially in the tissues with metastasis. High level of miR-20a-5p predicted poor prognosis in CRC patients.MethodsFive miRNA target prediction programs were applied to identify potential miRNA(s) that target(s) Smad4 in CRC. Luciferase reporter assay and transfection technique were used to validate the correlation between miR-20a-5p and Smad4 in CRC. Wound healing, transwell and tumorigenesis assays were used to explore the function of miR-20a-5p and Smad4 in CRC progression in vitro and in vivo. The association between miR-20a-5p expression and the prognosis of CRC patients was evaluated by Kaplan–Meier analysis and multivariate cox proportional hazard analyses based on tissue microarray data.ConclusionsmiR-20a-5p, as an onco-miRNA, promoted the invasion and metastasis ability by suppressing Smad4 expression in CRC cells, and high miR-20a-5p predicted poor prognosis for CRC patients, providing a novel and promising therapeutic target in human colorectal cancer.
Highlights
Clinical diagnosis and therapies have achieved much progress with the improvement of surgical and medical treatments, the prognosis of colorectal cancer (CRC) patients is still not optimistic [1]
What’s more, overexpression or knocking-down of strategies.Drosophila mothers against decapentaplegic protein4 (Smad4) could partially reverse the roles of miR20a-5p in epithelial– mesenchyme transition (EMT) process (Figure 5C P < 0.05, Figure 5D). All these results indicated that Smad4 was a direct functional target of miR-20a-5p in aggression process in CRC cells
Previous studies have revealed that loss of Smad4 is seen in 30%–40% CRC patients [15], occurs late in the adenoma-to-carcinoma sequence [16], and contributes to liver metastases, a poor response to chemotherapy followed with poor prognosis [17, 18]
Summary
Clinical diagnosis and therapies have achieved much progress with the improvement of surgical and medical treatments, the prognosis of CRC patients is still not optimistic [1]. Smad mutation brings about the functional switch of TGF –β from tumor suppressor to tumor promoter, driving aggression in many human cancers [3]. MiR-224, as an oncogenic miRNA, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 toward enhanced invasion and growth in non-small-cell lung cancer [7]. Overexpression of miR-301a- 3p inhibits the target gene Smad, enhancing pancreatic ductal adenocarcinoma (PDAC) cells colony, invasion and migration abilities in vitro as well as tumorigenesis in vivo [8]. Tumor metastasis is one of the leading causes of poor prognosis for colorectal cancer (CRC) patients. The underlying precise mechanism of aberrant Smad expression in CRC development is still little known
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