Ultraviolet Radiation and Basal Cell Carcinoma: An Environmental Perspective

Ultraviolet radiation (UVR) is a known carcinogen participated for the development of skin cancers. Solar UVR exposure, particularly ultraviolet B (UVB), is the mostly significant environmental risk factor for the occurrence and progress of basal cell carcinoma(BCC). Both cumulative and intermittent high-grade UVR exposure could promote the uncontrolled replication of skin cells. There are also exsiting other contributing environmental factors that combine with the UVR exposure to promote the development of BCC. DNA damage in formation of skin cancers is considered to be a result of UVR toxicity. It is UVR that could activate a series of oncogenes simultaneously inactivating tumor suppressor genes and aberrant proliferation and survival of keratinocytes that repair these damages. Furthermore, mounting evidence demonstrates that inflammatory responses of immune cells in the tumor microenvironment plays crucial role in the skin tumorigenesis as well. In this chapter, we will follow the function of UVR in the onset and development of BCC. We describe the factors that influence BCC induced by UVR, and also review the recent advances of pathogenesis of BCC induced by UVR from the genetic and inflammatory aspects.


INTRODUCTION
Cutaneous cancer is the most common cancer type worldwide, and basal cell carcinoma (BCC) generally accounts for 75-80% of cases arising from the basal layer of the epidermis and its appendages (1)(2)(3). Most diagnosed patients are between 60 and 79 years old, and men are twice as likely to develop BCC. However, BCC incidence has tripled over the last 30 years; and recently, there has been a significant rise in younger individuals and women (4)(5)(6). The annual growth rate of BCC in Europe is approximately 5% over the recent decades. In the United States, the incidence rate increased by 2% annually, contributing to about 2-5 million patients with BCC receiving treatment every year (3,7). Compared with Western countries, BCC incidence in the Asian population is 10to 100-fold lower; but recently, there has been an increasing number of cases (8)(9)(10). Although, BCC rarely causes metastatic disease or death as the result of the extremely low mortality, it can result in significant morbidity because of its destructive local spread (11,12). Ultraviolet radiation (UVR) is a known carcinogen that contributes to the development of cutaneous cancers containing both nonmelanoma skin cancers (NMSCs) and malignant melanoma (MM). Solar UVR exposure, in particular ultraviolet B (UVB), is the most significant environmental risk factor for the occurrence and progress of BCC. Both cumulative and intermittent high-grade UVR exposures could promote the uncontrolled replication of skin cells. Although, other risk factors for skin carcinogenesis exist, UVR exposure has still been attributed to the development of nearly 90% of NMSCs, such as squamous cell carcinoma (SCC) and BCC (13,14). DNA damage occurring during skin cancer formation is considered to be a result of UVR toxicity. UVR could activate a series of oncogenes while simultaneously inactivating tumor suppressor genes and aberrant proliferation and survival of keratinocytes that repair this damage. Furthermore, mounting evidence demonstrates that inflammatory responses of immune cells in the tumor microenvironment play a pivotal role in skin tumorigenesis (15). Therefore, environmental changes contributing to increased UV transmission have direct implications for human health. The public should be urged to use sunscreen and wear protective apparel to decrease BCC incidence.
In this review, we will assess the role of UVR in the onset and development of BCC. We describe the factors that influence BCC induced by UVR and review recent advances in BCC pathogenesis induced by UVR from genetic and inflammatory aspects. This is also a rare review to discuss the contributing factors associated with UVR-induced BCC and its specific pathogenesis. We searched associated studies using the following databases: Embase, Pubmed, Cochrane library, and Google Scholar. We conducted the literature by searching the Mesh terms denoting an exposure of interest ("UV rays, " "ultraviolet rays, " "UV radiation, " "ultraviolet radiation, " "UV, " "ultraviolet, " "environments, " "environmental impact, " and "environmental impacts") and an outcome of interest ("basal cell carcinoma/cancer"). All studies included are published until December 30, 2020 with no language restrictions.

THE FACTORS CONTRIBUTING TO UVR-INDUCED BCC
The occurrence and development of BCC mainly depend on the interaction between general characteristics, such as genotypic and phenotypic features and subsequent environmental risk factor exposure. Therefore, as a primary risk factor, UVR could be combined with or influenced by other factors, such as general characteristics, UVR sources (such as sun exposure, tanning beds, and ultraviolet phototherapy), and other environmental factors (such as alcohol consumption, long-term chemical exposure, and photosensitive agents) to induce the onset of BCC.

