MicroRNA-20a-5p promotes colorectal cancer invasion and metastasis by downregulating Smad4

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.

Breast cancer cell‐derived exosomal miR‐20a‐5p promotes the proliferation and differentiation of osteoclasts by targeting SRCIN1

“…MiR‐20a‐5p levels are dysregulated in various human cancers. Specifically, miRNA‐20a‐5p has been reported to elevate and promote colorectal cancer invasion and metastasis, but remained the same as normal control in atrophic gastritis and gastric cancer . Enhanced miRNA‐20a‐5p was observed in triple‐negative breast tumors than that in luminal A ones, which was confirmed in our study.…”

Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review

“…Two studies demonstrated the upregulation of miR-182 43, 44 associated with advanced TNM stage and others 22 studies pointed 23 different upregulated miRs associated with advanced TNM stage. In detail, miR-1296 84 , miR-888 64 , miR-21 29 , miR-130a 85 , miR-7 55 , miR-96 86 , miR-20a-5p 63 , miR-517a 87 , miR-106b 88 , miR-320e 89 , miR-592 90 , miR-196a 57 , miR-196b 57 , miR-720 91 , miR-133a 42 , miR-630 92 , miR-181a 31 , miR-210 93 , miR-25 94 , miR-191 95 , miR-92a 96 , miR-31 59 and miR-552 97 have been reported.…”

“…The downregulation of miR-466 68 , miR-944 71 , miR-30d 72 , miR-22 49, 50 , miR-296 73 , miR-140-5p 119 , miR-199b 48 , miR-155-5p 77 , miR-99b-5p 120 , miR-154 78 , miR-149 79 , miR-96-5p 121 , miR-133b 38, 39 , miR-126 40 , miR-138 110 , miR-625 111 and miR-212 112 was associated with the presence of distant metastasis in 19 studies. The upregulation of miR-888 64 , miR-20a-5p 63 , miR-517a 87 , miR-320e 89 , miR-592 90 , miR-720 91 , miR-494 61 , miR-133a 42 , miR-210 38 , miR-630 92 , miR-17-5p 60 , miR-181a 31 , miR-25 94 , miR-191 95 , miR-183 46 , miR-224 52 , miR-199a-3p 117 , miR-92a 96 , miR-372 122 , miR-185 39 and miR-21 26, 28, 30 was associated with the presence of distant metastasis in 23 studies.…”

“…Among the evaluated studies, 49 demonstrated the downregulation of miR-199b 47, 48 , miR-6852 106 , miR-302c 67 , miR-466 68 , miR-650 123 , miR-196b-5p 70 , miR-944 71 , miR-30d 72 , miR-296 73 , miR-187 124 , let-7a-5p 98 , miR-132 99 , miR-206 100 , miR-148a 125 , miR-33b 76 , miR-99b-5p 120 , miR-154 78 , miR-217 126 , miR-149 79 , miR-194 80 , miR-7 56 , miR-24-3p 54 , miR-29b 127 , miR-15a 34 , miR-16 34, 36 , miR-204-5p 128 , miR-96-5p 121 , miR-193a-5p 108 , miR-100 81 , miR-133a 41 , miR-139-5p 129 , miR-124-5p 130 , miR-335 82 , miR-378 101 , miR-126 40 , miR-378a-3p 58 , miR-378a-5p 58 , miR-218 83 , miR-138 110 , miR-625 111 , miR-212 112 , miR-124 131 , miR-22 49 , miR-133b 39 , miR-193a-3p 104 , miR-195 113 and miR-30c 103 associated with worse prognosis (lower overall survival) of CRC patients. Fifty-six studies identified the upregulation of miR-181a 31–33 , miR-182 43, 44 , miR-1296 84 , miR-888 64 , miR-28-5p 132 , miR-183 45, 46 , miR-200c 114 , miR-34a 133 , miR-15a-5p 134 , miR-181c 135 , miR-24-3p 53 , miR-16 35 , miR-7 55 , miR-96 86 , miR-1260b 115 , miR-20a-5p 63 , miR-517a 87 , miR-503 136 , miR-106b 88 , miR-211 137 , miR-320e 89 , miR-592 90 , miR-196a 57 , miR-196b 57 , miR-376a …”

MicroRNA‐224 suppresses osteoblast differentiation by inhibiting SMAD4

“…It has become increasingly clear that miRNAs could directly regulate expression of SMAD4 in human diseases (Cheng et al, ; Cui et al, ). In our study, we demonstrated that SMAD4 was a direct target of miR‐224, which was consistent with a previous study which identified SMAD4 as a miR‐224 target in colorectal cancer metastasis (Ling et al, ).…”