UV-induced DNA damage, repair, mutations and oncogenic pathways in skin cancer

https://doi.org/10.1016/S1011-1344(01)00199-3Get rights and content

Abstract

Repair of UV induced DNA damage is of key importance to UV-induced skin carcinogenesis. Specific signal transduction pathways that regulate cell cycling, differentiation and apoptosis are found to be corrupted in skin cancers, e.g., the epidermal growth-stimulating Hedgehog pathway in basal cell carcinomas (BCCs). Mutations in genes coding for proteins in these pathways lead to persistent disturbances that are passed along to daughter cells, e.g., mutations in the gene for the Patched (PTCH) protein in the Hedgehog pathway. Thus far only the point mutations in the P53 gene from squamous cell carcinomas and BCCs, and in PTCH gene from BCC of xeroderma pigmentosum (XP) patients appear to be unambiguously attributable to solar UV radiation. Solar UVB radiation is most effective in causing these point mutations. Other forms of UV-induced genetic changes (e.g., deletions) may, however, contribute to skin carcinogenesis with different wavelength dependencies.

Introduction

Proper physiological balances (‘homeostasis’) are maintained in tissues and among cells in circulation. To this end, normal cells function under the control of their environment and cancer is basically a disease of cells whose growth and function is ‘out of control’. Cells communicate through signal transduction pathways in which cascades of chemical interactions ultimately lead to the activation or de-activation of certain cellular processes. These signaling pathways run between and within cells. Internal cellular signaling pathways exist for further control of functioning of individual cells. Cell proliferation and terminal differentiation are regulated by such internal and external signaling pathways, and cancer appears to result from disturbances in a combination of growth-controlling pathways. The cells lose their original confinement and invade and disrupt surrounding tissues. Six essential alterations in cell physiology have recently been proposed that collectively dictate malignant growth: selfsuffiency in growth signals (‘anchorage free growth’ in vitro), insensitivity to growth-inhibitory signals, evasion of programmed cell death (apoptosis), limitless replicative potential (‘immortalization’), sustained angiogenesis, and tissue invasion and metastasis [1].

Many environmental factors may affect signaling pathways, and many are meant to in order to invoke proper cellular responses. Toxic agents may, however, adversely disturb growth-controlling pathways. The damage to proteins involved in the signal transduction will usually only have a temporary effect as proteins are broken down and synthesized in continuous renewal. Even damage to the mRNA from which the proteins are translated will have a temporary effect because the mRNA is also renewed. If these ‘epi-genetic’ interferences occur repeatedly, they may noticeably enhance or inhibit carcinogenic progression (i.e., the agent may act as a ‘promotor’ or ‘anti-carcinogen’, respectively).

A permanent disturbance in a signaling pathway may be introduced by damaging a gene that codes for a protein in the pathway. If the damage leads to an altered genetic code (mutation) or a complete loss of the gene, the altered protein or its complete absence can obviously corrupt the signal transduction pathway of a cell (an agent which causes these permanent oncogenic changes could be considered as a classical ‘initiator’). This genetic defect will be passed along to daughter cells, and thus the corresponding defect in signal transduction will propagate. There are two categories of genes with direct relevance to cancer: oncogenes whose proteins contribute to cancer formation through a dominant gain of function, and tumor suppressor genes whose proteins suppress carcinogenic progression. The latter enable cancer growth through a recessive loss of function. Viruses can introduce their own oncogenes into a cell, or genes that encode proteins capable to de-activate tumor suppressor proteins. In addition to the genetic (mutational) mechanisms as described, more recently epigenetic mechanisms, exemplified by promoter hypermethylation, have been demonstrated to contribute significantly to the gene inactivation [2].

UV radiation is a very prominent environmental toxic agent, but it does not penetrate the human body any deeper than the skin. Conjugated bonds in organic molecules absorb shortwave UV radiation around 200 nm, but in linear repeats or in ring structures the absorption shifts to longer wavelengths [3] up to and over 300 nm, i.e., in the range of the solar spectrum at ground level [4]. Proteins which contain tryptophan or tyrosine can therefore absorb solar UV radiation and start up (photo-) chemical reactions. Thus, UV exposure may cause (‘epigenetic’) disturbances in signaling pathways.