GENERAL CHARACTERISTICS
The primary risk factor associated with BCC onset is directly related to the sun exposure habits of an individual or susceptibility to solar UVR (16). The result of a cross-sectional prevalence survey of white male watermen (n = 808) establishes the relationship between UVB exposure and BCC, SCC, and actinic keratosis (AK). It demonstrated that older age, childlike freckles, and blue eyes significantly enhanced the risk of skin tumors (17). In a prospective cohort, van Dam et al. (18) investigated the association of constitutional factors and sun exposure in BCC onset and development. They identified individuals with red hair, lightly pigmented eyes, northern European ancestry, and a predisposition to sunburn as likely to develop BCC. Another retrospective cohort study also revealed that multiple BCCs tended to be formed in the elderly and men. Patients with a history of BCC, type 1 or 2 skin, and chronic sun exposure (N500 weeks of sun exposure, a high photoaging score, and the presence of AK) have an increased risk of BCC (19). Several previous studies have demonstrated that obesity might decrease the risk of NMSC incidence (20)(21)(22), Chan et al. (23) designed a study to investigate whether the risk of NMSC of different weight levels is consistent with sun exposure risk. The results indicated that women with a BMI ≥ 25 kg/m 2 or a WHR ≥.8 have a lower risk of NMSC. However, the influence of interactions with sun exposure should also be considered. This is because compared with the normal-weight group, hazard rates of the overweight group are higher when combined with increasing sun exposure time. Although, light exposure site is a common site for the development of BCC, it is not primarily associated with UV exposure. The simple theory that "More UV exposure, More skin cancer" could not perfectly explain the occurrence pattern of BCC. Heckmann et al. (24) investigated the correlation between anatomical prominences with peak UV exposure and frequencies and distinct histologic features of BCC. They found that the development of facial BCCs is poorly associated with the accumulative effects of UVR alone. Additionally, site-specific qualities, such as reduced tension and dermal thickness, could combine with UV exposure to promote the development of BCC. Additionally, there is no correlation between UV-exposed carcinoma and particular histologic features.

SOURCES OF UVR
Undoubtedly, sun exposure is the primary source of UVR associated with BCC onset. Artificial UVR exposure, namely, tanning beds, ultraviolet phototherapy, and arc welding has recently been reported to have a strong relationship with BCC onset.

SUN EXPOSURE
The result of a population-based, case-control study indicates that recreational sun exposure of children and adolescents increases risk, demonstrating that these life cycle stages are crucial to establishing the risk of developing BCC (25). The BCC risk is likely to depend on the nature and characteristics of sun exposure, such as pattern, timing, and amount. Previous studies have demonstrated that compared with cumulative, long-term UV exposure, intense intermittent exposure increases the risk of BCC (26,27). Despite that, Iannacone et al. (28) studied the significance of sun exposure patterns (intermittent or continuous) and timing (childhood or adulthood) in BCC. Results suggested that sun exposure was associated with both the risk of BCC incidence regardless of the exposure pattern (intermittent or continuous). Therefore, the relationship between sun exposure pattern and BCC risk is still unproven and requires further research. UVR exposure dosage is positively linked with BCC risk, but after a certain amount of exposure, this effect level decreases or even disappears (29). Additionally, geographic variation is positively correlated with the incidence of BCC. The relationship between the incidence rate and proximity to the equator could be explained by higher UV exposure at lower latitudes, such as Hawaii, and higher UV exposure in higher latitudes, such as the Midwest (30,31).

