Abstract
Accumulating evidence indicates that sustained activation of NF-κB in cancer cells contributes to inflammation, expansion of tumor-initiating cancer stem cells (CSCs), and tumor progression. On the other hand, recent studies reveal that CSCs exhibit increased inflammation due to constitutive NF-κB activation, which is able to 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 control is still ill-defined. In this study, we used bioinformatic analysis to show the upregulation of NF-κB-regulated proinflammatory genes and downregulation of Copper Metabolism (Murr1) Domain-containing 1 (COMMD1) during the enrichment of stemness in SAS head and neck squamous-cell carcinoma (HNSCC) cells. The 3′-UTR of COMMD1 mRNA consists of miR-205 target site. Parallel studies with SAS, human H460 and mouse D121 non–small-cell lung cancer cells indicated that miR-205 reduces COMMD1 expression, and the expression of miR-205 is upregulated upon NF-κB activation in stemness enriched cancer cells. COMMD1 effectively restrained inflammatory stimuli-induced NF-κB activation, cytokine production, as well as leukocytes migration. The lentiviral shRNA-mediated downregulation of COMMD1 in cancer cells increased the expression of stemness-associated genes, sphere-forming capacity, and potential for anchorage-independent growth. Moreover, study with cancer animal model showed that knockdown of COMMD1 enhances tumorigenesis and tumor growth. Tumors derived from COMMD1-knockdown cells displayed increased NF-κB activation and expression of inflammatory- and stemness-associated genes. In addition, expanded population of CD11b+ tumor-associated leukocytes and CD117+ stemness-enriched cancer cells were detected in these tumors. Overall, these results demonstrate that the miR-205-COMMD1-NF-κB axis forming a positive feedback loop for amplifying inflammatory- and stemness-associated properties in cancer cells is likely a underlying molecular mechanism for promoting the malignancy of tumors.