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Modified miR-15a has therapeutic potential for improving treatment of advanced stage colorectal cancer through inhibition of BCL2, BMI1, YAP1 and DCLK1.

ABSTRACT: Despite advances in colon cancer treatments, resistance and recurrence remain a significant challenge in treating patients. Novel therapeutic strategies are in urgent need to overcome resistance and improve patient outcomes. MicroRNA based therapeutics have potential to help combat resistance. In this study, we have shown that low miR-15a expression correlates with poor patient prognosis. We have demonstrated the therapeutic potential of miR-15a in colon cancer. miR-15a inhibits several important genes (BCL2, BMI1, YAP1 and DCLK1), decreasing cancer progression and resistance. Additionally, by replacing uracil in miR-15a with 5-fluorouracil, we created a novel miR-15a mimic with enhanced therapeutic potential. This mimic maintains target specificity and is more potent than unmodified miR-15a in vitro and inhibits colon tumor metastasis in vivo. This mimic has great potential for therapeutic development for treating colon cancer patients. This novel modification has potential to advance the development of other microRNA based therapeutics beyond miR-15a.

SUBMITTER: Fesler A

PROVIDER: S-EPMC5788646 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Modified miR-15a has therapeutic potential for improving treatment of advanced stage colorectal cancer through inhibition of BCL2, BMI1, YAP1 and DCLK1.

Fesler Andrew A Liu Hua H Ju Jingfang J

Oncotarget 20171219 2

Despite advances in colon cancer treatments, resistance and recurrence remain a significant challenge in treating patients. Novel therapeutic strategies are in urgent need to overcome resistance and improve patient outcomes. MicroRNA based therapeutics have potential to help combat resistance. In this study, we have shown that low miR-15a expression correlates with poor patient prognosis. We have demonstrated the therapeutic potential of miR-15a in colon cancer. miR-15a inhibits several importan ...[more]

PMID: 29416778

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Project description:BackgroundIdiopathic scoliosis (IS) is a complex disease with an unclear etiology, and the worldwide prevalence is approximately 2-3%. As an important link between environmental factors and phenotypic differences, epigenetic changes, such as lncRNA, miRNA, and DNA methylation, have recently been reported to be associated with the development of IS. However, the correlation between histone methylation, another classical epigenetic mechanism, and IS has not been determined. In this study, we investigated the morphological changes, alterations in the levels of histone methylation, and cell proliferation-related pathway in inferior facet joint cartilage in 11 IS patients and 10 comparable controls.ResultsCompared with the control group, narrowed facet joint cartilage but increased proliferative chondrocytes and upregulated collagen type II (COL2A1) and B-cell lymphoma-2 (Bcl2) were observed in IS patients. Additionally, tri-methylation levels of H3K9 (H3K9me3) rather than other lysine sites were significantly increased in IS patients, coinciding with the upregulation of its specific enzyme, suppressor of variegation 3-9, drosophila homolog of 1 (SUV39H1). In addition, Bcl2-targeted miR-15a was downregulated in IS patients, and the level of H3K9me3 in the promoter region of the miR-15a host gene was remarkably increased in IS patients compared with the control group. Moreover, overexpressing SUV39H1 in ATDC5 cells with increased H3K9me3 levels led to similar changes, with increased expression of COL2A1 and Bcl2, decreased expression of miR-15a, and increased cell proliferation.ConclusionsThus, our study suggests that increased chondrocyte proliferation occurs in the facet joint cartilage of IS patients compared with the control group and may be promoted by the elevated levels of H3K9me3 and SUV39H1, which regulate the miR-15a/Bcl2 pathway. This dysregulation of chondrocyte proliferation could result in abnormal spinal growth and may additionally participate in the development and progression of IS.

Dataset Information

Modified miR-15a has therapeutic potential for improving treatment of advanced stage colorectal cancer through inhibition of BCL2, BMI1, YAP1 and DCLK1.

Publications

Modified miR-15a has therapeutic potential for improving treatment of advanced stage colorectal cancer through inhibition of BCL2, BMI1, YAP1 and DCLK1.

Similar Datasets

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