Sustained activation of nuclear factor-κB (NF-κB) in
cancer cells has been shown to promote
inflammation, expansion of cancer stem cell (CSC) population, and
tumor development. In contrast, recent studies reveal that CSCs exhibit increased
inflammation due to constitutive NF-κB activation; however, the underlying molecular mechanism remains unclear. In the present study, the analysis of microarray data revealed upregulation of NF-κB-regulated pro-inflammatory genes and downregulation of
copper metabolism MURR1 domain-containing 1 (COMMD1) during the enrichment for stemness in SAS
head and neck squamous-cell carcinoma (
HNSCC) cells. The 3'-UTR of COMMD1
mRNA contains
microRNA (miR)-205 target site. Parallel studies with
HNSCC and NSCLC cells indicated that miR-205 is upregulated upon NF-κB activation and suppresses COMMD1 expression in stemness-enriched
cancer cells. COMMD1 negatively regulates the inflammatory responses induced by
TLR agonists, IL-1β, and TNF-α by targeting RelA for degradation. The
shRNA-mediated downregulation of COMMD1 in
cancer cells enhanced inflammatory response, generating favorable conditions for macrophage recruitment. In addition, genes associated with stemness were also upregulated in these cells, which exhibited increased potential for anchorage-independent growth. Furthermore, COMMD1 downregulation promoted in vivo
tumorigenesis and
tumor growth, and
tumors derived from COMMD1-knockdown cells displayed elevated level of NF-κB activation, increased expression of inflammatory- and stemness-associated genes, and contain expanded population of
tumor-associated leukocytes and stemness-enriched
cancer cells. These results suggest that COMMD1 downregulation by miR-205 promotes
tumor development by modulating a positive feedback loop that amplifies inflammatory- and stemness-associated properties of
cancer cells.