Inhibition of colorectal tumor formation using a new miR‐210 therapeutic inhibitor that targets the Lnc RNA Xist and Nme1

Abstract

In this report we investigate the role of microRNA‐210 (miR‐210) in the etiology of colorectal cancer (CRC) using both cell‐based and xenograft mouse models. We show that miR‐210 expression is higher in the colon cancer cell line SW620 versus normal colon epithelium and has been associated with decreased cancer survival rates. Stable expression of our new miR‐210 inhibitor changes the morphology, proliferation and gene expression of SW620 cells and tumor growth. RNAseq identified potential targets of miR‐210 and qPCR has verified several of these targets. We find that inhibition of miR‐210 can act as a tumor suppressor and reduce tumor formation of SW620 colon cancer cells in xenograft mouse models. Direct comparison with capecitabine treatments demonstrates the effectiveness of the miR‐210 inhibitor treatment. The direct administration of the miR‐210 inhibitor (MiRIS) to existing tumors can inhibit tumor growth in both NSG and Foxnu/j mouse models. The inhibition of miR‐210 can cause alterations in hypoxia responses and upregulation of several tumor suppressor genes, including Nme1. We demonstrate that the long non‐coding transcript XIST is regulated by miR‐210 and XIST expression is decreased in colon tumors. We show that XIST expression correlates with the expression of the tumor suppressor gene Nme1. Furthermore, the inhibition of miR‐210 effects epigenetic marks of the NME1 loci, with increases in H3K4me3 and H3K27ac near the transcription start site (TSS). We show that our new miR‐210 inhibitor can be used as an effective colorectal cancer therapeutic tool.