XIAP promotes melanoma growth by inducing tumour neutrophil infiltration

Abstract

Elevated expression of the X‐linked inhibitor of apoptosis protein (XIAP) has been frequently reported in malignant melanoma suggesting that XIAP renders apoptosis resistance and thereby supports melanoma progression. Independent of its anti‐apoptotic function, XIAP mediates cellular inflammatory signalling and promotes immunity against bacterial infection. The pro‐inflammatory function of XIAP has not yet been considered in cancer. By providing detailed in vitro analyses, utilising two independent mouse melanoma models and including human melanoma samples, we show here that XIAP is an important mediator of melanoma neutrophil infiltration. Neutrophils represent a major driver of melanoma progression and are increasingly considered as a valuable therapeutic target in solid cancer. Our data reveal that XIAP ubiquitylates RIPK2, involve TAB1/RIPK2 complex and induce the transcriptional up‐regulation and secretion of chemokines such as IL8, that are responsible for intra‐tumour neutrophil accumulation. Alteration of the XIAP‐RIPK2‐TAB1 inflammatory axis or the depletion of neutrophils in mice reduced melanoma growth. Our data shed new light on how XIAP contributes to tumour growth and provides important insights for novel XIAP targeting strategies in cancer.

Calycosin Ameliorates Bleomycin-Induced Pulmonary Fibrosis via Suppressing Oxidative Stress, Apoptosis, and Enhancing Autophagy

“…Bax, one of the Bcl-2 family members, promotes apoptosis by damaging mitochondrial membrane integrity, whereas Bcl-2 inhibits apoptosis by maintaining the integrity of the mitochondrial membrane [ 34 ]. The X-linked inhibitor of apoptosis protein has also been implicated in mitochondrial apoptosis [ 35 ]. It inhibits apoptosis mainly by interacting directly with caspases to inhibit them.…”

Neutrophil extracellular traps promote keratinocyte inflammation via AIM2 inflammasome and AIM2‐XIAP in psoriasis

“…54 Abnormal expression of XIAP is directly associated with cancer, autoimmune diseases and neurodegenerative diseases. 55,56 However, the role of XIAP in psoriasis has not been studied. In this study, RNA-seq analysis, qRT-PCR and western blot results showed that XIAP was highly expressed in both psoriatic skin lesions and psoriatic patient-derived NET-stimulated keratinocytes.…”

The Influence of the microbiome on the innate immune microenvironment of solid tumors

“…In excess, they can cause dysregulated inflammation and persistent mucosal injury as evidenced by inflammatory bowel disease [45] . They also constitute an important component of the immune interaction in a variety of solid tumors including breast [47] , gastric [48] , melanoma [49] , RCC [50] , and CRC [51] . A fair amount of literature supports the role for neutrophils both in circulation and within the TME as being associated with cancer progression and prognosis [51] , [52] , [53] .…”