MAPK/AP-1 signal pathway in tobacco smoke-induced cell proliferation and squamous metaplasia in the lungs of rats

Cai Yun Zhong, Ya Mei Zhou, Gordon C Douglas, Hanspeter Witschi, Kent E Pinkerton

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Overwhelming evidence has demonstrated tobacco smoke (TS) is causally associated with various types of cancers, especially lung cancer. Sustained epithelial cell hyperplasia and squamous metaplasia are considered as preneoplastic lesions during the formation of lung cancer. The cellular and molecular mechanisms leading to lung cancer due to TS are not clear. Mitogen-activated protein kinases (MAPK)/activator protein-1 (AP-1) can be activated by various stimuli and play a critical role in the control of cell proliferation and differentiation. To date, information on the response of the MAPK/AP-1 pathway during hyperplasia and squamous metaplasia induced by TS is lacking. We therefore investigated the effects of TS on the development of epithelial hyperplasia and squamous metaplasia, regulation of MAPK/AP-1 activation, and expression of AP-1-regulated cell cycle proteins and differentiation markers in the lungs of rats. Exposure of rats to TS (30 mg/m3 or 80 mg/m3, 6 h/day, 3 days/week for 14 weeks) dramatically induced cell proliferation and squamous metaplasia in a dose-dependent manner, effects that paralleled the activation of AP-1-DNA binding activity. Phosphorylated ERK1/2, JNK, p38 and ERK5 were significantly increased by exposure to TS, indicating the activation of these MAPK pathways. Expression of Jun and Fos proteins were differentially regulated by TS. TS upregulated the expression of AP-1-dependent cell cycle proteins including cyclin D1 and proliferating cell nuclear antigen (PCNA). Among the AP-1-dependent cell differentiation markers, keratin 5 and 14 were upregulated, while loricrin, filaggrin and involucrin were downregulated following TS exposure. These findings suggest the important role of MAPK/AP-1 pathway in TS-induced pathogenesis, thus providing new insights into the molecular mechanisms of TS-associated lung diseases including lung cancers.

Original languageEnglish (US)
Pages (from-to)2187-2195
Number of pages9
JournalCarcinogenesis
Volume26
Issue number12
DOIs
StatePublished - Dec 2005

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Transcription Factor AP-1
Metaplasia
Mitogen-Activated Protein Kinases
Smoke
Tobacco
Signal Transduction
Cell Proliferation
Lung
Lung Neoplasms
Hyperplasia
Cell Differentiation
Cell Cycle Proteins
Differentiation Antigens
Keratin-14
Keratin-5
Cyclin D1
Proliferating Cell Nuclear Antigen
Lung Diseases
Down-Regulation
Epithelial Cells

ASJC Scopus subject areas

  • Cancer Research

Cite this

MAPK/AP-1 signal pathway in tobacco smoke-induced cell proliferation and squamous metaplasia in the lungs of rats. / Zhong, Cai Yun; Zhou, Ya Mei; Douglas, Gordon C; Witschi, Hanspeter; Pinkerton, Kent E.

In: Carcinogenesis, Vol. 26, No. 12, 12.2005, p. 2187-2195.

Research output: Contribution to journalArticle

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