Abstract
microRNA-489 (miR-489) is a novel cancer-related miRNAs and functions as a tumor suppressor in human cancers. While, the clinical significance of miR-489 and its role in colorectal cancer (CRC) remain rarely known. Here, we found that the levels of miR-489 in CRC tissues were significantly lower than those in matched tumor-adjacent tissues. Furthermore, decreased levels of miR-489 also observed in CRC cell lines compared to HIEC cells. Clinicopathological analysis revealed that miR-489 underexpression was positively correlated with advanced pT stage, pN stage and AJCC stage. Moreover, miR-489 low expressing CRC patients showed a obvious shorter survival. Functionally, miR-489 restoration inhibited cell migration and invasion as well as epithelial-mesenchymal transition (EMT) in HCT116 cells, while miR-489 loss facilitated these cellular processes in SW480 cells. In vivo experiments revealed that miR-489 overexpression reduced the number of metastatic nodules in nude mice liver. Notably, TWIST1 was recognized as a direct downstream target of miR-489 in CRC cells. Interestingly, TWIST1 restoration abrogated the effects of miR-489 on CRC cells with enhanced cell migration, invasion and EMT process. Furthermore, overexpression of long noncoding RNA cardiac hypertrophy-related factor (lncRNA CHRF) was inversely correlated with miR-489 expression in CRC tissues. CHRF knockdown increased the expression of miR-489 and suppressed EMT events of HCT116 cells, while CHRF overexpression showed opposite effects on miR-489 expression and EMT in SW480 cells. Taken together, this work support the first evidence that lncRNA CHRF-induced miR-489 loss facilitates metastasis and EMT process of CRC cells probably via TWIST1/EMT signaling pathway.
Highlights
Colorectal cancer (CRC), which ranks fourth in cancer-related deaths, is the third most frequent cancer worldwide [1, 2]
We revealed that miR-489 suppressed migration and invasion as well as epithelial-mesenchymal transition (EMT) process of colorectal cancer (CRC) cells. miR-489 that was inversely regulated by long noncoding RNA cardiac hypertrophy-related factor exerted an anti-metastatic role probably by targeting TWIST1/EMT signaling pathway
CRC patients were divided into miR-489 high expression group and miR-489 low expression group according to the cutoff value, which was defined as the median level of miR-489
Summary
Colorectal cancer (CRC), which ranks fourth in cancer-related deaths, is the third most frequent cancer worldwide [1, 2]. During the last several decades, remarkable advances have been made regarding the early diagnosis and treatment of CRC [3]. The long term survival of CRC patients is still poor, especially for those in advanced stages [4]. Most patients in advanced stages were unavailable to effective treatments due to the occurrence of local and systemic metastasis of CRC cells. The exact mechanisms responsible for the malignant growth and metastatic behaviors of CRC cells remain largely uncovered. Investigating the molecular mechanisms underlying the growth and metastasis of CRC cells will potentially contribute to identification of novel biomarkers and therapeutic targets of CRC patients
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