Gender differences in UV-induced skin inflammation, skin carcinogenesis and systemic damage
Introduction
Ultraviolet (UV) radiation is a strong causal risk factor for skin cancer, according to the IARC review of human carcinogens (Armstrong et al., 2012). The epidemiological, mechanistic and clinical trial data have enabled the International Agency for Research on Cancer to classify UV radiation as a Group 1 (‘sufficient evidence’) carcinogen for human skin (Ghissassi et al., 2009). Besides, epidemiologic studies have reported that the incidence of non-melanoma skin cancer in men was twice as high as in women (Armstrong and Kricker, 2001). However, lack of studies reveals whether there is gender difference in the development of animal skin tumor.
UV radiation at earth’s surface is predominantly composed of 95% UVA (315−400 nm) radiation with a 5% percentage of UVB (280−315 nm) radiation (Diffey, 2002). Both UVA and UVB cause DNA damage and inflammation, even eventually lead to cancer (Sample et al., 2017; Balupillai et al., 2018). The inflammatory response and the presence of relative mediators at the UV-irradiated skin sites play a crucial role in all the three stages of tumor development, i.e., initiation, promotion and progression (Mukhtar and Elmets, 1996). Inflammatory signaling endorses multiple hallmarks of cancer (Hanahan and Weinberg, 2011), including evasion of apoptosis, induction of DNA damage, crosstalk with oxidative stress pathways, tumor growth/proliferation and metastasis.
Nuclear transcription factor-κB (NF-κB) has been known to be an important transcription factor for inflammation and tumor development. In skin cancer, enhanced NF-κB activity leads to hyperproliferation and dysplasia of mouse epidermis (Lee et al., 2018). Epidermal keratinocyte-specific deletion of p65 protects DMBA/TPA-induced skin carcinogenesis (Kim and Pasparakis, 2014). Several reports have demonstrated that chronic inflammation promoted epidermal cell transformation and malignant progression by enhancing the release of cytokines and chemokines and by infiltration of inflammatory cells (Lu et al., 2006). Besides, various inflammatory cytokines, including TNF-α, IL-1 and IL-6, promoted skin cancer development (Landskron et al., 2014).
UV also causes an increase in reactive oxygen species (ROS). Overproduction or inadequate removal of ROS result in oxidative stress (Trouba et al., 2002). Chronic inflammatory states, where oxidative stress increases with the migrating inflammatory cells, are closely associated with cancer development (Weitzman and Gordon, 1990). During chronic inflammation or in the tumor microenvironment, ROS have been proposed to contribute to tumorigenesis by inducing mutations in tumor cells and promoting the recruitment of myeloid cells (Grivennikov et al., 2010). ROS also functions as a second messenger in a number of signal transduction pathways including NF-κB signaling (Bubici et al., 2006).
Furthermore, damaged biomolecules as well as signaling molecules produced by UV exposure may enter the blood circulation and affect blood cells and internal organs (Day et al., 2017). Peripheral blood neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV) and red blood cell distribution width (RDW) are four hematological markers of systemic inflammation (Liu et al., 2018; Ozmen et al., 2017). Acute exposure to solar simulated UV radiation increased WBC number and decreased PLT number in the blood of the mice (Svobodová et al., 2011). Moreover, chronic UV irradiation also causes damage of internal organs. When exposed to UV, the weights of heart, liver, spleen and kidney of quails were significantly higher than those of normal quails not exposed to UV (Li et al., 2009; Li, 2010). Long wave UV also leads to the damage of the whole renal histological structure and reduces the function of the kidney in bufonids (Ting et al., 2012).
Although the epidemiologic studies have reported the gender differences in the development of non-melanoma skin cancer, to date there have few animal studies examining this difference. The current study aimed to compare the gender differences in UV-induced inflammation, skin carcinogenesis, systemic damage in mice exposed to equal dose of UV. We observed differences of male and female mice in visual appearance, histopathology changes, hematology, organs injuries, oxidative stress and inflammatory response during chronic inflammation-associated cancer development.
Section snippets
Chemical and reagents
Mouse TNF-α and IL-6 enzyme-linked immunosorbent assay (ELISA) kits were obtained from Biolegend (California, USA). Gomori aldehyde fuchsin was obtained from Solarbio (Beijing, China). Anti-NF-kB p65 (phospho S536) rabbit antibody (ab86299), anti-GAPDH mouse antibody (ab8245) and goat anti-rabbit lgG H&L (HRP) (ab6721) were purchased from Abcam. Anti-p65 rabbit antibody (#8242S) was purchased from Cell Signaling Technology. Goat anti-mouse IgG (H + L)-HRP (LK2003) was purchased from Tianjin
UV induces mice skin macroscopic lesions
For observing the cutaneous damage by UV irradiation, we took pictures of the macroscopic lesions of mice skin with a digital camera and determined skin perfusion by laser speckle perfusion imaging. The typical images of the UV-induced macroscopic skin lesions at the 9th week, the 24th week and the 31st week were shown in Fig. 1A. During the whole study period, the mice in the control group showed healthy skin with age-related slight wrinkles. In contrast, after nine-week UV irradiation, skin
Discussion
It has been demonstrated that sex is an important aspect in the development of a number of diseases. For instance, systemic sclerosis is more common in women but there are more severe visceral complications and higher mortality in men (Hughes et al., 2020). In addition, the occurrence and development of colorectal cancer (Conti et al., 2020) and lung cancer (Stapelfeld et al., 2020) have also been proved to be closely related to gender. However, there is little research on gender difference in
Conclusion
The present study evaluated that there are gender differences in UV-induced skin inflammation, carcinogenesis and systemic damage. Moreover, male mice are more sensitive to UV irradiation, which may be responsible to greater oxidative stress and inflammatory damage in male mice than in female mice. These results suggest that anti-inflammatory and antioxidant drugs could be beneficial to protect against skin photo-damage.
Author contributions statement
Janis Ya-Xian Zhan developed the concept, and designed the study. Qing-Yuan Zhong, Bing Lin, Yin-Ting Chen, Yin-Ping Huang, Wei-Peng Feng, Ying Wu, Gui-Hong Long, Yun-Nan Zou and Yu Liu conducted the experiments. Qing-Yuan Zhong and Bing Lin interpreted the results, and wrote the manuscript. Bao-Qin Lin and Nian-Li Sang participated in interpreting the results, and revised the manuscript.
Funding
This work was supported by the Guangzhou University of Chinese Medicine Young Talent Project (Grant No. QNYC20170106).
CRediT authorship contribution statement
Qing-Yuan Zhong: Visualization, Investigation, Data curation, Writing - original draft. Bing Lin: Visualization, Investigation, Data curation, Writing - original draft. Yin-Ting Chen: Visualization, Investigation. Yin-Ping Huang: Visualization, Investigation. Wei-Peng Feng: Visualization, Investigation. Ying Wu: Visualization, Investigation. Gui-Hong Long: Visualization, Investigation. Yun-Nan Zou: Visualization, Investigation. Yu Liu: Visualization, Investigation. Bao-Qin Lin: Writing - review
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Photoaging
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Both authors contributed equally to this work.