INDOOR TANNING
Indoor tanning first appeared in Western countries in the 1920's. Recently, this tanning trend has also become more prevalent among young people in China and other Asian countries who traditionally preferred lighter skin tones. Additionally, tanning services have increased, and online shops have begun to sell tanning products, such as tanning beds and tanning lamps. Indoor tanning equipment emits artificial UVR, which is one of the causes of skin cancer. Indoor tanning is also strongly correlated with BCCs of the trunk and extremities mainly exposed during tanning compared with head/neck lesions, which are only occasionally exposed to UVR to a considerable extent. The use of tanning beds has been correlated with an apparent increase in the development of NMSC (particularly early in life) (32,33). A large case-control study revealed that indoor tanning was correlated with a 69% increase in the risk of early-onset BCC, and this was more evident in women, multiple BCCs, and BCCs located on the trunk and extremities. Previous studies have predicted that if individuals never tanned indoors, about a quarter of early-onset BCCs (or 43% in women) could be prevented (34). Several other studies also proved that indoor tanning is correlated with the incidence risk of early-onset BCCs (35). Compared with tanning bed use at the age of 25-35, the risk of BCC from using tanning beds during high school/college is significantly higher. There is also a dose-response link between sunbed use and the risk of skin cancers, particularly for BCC, and this relationship is more robust for younger patients exposed to sunbathing (36). Moreover, a meta-analysis showed that the relative risk of BCC development after indoor tanning before 25 years old was 1.4 (95% CI = 1.29-1.52). Compared with the control group, this translates to a 40% increase in risk. Studies have concluded that this risk will increase in a dose-dependent pattern with indoor tanning equipment usage (years) (37).

ULTRAVIOLET PHOTOTHERAPY
Psoralen and ultraviolet A (PUVA) therapy and UVB therapy are both highly effective treatments for chronic cutaneous inflammatory diseases, in particular psoriasis. The BCC incidence related to ultraviolet phototherapy could be controversial. Previous studies have demonstrated that the BCC incidence rate among patients with psoriasis receiving a large number (>100-200) of PUVA treatments is significantly higher than expected, and this risk persists for some time after the discontinuation of PUVA therapy (38,39). However, Stern et al. (40) suggested that substantial PUVA exposure only increases the risk of SCC, and even high-dose exposure to PUVA does not significantly increase BCC risk. Compared with the PUVA therapy, UVB (>300 treatments) is reported to be correlated with modest increases in the risk of developing BCC (41). However, the function of broadband UVB or narrowband UVB therapy in human skin carcinogenesis in psoriasis has not been clarified clearly (42,43). A retrospective study showed that 80% of the statistical power in broadband UVB could detect six to seven times the increase in skin cancer, while in narrowband UVB, 83% of statistical power can detect five to six times the increase in skin cancer, and only one patient developed melanoma in situ. In this study, the tumor occurred within a year of phototherapy initiation. Hearn et al. (44) found no existing evident correlation between NB-UVB treatment and the incidence risk of BCC. Therefore, current studies do not offer strong evidence for increased BCC risk for patients treated with broadband and narrowband UVB phototherapy (45). Nevertheless, the concomitant potential risk of BCC should be considered when determining the risk of the therapy for long-term treatment of PUVA and UVB associated with the treatment for chronic inflammatory skin diseases (such as severe psoriasis).

ARC WELDING
Arc welding produces the full UVR spectrum, which may be a contributing cause of cutaneous cancer (46). Several case reports have reported the onset of BCC after several years of arc welding. Currie and Monk (47) reported five welders suffering from NMSC (average age of onset of 52 years). Three other case reports described welders developing BCC after exposure during unprotected arc welding (48). A study was conducted with a 25-year duration of systematic follow-up and eventually showed that long-term metal arc welding exposure might be associated with an increased BCC risk located exclusively at the neck. However, it could not provide evidence for the assumption that welding exposure enhances the risk in other locations (49).

OTHER ENVIRONMENTAL FACTORS
Although, UVR is the primary risk factor of BCC, recent evidence suggests that a small amount of UV exposure combined with other behavioral and/or environmental factors may lead to a higher incidence of BCC (50)(51)(52).

ALCOHOL CONSUMPTION
Alcohol consumption is a well-known risk factor associated with various malignant tumors, namely, pharynx and larynx, esophagus, breast, prostate, pancreatic, and colon cancers (53)(54)(55)(56). It has been observed that alcohol use can increase the prevalence of severe sunburn. It is hypothesized that the combination of alcohol consumption and UVR can enhance carcinogenicity in the skin via intermediate by-products or metabolites of alcohol (such as acetaldehyde), which can act as photosensitizers (57,58). However, the association between alcohol consumption and the risk of developing BCC has been controversial. Although, two previous studies have reported a correlation between alcohol consumption and BCC risk, a subsequent study and several case-control studies did not show evident association (59)(60)(61). The result of a large prospective study conducted by Wu et al. has demonstrated that alcohol consumption is associated with an increased risk of BCC in both women and men. According to the result of a case-control study, alcohol consumption is generally associated with aggressive tumors. This may result from the modulation of the peritumoral micro-environment associated with alcohol consumption, which may be considered a contributing factor to the progression and malignant behavior of tumor cells.

