Research Papers:

IL-8 confers resistance to EGFR inhibitors by inducing stem cell properties in lung cancer

Yi-Nan Liu, Tzu-Hua Chang, Meng-Feng Tsai, Shang-Gin Wu, Tzu-Hsiu Tsai, Hsuan-Yu Chen, Sung-Liang Yu, James Chih-Hsin Yang and Jin-Yuan Shih _

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Oncotarget. 2015; 6:10415-10431. https://doi.org/10.18632/oncotarget.3389

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Yi-Nan Liu1, Tzu-Hua Chang1, Meng-Feng Tsai2, Shang-Gin Wu3, Tzu-Hsiu Tsai1, Hsuan-Yu Chen4, Sung-Liang Yu5, James Chih-Hsin Yang6,7, Jin-Yuan Shih1,8

1Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan

2Department of Molecular Biotechnology, Dayeh University, Changhua, Taiwan

3Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan

4Institute of Statistical Science, Academia Sinica, Taipei, Taiwan

5Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan

6Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

7Graduate Institute of Oncology, Cancer Research Center, National Taiwan University, Taipei, Taiwan

8Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan

Correspondence to:

Jin-Yuan Shih, e-mail: [email protected]

Keywords: IL-8, EGFR, gefitinib, resistance, stemness

Received: October 15, 2014     Accepted: February 15, 2015     Published: March 18, 2015


Epidermal growth factor receptor (EGFR)-targeted strategy is limited by resistance. We identify the potential genes involved in EGFR TKI (tyrosine kinase inhibitor) resistance and study the therapeutic mechanism in the non-small cell lung cancers. Potential genes involved in resistance were examined by analyzing datasets from a pair of EGFR TKI-sensitive (PC9) and TKI-resistant cells (PC9/gef). Blood specimens from patients taking EGFR TKI as first-line treatment were used to examine the correlation between drug's efficacy and IL-8 level. The effects of IL-8 on gefitinib-induced apoptosis, stemness, and in vivo tumorigenicity were investigated using established cell lines. We identified IL-8 was up-regulated in gefitinib-resistant cells, and high plasma IL-8 level was correlated with shorter progression-free-survival time. IL-8 overexpression suppressed gefitinib-induced apoptosis in gefitinib-sensitive cells. By contrast, suppression of IL-8 enhanced gefitinib-induced cell death in gefitinib-resistant cells. IL-8 also increased stem-like characteristics including aldehyde dehydrogenase activity, expression of stemness-related genes, clonogenic activity, side-population, and in vivo tumorigenicity. Consistently, knockdown of IL-8 leads to loss of stem cell-like characteristics in gefitinib-resistant cells. Our study demonstrates an important role for IL-8, and suggests IL-8 is a potential therapeutic target for overcoming EGFR TKI resistance.

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