Abstract
The ultraviolet (UV) component of solar radiation is the major driving force of skin carcinogenesis. Most of studies on UV carcinogenesis actually focus on DNA damage while their proteome-damaging ability and its contribution to skin carcinogenesis have remained largely underexplored. A redox proteomic analysis of oxidized proteins in solar-induced neoplastic skin lesion and perilesional areas has been conducted showing that the protein oxidative burden mostly concerns a selected number of proteins participating to a defined set of functions, namely: chaperoning and stress response; protein folding/refolding and protein quality control; proteasomal function; DNA damage repair; protein- and vesicle-trafficking; cell architecture, adhesion/extra-cellular matrix (ECM) interaction; proliferation/oncosuppression; apoptosis/survival, all of them ultimately concurring either to structural damage repair or to damage detoxication and stress response. In peri-neoplastic areas the oxidative alterations are conducive to the persistence of genetic alterations, dysfunctional apoptosis surveillance, and a disrupted extracellular environment, thus creating the condition for transformant clones to establish, expand and progress. A comparatively lower burden of oxidative damage is observed in neoplastic areas. Such a finding can reflect an adaptive selection of best fitting clones to the sharply pro-oxidant neoplastic environment. In this context the DNA damage response appears severely perturbed, thus sustaining an increased genomic instability and an accelerated rate of neoplastic evolution. In conclusion UV radiation, in addition to being a cancer-initiating agent, can act, through protein oxidation, as a cancer-promoting agent and as an inducer of genomic instability concurring with the neoplastic progression of established lesions.
Highlights
Non-melanoma skin cancer (NMSC), because of its comparatively low invasion and metastatic activity, is commonly considered a rather benign condition
In a redox proteomic study on cervical neoplastic and pre-neoplastic lesions, we showed that elevated levels of carbonylation are associated with pre-neoplastic lesions and that carbonylation mostly affected proteins involved in cell morphogenesis and terminal differentiation and suggested that their deregulated function is a driving force in neoplastic progression [10]
To gain sound data about the very late state of proteome oxidation it is necessary to keep to a minimum the contribution of other concurring/confounding factors such as the p53 status and the possible infection with human papillomavirus (HPV)
Summary
Non-melanoma skin cancer (NMSC), because of its comparatively low invasion and metastatic activity, is commonly considered a rather benign condition. The prevention of cancer critically relies on the efficient coordinated actions of numerous proteins for appropriate DNA damage repair (DDR) as is strikingly emphasized by the case of Xeroderma Pigmentosum (XP) In this condition, inactivating mutations of genes encoding the NER proteins generate dysfunctional proteins causing a severe impairment of DNA repairing mechanisms and the consequent sharply increased risk of cancer development, mostly occurring in sun exposed areas [2]. In XP patients the UV radiation generates the same amount of DNA damage as in normal patients; because of inadequate protein function, the genetic lesions persist longer, increasing the chance for unrepaired DNA to undergo replication This generates mutations at an increased pace leading to cancer development. These authors report that in melanoma patients, upon UV irradiation the same amount of cyclobutane pyrimidine dimer (CPD)
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