CITRUS PRODUCTS
Furocoumarins, a group of natural chemicals that are abundant in citrus products, have relatively high UV absorbance. Two large prospective cohort studies reported positive dose-response relationships between citrus consumption and the risk of BCC in two cohorts of men and women. Also, it is suggested that UVR could amply this association between the citrus consumption and the risk of BCC (62). In the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) cohort study, Mahamat-Saleh et al. (63) also found that total citrus intake was associated with BCC risk. Specifically, they found that citrus juice intake was positively and linearly associated with BCC and mutagenic properties.

COFFEE INTAKE
Coffee intake has been demonstrated to have an anticarcinogenic potential in skin carcinogenesis. There is considerable and convincing experimental evidence that caffeine, which occurs naturally in seeds of the coffee plant, may have anti-proliferative effect via inducing apoptosis in UV-damaged keratinocytes via multiple pathways, such as the ataxia-telangiectasia and Rad3related (ATR) kinase/ checkpoint kinase 1 (Chk1) pathway (64,65). A review of the literature and meta-analysis conducted by Caini et al. (66) found that caffeinated coffee intake is moderately associated with a reduced risk of BCC development. However, the judgments on the strength of the evidence from the WCRF (World Cancer Research Fund International) regarding the influence of coffee on the BCC risk is evaluated to be limited suggestive. Increasing the number of randomized clinical trials is needed to verify the relationship.

VITAMIN D
Vitamin D has multiple functions for the human body via binding to vitamin D receptor (VDR) associated with cell growth, differentiation, apoptosis, and regulation of the immune system (67). Solar exposure is the major source of 25-hydroxyvitamin D3 (25-OH D3) synthesis. Vitamin D is known to have a protective effect against colon, breast, prostate cancers, and even NMSCs. It has been clarified that non-genomic pathways activated by vitamin D may have a protective role against DNA damage, which may contribute to the development of NMSCs (68). Ince et al. (69) found that maintaining the levels of 25-OH vitamin D3 more than 25 ng/ml in patients with an initial diagnosis of BCC can significantly decrease the recurrence rate. It could be a contradiction in terms that UV exposure has been recognized to be the predisposing factor of BCC. They think that patients with BCC should avoid sun exposure in the areas of high risk, but may expose other body areas without BCC during daylight for 10-15 min. The specific relationship between vitamin D and UV exposure in the development of BCC requests a long process of research.

LONG-TERM CHEMICAL EXPOSURE
Arsenic is a non-metallic element that occurs naturally in air, soil, and water in organic and inorganic states. The organic state is non-toxic, while the inorganic state is toxic. Arsenic exposure elicits oxidative stress that causes DNA damage, genome instability, and telomere shortening (70)(71)(72). Epidemiological studies have shown that long-term exposure to arsenic increases cancer risk, such as bladder, lung, and kidney cancer (73,74). Moreover, arsenic exposure has been widely involved in NMSC, and the strongest evidence comes from studies on people who drink highly polluted water (75,76). Surdu et al. (77) conducted a study to evaluate airborne arsenic exposures at the workplace and quantify the relationship with NMSC. Eventually, they found no association between workplace exposure to arsenic and NMSC. However, it was suggested that women exposed to arsenic in the air with co-exposure to sunlight at work might be more susceptible to NMSC than those who are not exposed to the sun. In another multi-center case-control study, Srinivas et al. (78) observed that contrary to consistent reports about the association between increased telomere length and rising incidence risk of different cancers, among people exposed to arsenic, short telomeres are correlated with increased risk of BCC. Data analysis also showed that arsenic exposure could regulate the direction of the telomere length effect.
Radon is a type of radioisotope with a half-life of 3.8 days. Radon-222 gas originates from the radioactive decay of radium-226 and is present over the crust of the Earth and many building materials. The primary source of radon in buildings is the gas released from the ground, which enters a house through cracks in the basement. Radon gas accumulates indoors. The skin and lungs are both known to be the primary target organs.
Radon progeny exposure can result from alpha emitters, such as polonium-218 and polonium-214, which are classified as human carcinogens. The evidence of a link between radon and lung cancer risk is derived from studies on miners exposed to relatively high concentrations and exposure of the general population to radon indoors (79)(80)(81)(82).
A large cohort study on a Danish population showed that long-term residential exposure might result in skin BCC development through detailed personal exposure assessment and control of several potential confounding factors. Investigators could not rule out confounding from sunlight exposure, nor could they conclude causality, because the correlation is stronger among people residing in apartments but not among those residing in single houses (83).

