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Haem oxygenase-1 plays a central role in NNK-mediated lung carcinogenesis

Depts of ¹ Surgery and ² Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, ³ Lung Cancer Research Institute, and ⁴ Cancer Center, Guangdong Provincial People's Hospital, Guangdong, Guangzhou, China.

CORRESPONDENCE: G. G. Chen, Dept of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. Fax: 852 26450605. E-mail: gchen{at}cuhk.edu.hk

Keywords: Extracellular signal-regulated kinase, haem oxygenase-1, lung cancer, NNK, nuclear factor-B

Received: April 28, 2008
Accepted May 19, 2008

The tobacco-specific nitrosamine, 4-(N-methyl-N-nitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), is a potent lung cancer inducer. However, how NNK induces lung cancer is still largely unknown.

Haem oxygenase (HO)-1 was evaluated in 30 pairs of lung cancer tumour samples and matched nontumour tissues from patients with a history of cigarette smoking. Expression of HO-1, p21^{Cip1/Waf1/Cid1} (p21), B-cell lymphoma (Bcl)-2 family members, mitogen-activated protein kinase and nuclear factor (NF)-B was also studied in lung cancer cells treated with NNK.

The levels of HO-1 and p21 were significantly increased in lung tumour tissues. There was a positive relationship between these two proteins in the tumour. NNK stimulated lung cell proliferation and elevated the levels of HO-1, p21, inhibitor of apoptosis protein (c-IAP)2 and Bcl-2, but downregulated Bad. These effects of NNK were blocked by zinc protoporphyrin-XII, an HO-1 inhibitor. The NNK-mediated expression of HO-1 was governed by NF-B and extracellular signal-regulated kinase 1/2, since blocking either of these prevented the stimulatory effect of NNK on HO-1, as well as molecules downstream of HO-1, such as p21, c-IAP2, Bcl-2 and Bad.

In conclusion, haem oxygenase-1 plays a central role in NNK-mediated cell proliferation by promoting the expression of p21^{Cip1/Waf1/Cid1}, inhibitor of apoptosis protein 2 and B-cell lymphoma-2 but inhibiting the activity of Bad. Nuclear factor-B and extracellular signal-regulated kinase 1/2 function upstream of haem oxygenase-1. Therefore, haem oxygenase-1 is likely to be a potential target in the treatment of smoking-related lung cancer.