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Chronic UVA Irradiation of Human Hacat Keratinocytes Induces Malignant Transformation Associated with Acquired Apoptotic Resistance

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Chronic UVA Irradiation of Human Hacat Keratinocytes Induces Malignant Transformation Associated with Acquired Apoptotic Resistance Oncogene (2006) 25, 3680–3688 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc ORIGINAL ARTICLE Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance Y-Y He1,JPi2, J-L Huang1, BA Diwan3, MP Waalkes2 and CF Chignell1 1Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; 2Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA and 3Basic Research Program, Science Applications International Corporation-Frederick, National Cancer Institute at Frederick, Frederick, MA, USA Ultraviolet A (UVA, 315–400 nm), constituting about Keywords: UVA; transformation; carcinogenesis; AKT; 95% of ultraviolet irradiation in natural sunlight, keratinocyte; PTEN represents a major environmental challenge to the skin and is clearly associated with human skin cancer. It has proven difficult to showdirect actions of UVA as a carcinogen in human cells. Here, we demonstrate that chronic UVA exposures at environmentally relevant doses Introduction in vitro can induce malignant transformation of human keratinocytes associated with acquired apoptotic resis- Ultraviolet (UV) radiation in sunlight is clearly an tance. As evidence of carcinogenic transformation, UVA- important environmental factor in human skin carcino- long-treated (24 J/cm2 once/week for 18 weeks) HaCaT genesis. Each year approximately one million new cases (ULTH) cells showed increased secretion of matrix of skin cancer are diagnosed in the United States alone, metalloproteinase (MMP-9), overexpression of keratin making it the most common type of cancer in this 13, altered morphology and anchorage-independent country. In animal models, UV radiation is a complete growth. Malignant transformation was established by carcinogen which can initiate and promote skin carci- the production of aggressive squamous cell carcinomas nogenesis resulting in squamous cell carcinoma (SCC), after inoculation of ULTH cells into nude mice (NCr-nu). basal cell carcinoma (BCC) and melanoma (de Gruijl ULTH cells were resistant to apoptosis induced not only et al., 1993; Setlow et al., 1993; Noonan et al., 2001). by UVA but also by UVB and arsenite, two other human UV radiation in sunlight is composed of Ultraviolet B skin carcinogens. ULTH cells also became resistant to (UVB 280–315 nm) and Ultraviolet A (UVA 315– apoptosis induced by etoposide, staurosporine and doxor- 400 nm). UVA has been considered far less carcinogenic ubicin hydrochloride. Elevated phosphorylation of protein based on limited direct damage to DNA (Setlow, 1974). kinase B (PKB, also called AKT) and reduced expression However, UVA is approximately 20-fold more abun- of phosphatase and tensin homologue deleted on chromo- dant than UVB in the sunlight and much more UVA some 10 (PTEN) were detected in ULTH cells. The penetrates the epidermis and reaches the basal germi- resistance of ULTH cells to UVA-induced apoptosis was native layers (Bruls et al., 1984). Recently, UVA was reversed by either inhibition of phosphatidylinositol shown to induce mutations in the basal layer of the skin 3-kinase (PI-3K) or adenovirus expression of PTEN or and UVA signature mutations have been detected in dominant negative AKT. These data indicate that UVA SCC and solar keratosis (Agar et al., 2004). Although has carcinogenic potential in human keratinocytes and UVA does induce mutations, mechanisms different from that the increased AKT signaling and decreased PTEN UVB may be involved (Dahle and Kvam, 2003). expression may contribute to this malignant transforma- Therefore, it is possible that UVA exposure may play tion. Further comparisons between the transformed a greater role in the development of human skin cancers ULTH and control cells should lead to a better under- than is generally assumed. It has been, however, difficult standing of the mechanism of UVA carcinogenesis and to convincingly show direct carcinogenic effects of UVA may help identify biomarkers for UVA-induced skin in vivo in human cells. malignancies. Apoptosis is a genetically programmed, morphologi- Oncogene (2006) 25, 3680–3688. doi:10.1038/sj.onc.1209384; cally distinct form of cell death that can be triggered by published online 8 May 2006 a variety of physiological and pathological stimuli. Apoptosis is characterized by cell rounding, membrane blebbing, cytoskeletal collapse, nuclear pyknosis, chro- Correspondence: Dr Y-Y He, LPC, NIEHS/NIH, 111 TW Alexander matin condensation/fragmentation and the formation Dr, POB 12233, MD F0-06, Research Triangle Park, NC 