The Role of IL-10 and FasL in Tumor Progression and Outcome in Non-Small Cell Lung Cancer

• Main Authors: Wen-Wei, 宋文瑋
• Other Authors: Huei Lee
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/54858814884154897262

博士 === 中山醫學大學 === 醫學研究所 === 100 === IL-10 is predominately secreted from immune cells and determines the process of virus clearance and persistent infection of host. IL-10 has been shown to play tumor suppressive and oncogenic role in viral-associated human cancers, revealing the fact that the role of IL-10 in virus-induced tumor progression is still controversial. Our previous study showed that lung tumors with high HPV copy number had higher IL-10-expression than those with low HPV copy number. In addition, IL-10 non-ATA haplotype patients with high IL-10 mRNA expression had poorer prognosis than IL-10 ATA haplotype patients with low IL-10 mRNA expression, especially in HPV16/18-infected lung cancer patients. Therefore, we expected that IL-10 might play an important role in HPV-associated lung tumorigenesis. In this study, a panel of lung cancer cells was collected to evaluate the IL-10 expression. Our data showed that HPV-infected lung cancer cells (TL1 and TL2) had higher IL-10 expression than in HPV-uninfected lung cancer cells. Different signaling pathway inhibitors were used to test which signaling pathways could be involved in E6-induced IL-10 transcription in lung cancer cells. The result showed that E6-induced IL-10 transcription was mainly through the phosphorylation of CREB by PI3K/AKT pathway. Interestingly, IL-10 induced by E6 significantly promoted soft-agar growth and matrigel invasion capability. To verify the underlying mechanism, PCR array showed that CIP2A upregulated by E6-mediated IL-10 may be responsible for IL-10-induced cell invasiveness and soft-agar growth. IL-10 can elevate antiapoptotic protein expression in tumor cells and contribute to cancer immune escape. Therefore, we next questioned whether FasL-mediated apoptosis could promote HPV-associated lung tumor progression and consequently result in patients with poorer prognosis. FasL -844CC genotype with high FasL expression has been shown to associate with tumor risks. We therefore collected 385 patients to determine FasL -844T/C polymorphism by PCR-RFLP. Patients with the FasL -844CC genotype had high prevalence with advanced tumors than with early tumors. Interestingly, patients with the FasL -844CC genotype were more prone to tumor relapse when compared with those with the FasL -844TT+TC genotype. Multivariate Cox regression analysis showed that patients with the FasL -844CC genotype had poorer overall survival and relapse-free survival than those with the FasL -844TT+TC genotype. Taken together, in this study, we demonstrated that IL-10 and FasL could contribute to HPV-associated lung tumor malignancy via immune escape and autocrine loop of IL-10/IL-10R. Therefore, IL-10 and FasL may be used as molecular targets for immunotherapeutic interventions for improving the clinical outcome of lung adenocarcinoma patients who had HPV16/18 E6-positive tumors.