Abstract
MicroRNAs (miRNAs) are important class of functional regulators involved in human cancers development, including colorectal cancer (CRC). Exploring aberrantly expressed miRNAs may provide us with new insights into the initiation and development of CRC by functioning as oncogenes or tumor suppressors. The aim of our study is to discover the expression pattern of miR-1249 in CRC and investigate its clinical significance as well as biological role in CRC progression. In our study, we found that miR-1249 was markedly downregulated in CRC tissues and cell lines, and negatively related to pN stage, pM stage, TNM stage, and overall survival (OS). Moreover, we demonstrated that miR-1249 was a direct transcriptional target of P53 and revealed that P53-induced miR-1249 inhibited tumor growth, metastasis and angiogenesis in vitro and vivo. Additionally, we verified that miR-1249 suppressed CRC proliferation and angiogenesis by targeting VEGFA as well as inhibited CRC metastasis by targeting both VEGFA and HMGA2. Further studying showed that miR-1249 suppressed CRC cell proliferation, migration, invasion, and angiogenesis via VEGFA-mediated Akt/mTOR pathway as well as inhibited EMT process of CRC cells by targeting both VEGFA and HMGA2. Our study indicated that P53-induced miR-1249 may suppress CRC growth, metastasis and angiogenesis by targeting VEGFA and HMGA2, as well as regulate Akt/mTOR pathway and EMT process in the initiation and development of CRC. miR-1249 might be a novel the therapeutic candidate target in CRC treatment.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies worldwide, and tumor metastasis are the leading causes of morality in these patients[1]
Results miR-1249 was markedly downregulated in CRC cell lines and tissues Firstly, we evaluated the expression of miR-1249 in six CRC cell lines (HCT116, HCT8, HT29, SW620, SW480, and DLD-1) and FHC
The results showed that miR-1249 was obviously downregulated in CRC tissues when compared to adjacent normal tissues (ANTs) (Fig. 1b)
Summary
Colorectal cancer (CRC) is one of the most common malignancies worldwide, and tumor metastasis are the leading causes of morality in these patients[1]. New drugs including inhibitors of EGFR signaling and angiogenesis have elevated survival time in metastatic CRC patients[2], metastatic CRC remains an incurable disease in most these patients. MicroRNAs (miRNAs) are a group of non-coding RNAs (18–22 nucleotide) that have been reported to be act as a tumor suppressor or oncogene via regulating their target gene through mRNA degradation, posttranscriptional repression or promoter activation[3,4,5]. Mounting miRNAs have been shown to play key roles in multiple biological processes in CRC6–8, including cell tumor growth, metastasis, drug-resistance, angiogenesis and apoptosis, and have been identified as potential therapeutic and prognostic biomarkers in CRC diagnosis and treatment. The function of miR-1249 and its underlying molecular mechanisms in CRC remain elusive.
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