PHOTOSENSITIVE AGENTS
The usage of photosensitizing medications has been identified to reduce UVR exposure that is likely to generate a sunburn-like erythema response, enhancing the risk of phototoxicity (84)(85)(86). A study (87) was conducted to assess the relationship between diuretic use and primary BCC, considering the history of sun exposure, constitutional characteristics, lifestyle factors, and geographically dispersed anthropometric measurements of individuals extensively exposed to ambient UVR. They found that among overweight participants, increased risk of BCC associated with diuretic use may be related to higher dosages, more extended periods of medication, decreased drug metabolism, or drug interaction. Tetracycline is a classical drug known to elicit photosensitivity, particularly phototoxic cutaneous disorders, and increase the susceptibility of the epidermis and dermis to UVR-induced damage. A prospective study demonstrated that tetracycline use is related to a mildly increased BCC risk but not to melanoma or SCC (88). Furocoumarins are natural chemicals that are abundant in certain plants, consisting of citrus products (89,90). Animal model studies have shown the photocarcinogenic characteristics of furocoumarins (91). Wu et al. (62) designed a study to investigate the association between citrus consumption and BCC and SCC incidence risk. They found a positive correlation between BCC and SCC in two groups of men and women and called for studies to further understand the potential photocarcinogenesis related to dietary intake.

THE PATHOGENESIS OF UVR-INDUCED BCC
Skin cancers caused by DNA damage are considered to be a direct result of UVR toxicity. UVR exposure can activate various oncogenes while inactivating tumor suppressor genes, leading to gene mutations, which induces the survival, and proliferation of keratinocytes, thereby, repairing this damage. Furthermore, increasing evidence shows that inflammatory responses of immune cells within a tumor microenvironment also significantly promote the onset of skin cancers.

GENETIC MUTATIONS
Ultraviolet radiation exposure, particularly UVB, to some degree, could induce different categories of DNA damage, including cyclobutene pyrimidine dimers (CPD) and 6-4 photoproducts (6-4 PP), DNA strand breaks, and crosslinks. If not repaired entirely, this could transform into genetic mutations, ultimately resulting in skin carcinogenesis (92,93). Here, we focus on some recently discovered genetic mutations involved in the onset and development of UVR-induced BCC.