The bases in DNA all contain ring structures with an abundance of conjugated bonds, which makes DNA a very prominent absorber of UV radiation in cells. Genes in cells are, therefore, easily damaged upon UV irradiation, and mutations may subsequently occur. This implies that human skin exposed to sunlight is under continuous threat of accumulating oncogenic damage. Skin cancers are not readily induced and mainly occur at old ages, which attests to an impressive adaptation of the human skin to this continuous environmental stress.

Section snippets

Three types of skin cancers

Skin cancer is a very common form of cancer among white Caucasians, and by far the most frequent form in white Caucasians living in tropical and subtropical areas: e.g., in the USA over 30% of cancer cases concern skin cancer, with more than 1 million cases per year [5]. The three main types are basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs) and cutaneous melanomas (CMs). All these types show a north–south gradient over the USA, i.e., a positive correlation with ambient UV

UV-induced DNA damage, repair and genetical alterations

Sites of neighboring pyrimidine bases in a DNA strand are preferentially damaged by UVC, UVB and UVA2 radiations, forming dimers between these bases: either a cyclobutane pyrimidine dimer (CPD), a 6-4 photoproduct (6-4PP) or its Dewar form. A dominance of pyrimidine dimers is considered to be specific for shortwave UV radiation. Moreover, methylation of cytosine has been shown to strongly enhanced the formation of dimers at pyrimidine bases when cells are exposed to UVB light [8] and those

Archetypal UV mutations in P53 from BCC and SCC

The P53 tumor suppressor gene is found to be mutated in a majority of human cancers. The p53 protein is therefore an apparent cellular ‘Achilles’ heel’, it plays a pivotal role in several signaling pathways related to DNA damage and expression of oncogenes [25]. Nuclear p53 expression is elevated after UV irradiation, and following a genotoxic insult p53 is involved in cell cycle arrest (late G1 and G2/M), apoptosis and NER. In SCC and BCC the P53 gene appears to bear point mutations with the

Hedgehog and BCC

Patients with Gorlin syndrome, or basal cell nevus syndrome (BCNS), suffer from developmental abnormalities, internal cancers and multiple BCC. This genetic trait was traced to locus 9q22 and turned out to be carried by mutations in the Patched (PTCH) gene [40]. Next to frequent LOH at this locus, many sporadic – non-familial – BCC showed mutations in the (remaining) PTCH allele [41]: 12 out of 37 tumors in SSCP screening, and nine of these tumors showed LOH of PTCH. The SSCP was apparently not

INK4a and melanoma

Some familial cutaneous melanomas (CMs) are linked to markers on chromosome 9p21, which led to the positional cloning of the ‘multiple tumor suppressor’ (MTS1) gene [59]. The locus is designated CDKN2A in the human genome project. It is also named INK4a [60] after the original finding that its product p16INK4a becomes associated with cyclin dependent kinases upon transformation of human fibroblasts by SV40 virus [61], and acts as an inhibitor of CDK4 and CDK6 [62]. CDK4 is thus prevented from

RTK mitogenic pathway and INK4a in CM

Another family of genes that is implicated in CM are the RAS oncogenes, more specifically N-RAS. 25–70% of CM from regularly sun-exposed sites have been reported to carry activating point mutations in N-RAS, whereas none of the CM from irregularly exposed sites carried such mutations [76], [77]. In a comparative study the percentage of N-RAS mutated CM from sun-exposed sites was higher in an Australian population (24%) than in a European population (12%) [76]. These mutations occur in the

Conclusions

Research is rapidly gaining ground in understanding DNA repair pathways and the signaling pathways, or rather signaling networks, that play a role in cancer. Generally, cancer appears to arise from disruption of signaling needed for normal cell proliferation and homeostasis: in SCC it is possibly an activated RTK/RAS pathway in combination with dysfunctional P53 tumor suppression, in BCC the HH pathway with possibly dysfunctional P53, and in CM again possibly an activated RTK/RAS in combination

Acknowledgments

The authors would like to thank the Dutch Cancer Society and the European Commission for the financial support of their research groups.

References (82)

  • H Fan et al.

    Induction of basal cell carinoma features in transgenic human keratinocytes expressing Sonic Hedgehog

    Nat. Med.

    (1997)
  • A.E Oro et al.

    Basal cell carcinomas in mice overexpressing sonic hedgehog

    Science

    (1997)
  • Y Xiong et al.

    Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation

    Genes Dev.

    (1993)
  • K.D Robertson et al.

    The human ARF cell cycle regulatory gene promotor is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53

    Mol. Cell Biol.

    (1998)
  • M.L Gonzalgo et al.

    Low frequency of p16/CDKN2A methylation in sporadic melanoma: comparative approaches from ethylation analysis of primary tumors

    Cancer Res.

    (1997)
  • J Wittbrodt et al.

    Novel putative receptor tyrosine kinase encoded by melanoma-inducing Tu locus in Xiphophorus

    Nature

    (1989)
  • R.P Feynman et al.
  • J JaggerJ Jagger
  • D Miller et al.

    Nonmelanoma skin cancer in the United States: incidence

    J. Am. Acad. Dermatol.

    (1994)
  • A Kricker et al.

    Does intermittent sun exposure cause basal cell carcinoma? A case-control study in Western Australia

    Int. J. Cancer

    (1995)
  • C.D.J Holman et al.

    Cutaneous malignant melanoma and indicators of total accumulated exposure to the sun: an analysis separating histogenic types

    J. Natl. Cancer Inst.

    (1984)
  • Y.H You et al.

    Similarities in sunlight-induced mutational spectra of CpG-methylated transgenes and the p53 gene in skin cancer point to an important role of 5-methylcytosine residues in solar UV mutagenesis

    J. Mol. Biol.

    (2001)
  • A de Vries et al.

    Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision gene XPA

    Nature

    (1995)
  • A.T Sands et al.

    High susceptibility to ultraviolet-induced carcinogenesis in mice lacking XPC

    Nature

    (1995)
  • C Masutani et al.

    The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta

    Nature

    (1999)
  • K Bebenek et al.

    Proofreading of DNA polymerase eta-dependent replication errors

    J. Biol. Chem.

    (2001)
  • G Ries et al.

    Elevated UV-B radiation reduces genome stability in plants

    Nature

    (2000)
  • D.E Brash et al.

    UV-induced ‘mutation hotspots’ occur at damage ‘hotspots’

    Nature

    (1982)
  • B Strauss et al.

    The role of DNA polymerase in base substitution mutatgenesis on non-instructional templates

    Biochimie

    (1982)
  • S Shibutani et al.

    Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxo-G

    Nature

    (1991)
  • E.A Drobetsky et al.

    A role for ultraviolet A in solar mutagenesis

    Proc. Natl. Acad. Sci. USA

    (1995)
  • V.I Poltev et al.

    The formation of mispairs by 8-oxo-guanine as a pathway of mutations induced by irradiation and oxygen radicals

    J. Mol. Recogn.

    (1990)
  • M Horiguchi et al.

    Molecular nature of ultraviolet B light-induced deletions in the murine epidermis

    Cancer Res.

    (2001)
  • R.A Keulers et al.

    The induction and analysis of micronuclei and cell killing by ultraviolet-B radiation

    Photochem. Photobiol.

    (1998)
  • G Emri et al.

    Low doses of UVB and UVA induce chromosomal aberrations in cultured human skin cells

    J. Invest. Dermatol.

    (2000)
  • D.E Brash et al.

    A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinomas

    Proc. Natl. Acad. Sci. USA

    (1991)
  • A.D Ziegler et al.

    Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers

    Proc. Natl. Acad. Sci. USA

    (1993)
  • S Kress et al.

    Carcinogen-specific mutational pattern in the p53 gene in ultraviolet B radiation-induced squamous cell carcinomas of mouse skin

    Cancer Res.

    (1992)
  • S Kanjilal et al.

    High frequency of p53 mutations in ultraviolet radiation-induced skin tumors: evidence for strand bias and tumor heterogeneity

    Cancer Res.

    (1993)
  • H.J van Kranen et al.

    Frequent p53 alterations but low incidences of ras mutations in UV-B induced skin tumors of hairless mice

    Carcinogenesis

    (1995)
  • N Dumaz et al.

    The role of UVB light in skin carcinomas through the analysis of p53 mutations in squamous cell carcinomas of hairless mice

    Carcinogenesis

    (1997)
  • Cited by (440)

    • Hydrogels for development of bioinks

      2023, Hydrogels for Tissue Engineering and Regenerative Medicine: From Fundamentals to Applications
    View all citing articles on Scopus
    View full text