CD44v6 expression in human skin keratinocytes as a possible mechanism for carcinogenesis associated with chronic arsenic exposure

  • S. Huang Suzuka University of Medical Science, Japan.
  • S. Guo Guangxi Medical University, China.
  • F. Guo Mie University Graduate School of Medicine, Japan.
  • Q. Yang Guangxi Medical University, China.
  • X. Xiao Guangxi Medical University, China.
  • M. Murata Mie University Graduate School of Medicine, Japan.
  • S. Ohnishi Suzuka University of Medical Science, Japan.
  • S. Kawanishi Suzuka University of Medical Science, Japan.
  • N. Ma | maning@suzuka-u.ac.jp Suzuka University of Medical Science, Japan.

Abstract

Inorganic arsenic is a well-known human skin carcinogen. Chronic arsenic exposure results in various types of human skin lesions, including squamous cell carcinoma (SCC). To investigate whether mutant stem cells participate in arsenic-associated carcinogenesis, we repeatedly exposed the HaCaT cells line to an environmentally relevant level of arsenic (0.05 ppm) in vitro for 18 weeks. Following sodium arsenic arsenite administration, cell cycle, colony-forming efficiency (CFE), cell tumorigenicity, and expression of CD44v6, NF-κB and p53, were analyzed at different time points (0, 5, 10, 15, 20, 25 and 30 passages). We found that a chronic exposure of HaCaT cells to a low level of arsenic induced a cancer stem- like phenotype. Furthermore, arsenic-treated HaCaT cells also became tumorigenic in nude mice, their growth cycle was predominantly in G2/M and S phases. Relative to nontreated cells, they exhibited a higher growth rate and a significant increase in CFE. Western blot analysis found that arsenic was capable of increasing cell proliferation and sprouting of cancer stem-like phenotype. Additionally, immunohistochemical analysis demonstrated that CD44v6 expression was up-regulated in HaCaT cells exposed to a low level of arsenic during early stages of induction. The expression of CD44v6 in arsenic-treated cells was positively correlated with their cloning efficiency in soft agar (r=0.949, P=0.01). Likewise, the expressions of activating transcription factor NF-κB and p53 genes in the arsenic-treated HaCaT cells were significantly higher than that in non-treated cells. Higher expressions of CD44v6, NF-κB and p53 were also observed in tumor tissues isolated from Balb/c nude mice. The present results suggest that CD44v6 may be a biomarker of arsenic-induced neoplastic transformation in human skin cells, and that arsenic promotes malignant transformation in human skin lesions through a NF-κB signaling pathway-stimulated expression of CD44v6.

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Author Biographies

S. Huang, Suzuka University of Medical Science
Faculty of Health Science and Faculty of Pharmaceutical Science
S. Guo, Guangxi Medical University
School of Public Health
F. Guo, Mie University Graduate School of Medicine
Department of Environmental and Molecular Medicine
Q. Yang, Guangxi Medical University
School of Public Health
X. Xiao, Guangxi Medical University
Department of Otorhinolaryngology
M. Murata, Mie University Graduate School of Medicine
Department of Environmental and Molecular Medicine
S. Ohnishi, Suzuka University of Medical Science
Faculty of Health Science and Faculty of Pharmaceutical Science
S. Kawanishi, Suzuka University of Medical Science
Faculty of Health Science and Faculty of Pharmaceutical Science
N. Ma, Suzuka University of Medical Science
Faculty of Health Science and Faculty of Pharmaceutical Science
Published
2013-01-14
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Original Papers
Supporting Agencies
This work was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan
Keywords:
arsenic, human skin keratinocytes, malignant transformation, cell surface markers, CD44v6
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How to Cite
Huang, S., Guo, S., Guo, F., Yang, Q., Xiao, X., Murata, M., Ohnishi, S., Kawanishi, S., & Ma, N. (2013). CD44v6 expression in human skin keratinocytes as a possible mechanism for carcinogenesis associated with chronic arsenic exposure. European Journal of Histochemistry, 57(1), e1. https://doi.org/10.4081/ejh.2013.e1