THE HEDGEHOG PATHWAY-ASSOCIATED GENES
As a highly conserved developmental pathway, the Hedgehog (Hh) pathway is responsible for various processes, such as organogenesis, stem cell maintenance, tissue repair, and regeneration (94). The Hh pathway is crucial for maintaining stem cell numbers and regulating hair follicle and sebaceous gland development in the skin. Abnormal activation of the Hh pathway induces various periods of tumorigenesis, such as onset, development, and recurrence (95,96). The pathway could be separated into two categories, the canonical and non-canonical Hh pathways. The former includes some crucial components, consisting of Hh ligands as sonic Hh, Indian Hh, and Desert Hh; transmembrane receptor proteins PTCH1 and PTCH2, the G protein-coupled receptor-like protein SMO, and the GLI transcription factors 1, 2, and 3 (GLI1, GLI2, andGLI3) (97). When the Hh ligands bind to PTCH1, the pathway is activated, thereby, releasing PTCH-mediated SMO suppression of the primary cilium. SMO is in turn transported to the cilium, driving a signaling cascade and inducing the release of the GLI proteins, which are sequestered in the cytoplasm by several proteins, such as the suppressor of fused (SUFU). Then, GLI transcription factors enter the nucleus, activate the transcription of contextspecific genes, and regulate self-renewal, cell fate, survival, and angiogenesis. Additionally, a feedback loop to automatically adjust the Hh signaling GLI1 has also been established to regulate the Hh signaling via PTCH1 modulation automatically (94,98). Any level of genetic mutations in the Hh signaling pathway, such as PTCH1, SMO, and SUFU, will develop an increased expression of GLI1 (99). In BCC, upregulation of Hh signaling is proved to be the most significant pathogenic event (99,100). Over 90% of BCCs have a deficiency of PTCH1 function by inactivating PTCH1 mutations and aberrant activation of SMO (101).
The PTCH1 gene is mapped to 9q22.3, composed of 23 exons with a length of about 74 kb, encoding a 1,447 transmembrane glycoprotein (102). Somatic mutations of PTCH1 range from 11-75%, which are mainly nonsense and splice site mutations through the entire length of the PTCH1 gene, and there is no evidence of hot spot (103)(104)(105). About half of these mutations include the "UV-signature" C-T and tandem CC-TT transitions (106). However, the UVR source of PTCH1 mutations is controversial, and other factors, such as oxidative stress, have been involved in the gene mutation (107, 108).
Ten to twenty percent of sporadic BCCs have the activating SMO mutations mainly manifested as missense mutations affecting codon 535 (109,110). Functional studies of the W535L mutant showed that it is a constitutively active variant whose fundamental Hh activity is enhanced in the absence of a Hh ligand. Recent studies indicated that up to 8% of BCCs have dysfunctional SUFU mutations, such as both missense and nonsense mutations. This disrupts their binding to GLI, thereby, resulting in the activation of the constitutive pathway. Urman et al. reported a higher frequency of SUFU mutations (111), even though they are conceived to be a type of passenger mutation. Eventually, the homolog PTCH2 gene has been muted in few sporadic BCCs, with 57% similarity to PTCH1 and acting as a receptor (112,113).

TP53
The second most common event related to the development of BCC is TP53 gene inactivation. As a type of tumor suppressor gene, it participated in the activation of cell cycle arrest and programmed cell death. As the genome's guardian, TP53 is stabilized by phosphorylation under pressure and alters the different downstream target gene expression categories, such as those that elicit cell cycle arrest (114). The inactivating TP53 genetic alterations are detected among almost all skin carcinomas, considered to be an early event in skin carcinogenesis (115,116). Most TP53 missense substitutions are located at the central DNA-binding core region (codons 102-292), including codons 177, 196, 245, 248, 278, and 282, which generate full-length protein function in skin cancers. Most of the TP53 mutations in BCC are transition from C to T, and the frequency of double base changes from CC to TT is relatively high, which indicates alterations induced by UVR. Individuals who wear sunscreen have fewer TP53 mutations in BCCs compared with people who do not wear sunscreen (117).

TERT
The TERT gene can maintain the length of telomere via encoding the catalytic reverse transcriptase subunit of telomerase. Increased telomerase activity is known to be one of the primary characteristics of human cancers, and the transcriptional mediation of the TERT gene is the main cause for its cancerspecific activation (118).
The TERT gene is located at chromosome 5p15.33. Its promoter region is considered to be the essential regulatory component of telomerase expression. TERT promoter mutations are frequently detected in various cancers such as skin and glioma (119,120). They have been associated with increased TERT expression by recreating the binding sites for ETS/TCF transcription factors, higher telomere length, and poor prognostic factors. The fact that they are driving events in cancer development rather than passenger events is supported by the high recurrence, specificity, and functional acquisition of non-coding promoter TERT mutations. Several recent studies have investigated the role of the TERT promoter in BCCs and identified a high incidence of mutations. Most of these mutations have a UV-signature with C to T or CC to TT changes, which favors an etiologic role for UVR exposure (120)(121)(122).

DPH3-OXNAD1 BIDIRECTIONAL PROMOTER
Similar to the TERT gene, it is reported that in the bidirectional promoter of both DPH3 and oxidoreductase NAD-binding domain containing 1 (OXNAD1) genes, recurrent mutations of non-coding sites close to the transcription start site are often present. DPH3, essential to the synthesis of diphthamide, is a modified histidine residue in the eukaryotic translation elongation factor 2, which helps keep the fidelity of translation. The silencing of DPH3 can damage the in vivo deterioration of mouse melanoma cells. Its family member DPH1 is also considered a tumor suppressor, necessary for the synthesis of diphthamide (123). Typical UVR mutations in the region of the DPH3 promoter were recently shown to be ubiquitous in BCC (42%) (124). The adjacent site and binding motif of the ETS /TCF transcription factor were mutated at−8 and−9 bp of the DPH3 transcription start site.

