USP17 mediates macrophage-promoted inflammation and stemness in lung cancer cells by regulating TRAF2/TRAF3 complex formation

Abstract

Macrophage accumulation and inflammation in the lung owing to stresses and diseases is a cause of lung cancer development. However, molecular mechanisms underlying the interaction between macrophages and cancer cells, which drive inflammation and stemness in cancers, are poorly understood. In this study, we investigated the expression of ubiquitin-specific peptidase 17 (USP17) in lung cancers, and role of elevated USP17 in the interaction between macrophages and lung cancer cells. USP17 expression in lung cancers was associated with poor prognosis, macrophage, and inflammatory marker expressions. Macrophages promoted USP17 expression in cancer cells. TNFR-associated factor (TRAF) 2-binding and TRAF3-binding motifs were identified in USP17, through which it interacted with and disrupted the TRAF2/TRAF3 complex. This stabilized its client proteins, enhanced inflammation and stemness in cancer cells, and promoted macrophage recruitment. In different animal studies, co-injection of macrophages with cancer cells promoted USP17 expression in tumors and tumor growth. Conversely, depletion of macrophages in host animals by clodronate liposomes reduced USP17 expression and tumor growth. In addition, overexpression of USP17 in cancer cells promoted tumor growth and inflammation-associated and stemness-associated gene expressions in tumors. These results suggested that USP17 drives a positive-feedback interaction between macrophages and cancer cells to enhance inflammation and stemness in cancer cells, and promotes lung cancer growth.

The Deubiquitinase USP4 Stabilizes Twist1 Protein to Promote Lung Cancer Cell Stemness

“…Several embryonic transcription factors, including Oct4, Sox2, Nanog, MYC and KLF4, are essential in the regulation of stemness of CSCs [8,[12][13][14][15]. In addition, CSCs characteristically exhibit activation of several highly conserved pathways involved in cell renewal and tissue homeostasis, including Hedgehog, Notch, WNT/β-Catenin and TNF-α, to promote cell survival, self-renewal, and metastasis [16][17][18][19]. Targeting proteins critical for CSCs stemness has been a potential strategy for cancer treatment [20,21].…”

Macrophages Interaction and MicroRNA Interplay in the Modulation of Cancer Development and Metastasis

“…M0 (macrophages in resting state), M1, and M2 macrophages can enhance the intracellular level of ubiquitin-specific protease (USP17) in Lewis lung cancer cells, which further causes the upregulation of USP17 to both pro-inflammatory (TNF-α, IL-1β, IL-6, IL-8, CXCL12) and the anti-inflammatory factors IL-4 and IL-10. USP overexpression maintains cancer cell stemness resulting in an enhanced adaptability of cancer cells (55).…”

The Role of Deubiquitinating Enzymes in Acute Lung Injury and Acute Respiratory Distress Syndrome

“…NLRP3 [38] Regulates NLRP3 inflammasome activation [38] NF-κB [39], NEMO [33] Regulates NF-κB signaling [33,39] VP24 [49] Involves in virus replication [49] Tat [50] Involves in virus production [50] TRAF3/TRAF6 [51] Modulates antiviral signaling [51] TRAF6/IKKγ [34] Regulates TLR signaling [34] USP-10 CFTR [37,52] Epithelial mucosal clearance [37,52] NICD1 [53] Regulates Notch signaling [53] USP-11 E2F1 [54] Regulates lung epithelia proliferation and wound healing [54] LPA1 [36] Enhances inflammation [36] USP-13 IL-1R8/Sigirr [40] Suppresses lung inflammation [40] PTEN [41] Regulates cell apoptosis [41] MCL1 [42] Regulates transformation of fibroblasts [42] STAT1 [55] Regulates IFN Signaling [55] STING [56] Negatively regulates antiviral responses [56] USP-14 I-kB [31] Increases cytokine release [31] CBP [32] Lung inflammation [32] USP-15 IκBα [57] NF-κB activation [57] USP-17 HDAC2 [58] Reverses glucocorticoid resistance [58] TRAF2/TRAF3 [59] Lung inflammation [59] [92] Inhibits type I IFN signaling and antiviral response [92] POH1 pro-IL-1β [93] Negatively regulates the immune response [93] BRCC3 NLRP3…”

“…In addition, inhibition of USP7 and USP47 blocks the NLRP3 inflammasome by preventing apeck-like protein containing a CARD (ASC) oligomerization and speck formation in macrophages [38]. USP17 mediates macrophage-promoted inflammation and stemness in lung cancer cells by regulating TRAF2/TRAF3 complex formation [59]. The activity of deubiquitination regulates inflammasome assembly and function.…”