Fang Yujiang, Zhao Lei, Xiao Huaping, Cook Kathryn M, Bai Qian, Herrick Elizabeth J, Chen Xuhui, Qin Chenglu, Zhu Ziwen, Wakefield Mark R, Nicholl Michael B
Department of Microbiology, Immunology and Pathology, College of Osteopathic Medicine, Des Moines University, Des Moines, IA, 50312, USA.
Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
Med Oncol. 2017 Feb;34(2):23. doi: 10.1007/s12032-016-0880-3. Epub 2017 Jan 5.
IL-33 is a member of the IL-1 family of cytokines, and no study has been performed to address its direct anti-tumor effect. This study is designed to investigate whether IL-33 has any direct effect on pancreatic cancer. Clonogenic survival assay, immunohistochemistry, TUNEL staining, proliferation, caspase-3 activity kits and RT-PCR were used to evaluate the effects of IL-33 on cell survival, proliferation and apoptosis of a pancreatic cancer cell line, MIA PaCa-2. We found that the percentage of colonies of MIA PaCa-2 cells, PCNA+ cells and the OD value of cancer cells were all decreased in the presence of IL-33. TUNEL+ cells and the relative caspase-3 activity in cancer cells were increased in the presence of IL-33. We further found that its anti-proliferative effect on cancer cells correlated with downregulation of pro-proliferative molecules cdk2 and cdk4 and upregulation of anti-proliferative molecules p15, p21 and p53. Its pro-apoptotic effect correlated with downregulation of anti-apoptotic molecule FLIP and upregulation of pro-apoptotic molecule TRAIL. These results suggest that IL-33 presents significant anti-tumor effects by inhibition of proliferation and induction of apoptosis of MIA PaCa-2 pancreatic cancer cells. Thus, strength of IL-33/ST2 signal pathway might be a promising way to treat pancreatic cancer.
白细胞介素-33（IL-33）是细胞因子白细胞介素-1家族的成员，尚未有研究探讨其直接抗肿瘤作用。本研究旨在调查IL-33对胰腺癌是否有直接作用。采用克隆形成存活试验、免疫组织化学、TUNEL染色、增殖检测、半胱天冬酶-3活性检测试剂盒及逆转录聚合酶链反应（RT-PCR）来评估IL-33对胰腺癌细胞系MIA PaCa-2的细胞存活、增殖和凋亡的影响。我们发现，在有IL-33存在的情况下，MIA PaCa-2细胞的集落百分比、增殖细胞核抗原（PCNA）阳性细胞以及癌细胞的光密度值均降低。在有IL-33存在的情况下，TUNEL阳性细胞以及癌细胞中的半胱天冬酶-3相对活性增加。我们进一步发现，其对癌细胞的抗增殖作用与促增殖分子细胞周期蛋白依赖性激酶2（cdk2）和细胞周期蛋白依赖性激酶4（cdk4）的下调以及抗增殖分子p15、p21和p53的上调相关。其促凋亡作用与抗凋亡分子FLICE抑制蛋白（FLIP）的下调以及促凋亡分子肿瘤坏死因子相关凋亡诱导配体（TRAIL）的上调相关。这些结果表明，IL-33通过抑制MIA PaCa-2胰腺癌细胞的增殖和诱导其凋亡而呈现出显著的抗肿瘤作用。因此，增强IL-33/ST2信号通路可能是治疗胰腺癌的一种有前景的方法
