Autophagy gene ATG7 regulates ultraviolet radiation-induced inflammation and skin tumorigenesis

Abstract

Macroautophagy (hereafter autophagy) is a cellular "self-eating" process that is implicated in many human cancers, where it can act to either promote or suppress tumorigenesis. However, the role of autophagy in regulation of inflammation during tumorigenesis remains unclear. Here we show that autophagy is induced in the epidermis by ultraviolet (UV) irradiation and autophagy gene Atg7 promoted UV-induced inflammation and skin tumorigenesis. Atg7 regulated UV-induced cytokine expression and secretion, and promoted Ptgs2/Cox-2 expression through both a CREB1/CREB-dependent cell autonomous mechanism and an IL1B/IL1β-dependent non-cell autonomous mechanism. Adding PGE increased UV-induced skin inflammation and tumorigenesis, reversing the epidermal phenotype in mice with Atg7 deletion in keratinocytes. Similar to ATG7 knockdown in human keratinocytes, ATG5 knockdown inhibited UVB-induced expression of PTGS2 and cytokines. Furthermore, ATG7 loss increased the activation of the AMPK pathway and the phosphorylation of CRTC1, and led to endoplasmic reticulum (ER) accumulation and reduction of ER stress. Inducing ER stress and inhibiting calcium influx into the ER by thapsigargin reverses the inflammation and tumorigenesis phenotype in mice with epidermal Atg7 deletion. Taken together, these findings demonstrate that deleting autophagy gene Atg7 leads to a suppression of carcinogen-induced protumorigenic inflammatory microenvironment and tumorigenesis of the epithelium.

Autophagy and Its Relationship to Epithelial to Mesenchymal Transition: When Autophagy Inhibition for Cancer Therapy Turns Counterproductive

“…Cells with high autophagy secreted higher levels of IL-1β, LIF, CXCL8, and MMP2, all with known roles in inflammation and tumorigenesis [128], and secretion was downregulated by ATG7 silencing, indicating that secretion was dependent on autophagy and that high autophagy levels could be used as a marker of highly secretory cells. In agreement with the previous data, skin cells of mice treated with UV light showed increased levels of autophagy and higher secretion of proinflammatory cytokines (such as CSF3/G-CSF, CXCL1, IL-6, TREM1, CCL2, CCL3/MIP-1α, IL-1β, and CXCL2), and secretion was related to the promotion of tumorigenesis [129].…”

Deciphering UV‐induced DNA Damage Responses to Prevent and Treat Skin Cancer

“…Also, UV induces autophagy in the epidermis, and the autophagy gene Atg7 regulates UV‐induced cytokine expression and secretion. Deletion of Atg7 suppressed UV‐induced inflammation and skin tumorigenesis (171). Thus, autophagy is another potential target for skin cancer prevention.…”

PTX3 Predicts Myocardial Damage and Fibrosis in Duchenne Muscular Dystrophy

“…Moreover, we established that even though the TGF-β extent was higher in 10w mdx mice and lower in 9m mdx related to younger animals (9m mdx versus 11dy mdx, p = 0.0366; 10w mdx versus 11dy mdx, p = 0.0066), its expression did not vary significantly with the age, as described in Van Erp et al 2010 (Figures 7A,B). PTX3 has been shown to regulate mitochondrial membrane potential and apoptosis (Lee et al, 2018) and, vice versa, its expression can be controlled by ATG7 (Qiang et al, 2017). Thus, we investigated the expression of autophagy markers ATG7, p62, and LC3B, and we found an increased ATG7 expression at 18 months of age (18m mdx versus 9m mdx, p = 0.0026; 18m mdx versus 10w mdx, p = 0.0004; 18m mdx versus 11dy mdx, p = 0.0003), confirming a dependency on the age (Figures 7C,D).…”