ULTRAVIOLET RADIATION-INDUCED INFLAMMATORY RESPONSES
Chronic inflammation participates significantly in all three periods necessary for BCC development, namely, initiation, promotion, and progression. The inflammatory responses induced by UVR contribute to increased blood flow and vascular permeability, leading to edematous erythema, thickening response, and cyclooxygenase-2 (COX-2) and prostaglandin (PG) metabolite activation. Inflammation recruits many leukocytes that secrete various pro-inflammatory cytokines at the UV-irradiated site and are considered necessary in the onset of the tumor. Additionally, various animal models and the effective use of anti-inflammatory chemotherapy agents all underline the significance of inflammation induced by UVR exposure in the onset and development of BCC (125)(126)(127).

NUCLEAR FACTOR-KAPPA B
Nuclear factor-kappa B (NF-kB), expressed in almost all types of cells, is a dimeric transcription factor that includes p50 and p65 Rel family proteins (128). Notably, it also functions in inflammatory response and cell proliferation, which are both associated with tumor onset. It is demonstrated that the constitutive expression of NF-kB is upregulated in a variety of tumor cells (129)(130)(131). UVR promotes the activation of IKKa, phosphorylation, and degradation of IkBa in epidermal keratinocytes. Interestingly, UVB sequentially mediates the activities of different subunits of NF-kB. NF-kB/p50 is downregulated in the early stage (6 h), and NF-kB/p65 is downregulated in the later stage (12 h) (132). Thus, UVB exposure is suggested to activate NF-kB, in turn leading to skin carcinogenesis. Weng et al. (133) found that NF-kB p65 might promote the highly aggressive type of BCC. It contributes to diagnosing malignant epidermal tumors, combined with TLR4 detection on epithelial cell membranes and p65 in epithelial cell nuclei. Tong and Wu (134) reported that activation of cNOS leads to the activation of NF-kB after UVB exposure. Continuous, rather than acute, suppression of IkB reduction and subsequent NF-kB activation is induced by the inhibition of cNOS.

HIGH-MOBILITY GROUP BOX-1
High-mobility group box-1 is released into the cytoplasm and, in turn, extracellular matrix by interacting with the Toll-like receptors (TLRs) or receptor of advanced glycation end products (RAGE) to stimulate an inflammatory response. Recently Johnson and Wulff revealed that UVR induced the release of HMGB1 from in vitro keratinocytes, which is likely to be expressed in cutaneous tumors after recurrent and longterm exposure to UVR (134,135). Similar to NF-kB, HMGB1 released by necrotic tumor cells was significantly expressed extracellularly in BCC. It is suggested that HMGB1 could be considered a potential prognostic indicator or treatment target for BCC treatment (136).

TOLL-LIKE RECEPTORS
Toll-like receptors are expressed on various skin cells, such as keratinocytes and epidermis Langerhans cells, and function as a primary group of pattern recognition receptors activating skin immune responses (137). They mediate the pathogens and inflammatory response induced by potential endogenous molecules. Recent studies demonstrate that TLR activation contributes to the upregulation of host defense mechanisms and the upregulation of DNA repair genes, and increased functional DNA repair, thereby, providing an association between inflammatory response and DNA damage. DNA damage and repair induced by UVB radiation have been shown to involve TLR2, 3, 4, 7, 8, and 9 molecules. TLR7 is located in the endosome membrane and is highly expressed in BCC (138). Imiquimod, a kind of TLR7 agonist, is being extensively used topically nowadays to treat BCC (139). The results of animal research indicate that the mechanism of action for imiquimod is to enhance the expression of DNA repair genes and perform the functional repair of the DNA damage mechanism (140).

