Oncogenic KRAS-induced interleukin-8 overexpression promotes cell growth and migration and contributes to aggressive phenotypes of non-small cell lung cancer

• Published in: International journal of cancer 2012-04, Vol.130 (8), p.1733-1744
• Main Authors: Sunaga, Noriaki, Imai, Hisao, Shimizu, Kimihiro, Shames, David S., Kakegawa, Seiichi, Girard, Luc, Sato, Mitsuo, Kaira, Kyoichi, Ishizuka, Tamotsu, Gazdar, Adi F., Minna, John D., Mori, Masatomo
• Format: Article
• Language: English
• Subjects: Aged; Biological and medical sciences; Butadienes - pharmacology; Cancer; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell growth; Cell Line; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Humans; Imidazoles - pharmacology; interleukin-8; Interleukin-8 - genetics; Kaplan-Meier Estimate; Kinases; KRAS; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Medical research; Medical sciences; molecular target; Mutation; Nitriles - pharmacology; non-small cell lung cancer; Oligonucleotide Array Sequence Analysis; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Phenotype; Pneumology; Pyridines - pharmacology; ras Proteins - genetics; Receptor, Epidermal Growth Factor - genetics; RNA Interference; Smoking; Tumors; Tumors of the respiratory system and mediastinum
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.26164

The CXC chemokine interleukin‐8 (IL‐8) is an angiogenic growth factor that is overexpressed in various cancers, including non‐small cell lung cancer (NSCLC). Previously, IL‐8 was shown as a transcriptional target of RAS signaling, raising the possibility of its role in oncogenic KRAS‐driven NSCLC. Using microarray analysis, we identified IL‐8 as the most downregulated gene by shRNA‐mediated KRAS knockdown in NCI‐H1792 NSCLC cells where IL‐8 is overexpressed. NSCLC cell lines harboring KRAS or EGFR mutations overexpressed IL‐8, while IL‐8 levels were more prominent in KRAS mutants compared to EGFR mutants. IL‐8 expression was downregulated by shRNA‐mediated KRAS knockdown in KRAS mutants or by treatment with EGFR tyrosine kinase inhibitors and EGFR siRNAs in EGFR mutants. In our analysis of the relationship of IL‐8 expression with clinical parameters and mutation status of KRAS or EGFR in 89 NSCLC surgical specimens, IL‐8 expression was shown to be significantly higher in NSCLCs of males, smokers, and elderly patients and those with pleural involvement and KRAS mutated adenocarcinomas. In KRAS mutant cells, the MEK inhibitor markedly decreased IL‐8 expression, while the p38 inhibitor increased IL‐8 expression. Attenuation of IL‐8 function by siRNAs or a neutralizing antibody inhibited cell proliferation and migration of KRAS mutant/IL‐8 overexpressing NSCLC cells. These results indicate that activating mutations of KRAS or EGFR upregulate IL‐8 expression in NSCLC; IL‐8 is highly expressed in NSCLCs from males, smokers, elderly patients, NSCLCs with pleural involvement, and KRAS‐mutated adenocarcinomas; and IL‐8 plays a role in cell growth and migration in oncogenic KRAS‐driven NSCLC.