Abstract. Our previous study showed that patients with advanced stages of non-small cell lung cancer (NSCLC) were frequently detected with upregulation of hepatocyte growth factor (HGF). In vitro, HGF reduced expression of apoptosis-inducing factor (AIF) and cisplatin sensitivity in NSCLC cells. The effect of HGF was via HGF receptor (c-MET) and the downstream effector, focal adhesion kinase (FAK). In this study, we determined the prognostic value of AIF in NSCLC patients. AIF expression was determined by immunohistochemistry and immunoblotting. Our data show that AIF expression was associated with better prognosis. Expression of AIF inversely correlated with that of positive NSCLC markers, e.g., dihydrodiol dehydrogenase (DDH), c-MET, short oncostatin M receptor (OSMRs), matrix metalloproteinase (MMP)-1, and HER2/neu, which were closely associated with drug resistance, tumor recurrence, metastasis and poor prognosis. Noteworthy, silence of HER2/neu gene expression increases AIF level and drug sensitivity. Addition of HGF inhibits AIF expression in HER2/neu-silenced cells. These results suggested that both HGF and HER2/neu affect drug resistance by regulating AIF expression in NSCLC.
IntroductionLung cancer is one of the leading causes of cancer death worldwide. In the United States, the annual mortality rate of lung cancer (estimated 180,000 deaths, male: 73.5/10 5 personyear; female: 41.5/10 5 person-year) is approximately 30% of total cancer-related deaths (1), and nearly 85-90% of lung cancer deaths are attributed to tobacco smoking (2). In Taiwan, the annual mortality rate of lung cancer is approximately 20% (estimated 6,000 deaths, male: 21/10 5 person-year; female: 10.3/10 5 person-year) (3). Lung carcinoma is categorized into small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) with neuroendocrine features of the cancer cells. Based on the histopathological characteristics, NSCLC can be subcategorized into adenocarcinoma (ADC), squamous cell carcinoma and large cell carcinoma (4). Of note, among these, ADC, which is associated with a higher frequency of drug resistance and mortality than the other types, is most commonly found in women and smokers (5).Previous studies have indicated that tobacco smoking is a key risk factor for lung cancer (1,2,5,6). In patients with stage I NSCLC, we demonstrated that tobacco smoking and tumor size, but not visceral pleural invasion, are major factors influencing overall and disease-free survival (6). Moreover, accumulated evidence showed that NSCLC patients who continued to smoke were more resistant to chemotherapy and irradiation, and had poorer prognosis (6-9). Although nicotine per se is not directly associated with tumorigenesis, catalyzed nicotine is carcinogenic (10,11). In addition, nicotine induces NSCLC growth, and increases angiogenesis in tumors probably via activating nicotinic acetylcholine receptor (nAchR), epidermal growth factor receptor (EGFR) and .Using differential display alone or in combination with microarray, we previously identifi...