ERBB2
As a proto-oncogene, Erbb2 (human epithelial growth factor receptor 2 (HER2)/neu) is activated in different types of cancer, related to invasive and treatment-resistant characteristics, which UVR exposure can activate. The expression of Erbb2 is located at both follicular and epidermal keratinocytes and acts in various crucial roles, such as regulating cell migration, differentiation, adhesion, inflammation, and angiogenesis after UVR exposure (141,142). Suppression or deletion of Erbb2 inhibits cell proliferation, cell survival, and inflammation induced by UV. Recently, Rao et al. (143) indicated that it could accelerate skin carcinogenesis through the upregulation of ADAM12 (Disintegrin and metalloproteinase domain-containing protein 12). This demonstrated a new mechanism where the metastasis of UVR-induced BCC resulted from Erbb2.

NLRP3
Nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome is significant in innate immune responses by activating caspase-1 that contributes to the activation of pro-inflammatory cytokines, such as IL-1β and IL-18 (144)(145)(146). Ahmad et al. (147) indicated that NLRP3 is found to be expressed in cells of human BCCs and is involved in the inflammatory response of BCC. In comparison, UVB exposure can inhibit Ca 2+ mobilization by downregulating the expression of sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA2), which contributes to activation of the NLRP3 inflammasome.

CYCLOOXYGENASES
Increasing evidence demonstrates that COX are likely to participate in the formation of NMSC. It is known that COX mainly includes two isoforms, COX-1 and COX-2. Most cell types have a constitutive expression of COX-1, while various factors elicit the COX-2 expression. UVR exposure has been shown to enhance the expression of COX-2 in human skin. Furthermore, COX-1 and COX-2 are both demonstrated to have a role in BCC progression. Various pathways, such as AKT, p38, AMPK, and SIRT6, have been shown to regulate COX-2 associated with UVB (148,149). Previous studies have shown that skin carcinogenesis is reduced by the suppression of p38a, AKT, and SIRT6, or activating AMPK (150)(151)(152)(153).
Moreover, blocking the COX-2 expression may inhibit NMSC and is considered a functional chemopreventive agent for BCCs. However, it has been proved by animal studies that both selective COX-2 inhibitors like celecoxib and non-selective COX inhibitors (such as indomethacin and naproxen) can be regarded as effective agents to suppress BCCs induced by UVR (154-157).

INTERLEUKIN-12
As a pleiotropic cytokine that participates in the inflammatory process, IL-12 consists of two subunits (p35 and p40), which have an antitumor function in various tumor models (158). It possesses an antitumor effect via repairing UVR-induced DNA damage in the form of cyclobutene pyrimidine dimmers (159)(160)(161). Meeran et al. (162) investigated the mechanism of antitumor activity of IL-12. They found that IL-12 deletion contributed to increased COX-2 expression and production of PGE2, along with upregulated inflammatory cytokines such as IL-1β, TNF-a, and IL-6. Infiltration of leukocytes, NF-kB activation, and cyclin D expression are induced via recombinant IL-12 before UVR exposure, confirming the function of IL-12 in the suppression of UVR-induced BCC.

CONCLUSIONS
The incidence of BCC increases with age, while the etiology and mechanism of this disease are still not well-known. Its early diagnosis is difficult and often delayed. Furthermore, BCC rarely invades, metastasizes, or leads to death but contributes to widespread morbidity via tissue damage and local infiltration. Therefore, investigating the possible risk factors and the pathogenic mechanism is a worthwhile endeavor. As the primary risk factor in the etiology of BCC, excessive UVR exposure plays a crucial role in tumor-related gene mutation, microenvironment changes, and immune system disorders. The incidence of BCC induced by UVR is also influenced by several other factors, such as general characteristics, source of UVR, and other associated environmental factors. Additionally, an excessive amount of UVR exposure directly or indirectly induced DNA damage of the skin, contributing to mutations of an associated group of proto-oncogenes and tumor suppressor genes and alterations in the inflammation response, eventually leading to the onset and development of BCC. However, the understanding of UV-induced BCC is not comprehensive and complete. The association with its tumor-related genes, immune regulation, and inflammation response need to be further investigated to offer more effective and selective immunomodulatory strategies for patients with BCC that occurs in exposed areas.

AUTHOR CONTRIBUTIONS
YF: study concepts. XT and YT: study design. SL and YY: literature research. YT: manuscript preparation. YH: manuscript defnition of intellectual content. YT and DX: manuscript editing. XT: manuscript revision/review. YF: manuscript final version approval. All authors contributed to the article and approved the submitted version.