27709, USA. E-mail: [email protected] of membrane-bound apoptotic bodies (Kerr et al., 1972; Received 4 November 2005; revised 7 December 2005; accepted 7 Wyllie et al., 1980; Clarke, 1990). These bodies are December 2005; published online 8 May 2006 rapidly phagocytosed and digested by macrophages or Chronic UVA irradiation induces malignant transformation Y-Y He et al 3681 neighboring cells. Apoptotic cell death plays a key role a Control ULTH in eliminating damaged and/or potentially transformed cells. Disruption of apoptosis clearly contributes to the pathogenesis of cancer, and is a contributing factor in chemotherapeutic resistance observed in many human tumor cells (Thompson, 1995). Indeed, suppression of apoptosis is a consistent characteristic of tumors and malignantly transformed cells (Johnstone et al., 2002). In order to better define the role of UVA in human skin carcinogenesis, we studied the transforming poten- Control ULTH tial of chronic UVA exposure in HaCaT cells, a human b keratinocyte line. Accordingly, these UVA-long treated HaCaT (ULTH) cells showed clear signs of malignant transformation, including formation of aggressive SCC upon inoculation into nude mice. The ULTH cells became highly resistant to apoptosis induced not only by UVA, and but also by UVB, arsenite, etoposide, staurosporine and doxorubicin. Additional studies indicated that reduced phosphatase and tensin homo- logue deleted on chromosome 10 (PTEN) levels and increased protein kinase B (PKB also called AKT) signaling may be key events that mediate both c Control ULTH transformation and acquired apoptotic resistance. These data clearly demonstrate the carcinogenic potential of MMP-9 UVA in human skin cells. d 5 Control ULTH * Results 4 Chronic UVA treatment-induced malignant 3 transformation of normal human HaCaT keratinocytes In an attempt to achieve carcinogenic transformation, 2 normal HaCaT (control) cells were chronically exposed Relative Fold to UVA (24 J/cm2 once a week for 18 weeks). The UVA 1 treated cells, designated ULTH, were subsequently compared to passage-matched control HaCaT cells. 0 MMP-9 Anchorage-independent growth is common in tumor cells (Cox and Der, 1994). To determine if ULTH cells Figure 1 Chronic UVA exposure induced malignant transforma- tion of human HaCaT cells. (a) Anchorage-independent growth had acquired the ability for such growth, cells were assay. Control HaCaT (control) and ULTH cells were seeded at a seeded in soft agar, and colony formation was deter- density of 2 Â 104 in a 0.33% soft agar over a 0.5% agar bottom mined. The colony formation was common with ULTH layer. Colony was observed at 21 days. (b) Plasma membrane and cells (Figure 1a) and more than 800 colonies were nuclei of control and ULTH cells were stained with Image-iTt 4 LIVE Plasma Membrane and Nuclear Labeling Kit. Morphology formed from the initial 2 Â 10 ULTH cells. Thus of the cells was observed by using confocal microscopy. chronic UVA treatment induced anchorage-independent (c) Analysis of MMP-9 activity in control and ULTH in cell growth in ULTH cells. Control cells did not form conditioned medium by zymogram gel showing increased MMP-9 colonies. activity in ULTH conditioned medium. (d) Quantitative analysis of Morphological differences were observed between the zymography results. Data expressed as fold-control activity and are represented as means (n ¼ 3); bars, s.e.m.; *significant differences UVA-exposed and passage-matched control cells. Con- from the activity in control cells (Po0.05). trol cells exhibited epithelial-like morphology, with uniformity of cell size and shape (Figure 1b). However, in contrast, cells treated chronically with UVA showed a heterogeneous morphology characterized by the pre- control cells (Figure 1c). The activity of MMP-9 in sence of giant cells with multiple nuclei (Figure 1b), ULTH-conditioned medium was 4.0-fold higher than in possibly indicating genomic instability in ULTH cells. control cell medium (Figure 1d). The hypersecretion of MMPs, secreted enzymes that degrade the extra- this MMP is consistent with the aggressive nature of the cellular matrix, have been implicated in tumor cell inva- tumors derived from these cells (see below). MMP-9 sion and are commonly upregulated in cancer cells activation is commonly observed in SCC from various (Bernhard et al., 1990). Zymographic analysis revealed locations (Juarez et al., 1993; Borchers et al., 1997) and marked increases in secretion of active matrix metallo- indicates a potential role of UVA in both tumor proteinase-9 (MMP-9) from ULTH cells compared to promotion and progression. Oncogene Chronic UVA irradiation induces malignant transformation Y-Y He et al 3682 a Control ULTH C ULTH Keratin 13 Figure 3 Increased expression of
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