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MiR-144-3p inhibited the growth, metastasis and epithelial-mesenchymal transition of colorectal adenocarcinoma by targeting ZEB1/2.

ABSTRACT: miR-144-3p is aberrantly expressed in several types of human cancer and functions as a tumor suppressor by inhibiting metastasis. However, the clinical significance and biological function of miR-144-3p in colorectal adenocarcinoma (CRA) have yet to be elucidated. Here we reported that miR-144-3p expression level was significantly down-regulated in CRA tissues compared with matched noncancerous colorectal mucosae tissues. Low miR-144-3p expression was correlated with adverse clinicopathologic characteristics and poor prognosis of CRA patients. Cox regression analysis showed that low miR-144-3p expression was an independent risk factor for DFS and OS in CRA. In vitro and in vivo assays showed that miR-144-3p significantly inhibited proliferation, migration and invasion of CRA cells. In particular, miR-144-3p could suppress EMT process of CRA cells by regulating the cytoskeleton and EMT markers. Bioinformatics analysis indicated that EMT associated transcription factors ZEB1 and ZEB2 were potential targets of miR-144-3p, and miR-144-3p inhibited ZEB1 and ZEB2 expression and was negatively correlated with their expression in CRA. Finally, we confirmed that ZEB1 and ZEB2 down-regulation collaboratively mediated the inhibitory effect of miR-144-3p on proliferation, invasion and EMT of CRA cells. In conclusion, our study provided evidence that miR-144-3p could inhibit CRA cell proliferation, invasion and EMT by targeting ZEB1/2.

SUBMITTER: Li T

PROVIDER: S-EPMC8312459 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundWe have previously developed a unique metastasis-associated signature consisting of six long non-coding RNAs (lncRNAs), including a novel lncRNA, namely LINC02323. In the present study, we aimed to investigate the underlying roles of LINC02323 in the migration, invasion and TGF-β-induced epithelial-mesenchymal transition (EMT) of lung adenocarcinoma (LUAD) cells.MethodsThe distribution of LINC02323 was detected by the nuclear-plasma separation experiment. Cell proliferation was assessd by MTT assay, and cell migration and invation were detected by transwell assays. EMT was detected by RT-qPCR and western blotting. Interaction between miRNA and LINC02323 was predicted by starBase v2.0 and confirmed by the double luciferase reporting system.ResultsLINC02323 was distributed in the cytoplasm and nucleus. The overexpression or deletion of LINC02323 did not affect the proliferation of LUAD cells, while significantly affected the migration and invasion of LUAD cells. TGF-β-induced EMT process was significantly affected by both RNA interference (RNAi) and overexpression of LINC02323. The predicted results showed that there were binding sites between LINC02323 and miR-1343-3p. The expression of LINC02323 was found to be negatively correlated with miR-1343-3p in LUAD by analyzing The Cancer Genome Atlas (TCGA) database. The double luciferase reporting system, RT-qPCR and western blotting experiments confirmed that LINC02323 could bind to miR-1343-3p, which bound to TGF-β receptor 1 (TGFBR1). Inhibition of miR-1343-3p reversed LINC02323 silencing-mediated suppression of migration, invasion and EMT.ConclusionsLINC02323 acts as a competing endogenous RNA (ceRNA), which sponged miR-1343-3p to upregulate the TGFBR1 expression and promote the EMT and metastasis in LUAD.Key pointsSIGNIFICANT FINDINGS OF THE STUDY: LINC02323 promotes epithelial-mesenchymal transition and metastasis via sponging miR-1343-3p in lung adenocarcinoma.What this study addsLINC02323 is a key molecule in the process of invasion and metastasis of LUAD and might be used as a potential target in metastatic cancer.

Project description:BackgroundMicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression, influence cellular processes, and promote disease development. Variations in miRNA expression have been observed in many diseases, including hepatitis, cardiovascular disease, and cancer. The aim of this study is to investigate the effect of miR-144-3p on the invasion and metastasis of lung adenocarcinoma by targeting recombinant insulin receptor substrate 1 (IRS1).MethodsThe expression of miR-144-3p in patients with lung adenocarcinoma was queried through bioinformatics database. MirTarPathway was used to analyze the KEGG enrichment pathway of miRNA. The expression and plasmid transfection efficiency of miR-144-3p in lung adenocarcinoma cell lines were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Transwell assay was used to detect the changes of cell invasion and migration ability in different groups. Bioinformatics determined the key genes (Hub genes) of miR-144-3p; Double luciferase target assay was used to detect the mutual binding of miR-144 and IRS1. Western blot assay was used to detect the expression of IRS1 in different cell lines and the expression of after overexpression of miR-144.ResultsThe expression of miR-144-3p in lung adenocarcinoma tissues was decreased, qRT-PCR results indicated that the expression of miR-144-3p in lung adenocarcinoma cell A549 was significantly decreased (P<0.05), and the overexpressed plasmid was successfully transfected (P<0.05). Overexpression of miR-144 decreased the ability of cell migration and invasion (P<0.05). The expression of IRS1 was up-regulated in lung adenocarcinoma tissues. Survival analysis showed that patients with lung adenocarcinoma with high IRS1 expression had a poor prognosis (P<0.05). Double luciferase assay results showed that miR-144 could specifically identify 3'-UTR of IRS1 and inhibit reporter enzyme expression (P<0.05). Western blot indicated that the expression of IRS1 was increased in A549 cells (P<0.05). After overexpression of miR-144, the expression level of IRS1 protein was decreased (P<0.05). Transwell experiment proved that miR-144-3p could inhibit invasion and metastasis of lung adenocarcinoma cells by targeting IRS1 (P<0.05).ConclusionsMiR-144-3p inhibits the invasion and migration of A549 cells through targeted regulation of IRS1, thus playing an anticancer role in tumors.

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MiR-144-3p inhibited the growth, metastasis and epithelial-mesenchymal transition of colorectal adenocarcinoma by targeting ZEB1/2.

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