Control of NF‐κB activity, inflammation and stemness properties in cancer cells by Copper Metabolism (Murr1) Domain‐Containing 1

Abstract

It has been shown that persistant activation of NF‐κB in cancer cells contributes to inflammation, expansion of tumor‐initiating cancer stem‐like cells (CSCs), and tumor progression. In contrast, NF‐κB activation in CSCs can elevate expression and release of pro‐inflammatory mediators into the tumor microenvironment and further increase stemness and inflammatory conditions in cancer cells. Nevertheless, the underlying molecular controls are still ill‐defined. In this study, we used bioinformatic analysis to show the upregulation of NF‐kB‐target pro‐inflammatory gene and downregulation of Copper Metabolism (Murr1) Domain‐containing 1 (COMMD1) during the enrichment of stemness of SAS, an oral cancer cell line in tumor sphere culture. The 3′‐UTR of COMMD1 mRNA consists of miR‐205 target site. Parallel studies with SAS and non–small‐cell lung cancer cells, H460 and D121 indicated that miR‐205 reduces COMMD1 expression and the expression of miR‐205 was upregulated upon NF‐kB activation. COMMD1 effectively restrained inflammatory stimuli‐induced NF‐κB activation, cytokine production, as well as leukocytes migration. The lentiviral shRNA‐mediated knockdown of COMMD1 increased the expression of stemness genes, sphere‐forming capacity, and potential for anchorage‐independent growth in cancer cells. Moreover, study with cancer animal model showed that COMMD1 knockdown enhances tumorigenesis and tumor growth, as well as expanded population of CD11b+ tumor‐associated leukocytes and CD117+ stemness‐enriched cancer cells. These results suggest that the miR‐205‐COMMD1‐NF‐κB axis forming a positive feedback loop for amplifying inflammatory and stemness‐associated properties of cancer cells that further promote pro‐inflammatory tumor microenvironment.