Cutaneous manifestations of chronic arsenicism: Review of seventeen cases

Wong, Sai Siong; Tan, Kiang Hwee; Goh, Chee Leok

doi:10.1016/s0190-9622(98)70596-1

Cited by 133 publications

(98 citation statements)

References 27 publications

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“…Importantly, SCC can arise from arsenic-induced hyperkeratotic lesions [36], suggesting dysfunctional keratinization may be critical in arsenic-induced skin carcinogenesis. In the current study, As-TM cells were observed to exhibit dramatically increased expression levels of keratin-1, keratin-10, involucrin, and loricrin, major markers of squamous differentiation that play important roles in skin keratinization [37].…”

Section: Discussionmentioning

confidence: 99%

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Diwan

Sun

et al. 2008

Free Radical Biology and Medicine

160

147

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Arsenic is a well-known human skin carcinogen but the underlying mechanisms of carcinogenesis are unclear. Transcription factor Nrf2-mediated antioxidant response represents a critical cellular defense mechanism, and emerging data suggest that constitutive activation of Nrf2 contributes to malignant phenotype. In the present study when an immortalized, non-tumorigenic human keratinocyte cell line (HaCaT) was continuously exposed to environmentally relevant level of inorganic arsenite (100 nM) for 28 weeks, malignant transformation occurred as evidenced by the formation of highly aggressive squamous cell carcinoma after inoculation into nude mice. To investigate the mechanisms involved, a broad array of biomarkers for transformation were assessed in these arsenic-transformed cells (termed As-TM). In addition to increased secretion of matrix metalloproteinase-9 (MMP-9), a set of markers for squamous differentiation and skin keratinization, including keratin-1, keratin-10, involucrin, and loricrin, were significantly elevated in As-TM cells. Furthermore, As-TM cells showed increased intracellular glutathione, elevated expression of Nrf2 and its target genes, as well as generalized apoptotic resistance. In contrast to increased basal Nrf2 activity in As-TM cells, a diminished Nrf2-mediated antioxidant response induced by acute exposure to high dose of arsenite or tert-butyl hydroxyquinone occurred. The findings that multiple biomarkers for malignant transformation observed in As-TM cells, including MMP-9 and cytokeratins, are potentially regulated by Nrf2 suggest constitutive Nrf2 activation may be involved in arsenic carcinogenesis of skin. The weakened Nrf2 activation in response to oxidative stressors observed in As-TM cells, coupled with acquired apoptotic resistance, would potentially have increased the likelihood of transmittable oxidative DNA damage and fixation of mutational/DNA damage events.

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Section: Discussionmentioning

confidence: 99%

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Diwan

Sun

et al. 2008

Free Radical Biology and Medicine

160

147

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“…In the most extensive analysis of PTCH mutations in sporadic BCCs to date, it was found that seven out of 16 mutations detected were of this type, and all tumours with such mutations had been removed from sun-exposed sites of the body . However, there is evidence from epidemiological data that factors other than sun exposure may be involved in BCC induction (Scotto et al, 1996), with one such factor being the trivalent form of inorganic arsenic (Nakjang and Kullavanijaya, 1994;Tay and Seah, 1975;Wong et al, 1998;Yeh, 1973). It Figure 2 Patched is expressed in the developing hair follicle.…”

Section: Patched and Bccsmentioning

confidence: 99%

The hedgehog signalling pathway in tumorigenesis and development

1999

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“…3 Other proliferative skin lesions associated with human arsenic exposure include Bowen's disease and squamous cell or basal cell carcinoma. 1,7,8 It is estimated that in the United States 1.3 million new cases of skin cancer are diagnosed annually. 9 Ultraviolet (UV) radiation from sunlight is the primary carcinogen in development of human skin cancer and can act as both an initiator and promoter.…”

mentioning

confidence: 99%

Low level, long‐term inorganic arsenite exposure causes generalized resistance to apoptosis in cultured human keratinocytes: Potential role in skin co‐carcinogenesis

Bortner

et al. 2005

Intl Journal of Cancer

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Inorganic arsenic is a human carcinogen that targets the skin. Carcinogenesis is a multistep process in which acquired apoptotic resistance is a common event and prior work in non-skin cells shows acquired resistance to apoptosis occurs with chronic arsenite exposure. In the present study, when HaCaT cells, an immortalized, non-tumorigenic human keratinocyte cell line, were continuously exposed to low-level inorganic arsenite (as sodium arsenite; 100 nM) for 28 weeks, the cells acquired a generalized resistance to apoptosis. This included resistance to apoptosis induced by acute high concentrations of arsenite, ultraviolet A (UVA) irradiation, and several chemotherapeutic compounds (cisplatin, etoposide and doxorubicin). These arsenite-tolerant (As-TL) cells showed similar levels of UVA-induced reactive oxygen species (ROS) and oxidative DNA damage when compared to passage match control cells. Because cellular apoptosis is dependent on the balance between proapoptotic and survival pathways, the roles of protein kinase B (PKB), a key antiapoptotic molecule, in this acquired apoptotic resistance were investigated. Stimulation of apoptosis markedly decreased nuclear phosphorylated PKB (P-PKB) levels in control cells, but As-TL cells showed greatly increased stability of nuclear P-PKB. Pretreatment of the As-TL cells with LY294002 or Wortmannin, which specifically inhibit PKB phosphorylation, completely blocked apoptotic resistance in As-TL cells, indicating acquired apoptotic resistance is associated with increased stability of nuclear P-PKB. Because arsenic and UV irradiation are co-carcinogenic in mouse skin, resistance to UV-induced apoptosis in As-TL cells may allow UV-damaged cells to escape normal cell population controls and initiate the carcinogenic cascade. The observation that As-TL cells show no lessening of UV-induced genotoxicity supports this possibility. ' 2005 Wiley-Liss, Inc.

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Cutaneous manifestations of chronic arsenicism: Review of seventeen cases

Cited by 133 publications

References 27 publications

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

The hedgehog signalling pathway in tumorigenesis and development

Low level, long‐term inorganic arsenite exposure causes generalized resistance to apoptosis in cultured human keratinocytes: Potential role in skin co‐carcinogenesis

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