MicroRNA-96 promotes the proliferation of colorectal cancer cells and targets tumor protein p53 inducible nuclear protein 1, forkhead box protein O1 (FOXO1) and FOXO3a

Abstract

Abstract. MicroRNAs (miRNAs) are a conserved class of small, endogenous, non protein-coding RNA molecules that are capable of regulating gene expression at post-transcriptional levels and are involved in diverse cellular processes, including cancer pathogenesis. It has previously been reported that miRNA-96 (miR-96) is overexpressed in human colorectal cancer (CRC). However, the underlying mechanism of miR-96 regulation in CRC remains to be elucidated. In the present study, miR-96 was confirmed to be upregulated in CRC tissues by reverse transcription quantitative polymerase chain reaction. MTT assay, colony formation assay and cell cycle analysis revealed that miR-96 overexpression led to increased tumor cell viability, colony formation ability and cell cycle progression. By contrast, inhibition of miR-96 resulted in the suppression of cell proliferation. It was also demonstrated that miR-96 reduced the messenger RNA and protein expression levels of tumor protein p53 inducible nuclear protein 1 (TP53INP1), forkhead box protein O1 (FOXO1) and FOXO3a, which are closely associated with cell proliferation. A luciferase reporter assay indicated that miR-96 inhibited luciferase intensity controlled by the 3'UTRs of TP53INP1, FOXO1 and FOXO3a. In conclusion, the results of the present study demonstrated that miR-96 contributed to CRC cell growth and that TP53INP1, FOXO1 and FOXO3a were direct targets of miR-96, suggesting that miR-96 may have the potential to be used in the development of miRNA-based therapies for CRC patients.

Dysregulation and functional roles of miR-183-96-182 cluster in cancer cell proliferation, invasion and metastasis

“…Targetscan prediction revealed three members of the FOXO protein family, including FOXO1, FOXO3 and FOXO4 as potential targets of the miR-183-96-182 cluster. However, only FOXO1 and FOXO3 have been confirmed by previous studies [16, 35, 49, 61–65], in various types of cancers such as, prostate [63, 66, 67], bladder [43, 68], colorectal [62], breast [69], lung [61], lymphoma [64], and endometrial carcinoma [70] (Table 1). Additionally, recent studies have indicated that miR-182 promotes cell proliferation and tumor invasion by targeting FOXF2 [71, 72], a known inhibitor of MMPs and WNT5A [73, 74].…”

“…Notably, miR-96 has also been found to inhibit the TSG RECK [40, 83, 84] and EFNA5 [85]. Besides, miR-96 and miR-182 were found to have an inhibitory effect on TP53INP1 expression [62, 86]. Collectively, the available evidence indicates that miR-183-96-182 cluster could promote cell proliferation in various cancer types (Table 1).…”

Variation at 2q35 (PNKDandTMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease

“…At this threshold, in addition to rs2382817, 11 IBD risk SNPs were associated with CRC risk (Table 1), of which five were positively associated with CRC risk, whereas the other seven displayed an inverse relationship. A number of these SNPs annotate genes with documented roles that are relevant to CRC development, such as Wnt-signalling [ WNT4 , (17)], tumour suppression [ MAPKAPK5 , FOXO1 (18,19)] and cellular transformation [ CDC42 , CEBPB (20,21)] (Table 1). We examined for an association between the genotype of these 12 SNPs and the molecular subtype of CRC, and found no evidence of a relationship (Supplementary Material, Table S3).…”

MicroRNAs as regulators and mediators of forkhead box transcription factors function in human cancers

“…A single miRNA might regulate several target mRNAs due to the relatively short seed region. For instance, FOXO1 and FOXO3a are both direct targets of miR-96 in colorectal cancer and HCC [71, 75]. Meanwhile, FOXO3 and FOXO1 are found to be critical targets of miR-9 in hematopoietic cells [76].…”