title: Downregulation of COMMD1 by miR-205 promotes a positive feedback loop for amplifying inflammatory- and stemness-associated properties of cancer cells.
abstract: 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.
authors.affiliation: Immunology Research Center, National Health Research Institutes, Miaoli, Taiwan.|Institute of Molecular Medicine, National Tsing-Hua University, Hsinchu, Taiwan.
authors.forename: D-W
authors.initials: DW
authors.lastname: Yeh
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Chen
authors.affiliation: Immunology Research Center, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Lai
authors.affiliation: Immunology Research Center, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Liu
authors.affiliation: Immunology Research Center, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Lu
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: J-F
authors.initials: JF
authors.lastname: Lo
authors.affiliation: Institute of Molecular Medicine, National Tsing-Hua University, Hsinchu, Taiwan.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: L-C
authors.initials: LC
authors.lastname: Hsu
authors.affiliation: Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.affiliation: School of Medicine, University of Nankai, Tianjin, PR China.
authors.forename: R
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Immunology Research Center, National Health Research Institutes, Miaoli, Taiwan.|Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Research and Development Center for Immunology, China Medical University, Taichung, Taiwan.
authors.forename: T-H
authors.initials: TH
authors.lastname: Chuang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D025461:Feedback, Physiological; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D035683:MicroRNAs; C480519:COMMD1 protein, human; C534425:MIR205, human