High expression of heme oxygenase-1 is associated with tumor invasiveness and poor clinical outcome in non-small cell lung cancer patients
- 427 Downloads
Heme oxygenase-1 (HO-1), a rate-limiting enzyme in heme catabolism, is known to play a role in the protection of cells against oxidative stress, inflammation, anomalous proliferation and apoptosis. As yet, the role of HO-1 expression in non-small cell lung cancer (NSCLC) development and metastasis remains unclear and insufficient data are available regarding its impact on the prognosis of NSCLC patients.
Seventy NSCLC patients who underwent surgical resection were included in this HO-1 expression study and, concomitantly, clinical parameters were collected. Two lung adenocarcinoma cell lines (A549 and H441) were used to assess both invasive and migratory parameters in vitro.
NSCLC patients with a high HO-1 expression ratio (tumor tissue/normal tissue) (> 1) exhibited a significantly poorer prognosis and a higher metastatic rate compared to those with a low HO-1 expression ratio (p < 0.05). The invasive and migratory abilities of A549 and H441 cells significantly increased after exogenous HO-1 over-expression and significantly decreased after siRNA-mediated HO-1 expression silencing. HO-1 up- and down-regulation also positively correlated with the expression of metastasis-associated proteins EGFR, CD147 and MMP-9. In addition, we found that HO-1 expression can be inhibited by PI3K and AKT inhibitors, but not by MAPK inhibitors.
HO-1 is a poor prognostic NSCLC predictor and its over-expression may increase the metastatic potential of NSCLC. Based on our findings and those of others, HO-1 may be considered as a novel NSCLC therapeutic target.
KeywordsHeme Oxygenase-1 Metastasis Prognosis Non-small cell lung cancer
This study was supported by grants from the National Science Council, grants NSC NSC99-2314-B-037-058-MY2 and NSC 100-2320-B-039-008-MY2, Kaohsiung Medical University Hospital grant KMUH99-9 M64, and Kaohsiung Medical University grant KMU-Q098022, Taiwan.
Disclosure/state of interest
The authors declare that they have no competing interests.
- 17.H. Sasaki, H. Yukiue, K. Mizuno, A. Sekimura, A. Konishi, M. Yano et al., Elevated serum epidermal growth factor receptor level is correlated with lymph node metastasis in lung cancer. International journal of clinical oncology/Japan Society of Clinical Oncology. 8, 79–82 (2003)PubMedCrossRefGoogle Scholar
- 33.S.J. Lin, I.T. Lee, Y.H. Chen, F.Y. Lin, L.M. Sheu, H.H. Ku et al., Salvianolic acid B attenuates MMP-2 and MMP-9 expression in vivo in apolipoprotein-E-deficient mouse aorta and in vitro in LPS-treated human aortic smooth muscle cells. J. Cell. Biochem. 100, 372–384 (2007)PubMedCrossRefGoogle Scholar
- 36.A. Albini, R. Benelli, The chemoinvasion assay: A method to assess tumor and endothelial cell invasion and its modulation. Nat. Protoc. 2(504–11) (2007)Google Scholar
- 46.P.L. Liu, J.R. Tsai, A.L. Charles, J.J. Hwang, S.H. Chou, Y.H. Ping et al., Resveratrol inhibits human lung adenocarcinoma cell metastasis by suppressing heme oxygenase 1-mediated nuclear factor-kappaB pathway and subsequently downregulating expression of matrix metalloproteinases. Mol. Nutr. Food Res. 54(2), S196–S204 (2010)PubMedCrossRefGoogle Scholar
- 48.G. De Palma, P. Mozzoni, O. Acampa, E. Internullo, P. Carbognani, M. Rusca et al., Expression levels of some antioxidant and epidermal growth factor receptor genes in patients with early-stage non-small cell lung cancer. Journal of nucleic acids (2010).Google Scholar