Bai Ming, Li Wei, Yu Nanze, Zhang Hailin, Long Fei, Zeng Ang
Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing 100730, China.
Center of Interventional Oncology and Liver Diseases, Beijing You'an Hospital, Capital Medical UniversityBeijing 100069, China.
Am J Transl Res. 2017 Jun 15;9(6):2788-2797. eCollection 2017.
BACKGROUND/OBJECTIVE: IFNs induce potent antiviral and antitumor activities. β-catenin pathway is a surviving pathway adapted by carcinogenetic mechanisms of various cancers. Crosstalk between these pathways has not been well described in lung cancer cells.
Lung cancer cell lines, A549 and Calu-3, were used in this study. β-catenin protein levels and signaling activities were tested by flow cytometry and luciferase assay. Cell proliferation was measured by counting viable cells under microscope, and apoptosis by TUNEL assay and caspase 3 activation. DKK1 and GSK3β levels were tested by flow cytometry. Secreted DKK1 was measured by ELISA. αDKK1 , FLUD and S3I were to inhibit DKK1, STAT1 and STAT3 activities, respectively.
All of IFNα, IFNγ and IFNλ1 suppressed β-catenin signaling in A549 and Calu-3 cells, where IFNγ was the strongest (P<0.05). They inhibited cellular proliferation and promoted apoptosis. IFNγ gave greater induction ability compared to IFNα and IFNλ1 (P<0.05). All tested IFNs promoted DKK1 activation but not GSK3β in A549 and Calu-3 cells. IFNs activated STAT1 and STAT3. But only STAT3 was vital for IFN-mediated DKK1 activation and apoptosis. Plus, DKK1 antagonist abrogated IFN-mediated apoptosis. The degree of STAT3 activation was corresponding to the level of apoptosis induced by different IFNs (P<0.05).
In lung cancer cells, all three types of IFNs can induce apoptosis via suppressing β-catenin signaling by a STAT3- and DKK1-dependent manner. This findings demonstrate a link between IFNs and β-catenin signaling, which may possess potentials on the development of novel therapeutic measures against lung cancer.
背景/目的：干扰素可诱导强大的抗病毒和抗肿瘤活性。β-连环蛋白通路是多种癌症致癌机制所采用的生存通路。这些通路之间的相互作用在肺癌细胞中尚未得到充分描述。
本研究使用肺癌细胞系A549和Calu-3。通过流式细胞术和荧光素酶测定法检测β-连环蛋白的蛋白水平和信号活性。通过在显微镜下计数活细胞来测量细胞增殖，并通过TUNEL测定法和半胱天冬酶3激活来检测细胞凋亡。通过流式细胞术检测DKK1和GSK3β水平。通过酶联免疫吸附测定法测量分泌的DKK1。αDKK1、FLUD和S3I分别用于抑制DKK1、STAT1和STAT3的活性。
IFNα、IFNγ和IFNλ1均抑制A549和Calu-3细胞中的β-连环蛋白信号传导，其中IFNγ作用最强（P<0.05）。它们抑制细胞增殖并促进细胞凋亡。与IFNα和IFNλ1相比，IFNγ具有更强的诱导能力（P<0.05）。所有测试的干扰素均促进A549和Calu-3细胞中DKK1的激活，但不促进GSK3β的激活。干扰素激活STAT1和STAT3。但只有STAT3对干扰素介导DKK1的激活和细胞凋亡至关重要。此外，DKK1拮抗剂可消除干扰素介导的细胞凋亡。STAT激活的程度与不同干扰素诱导的细胞凋亡水平相对应（P<0.05）。
在肺癌细胞中，所有三种类型的干扰素均可通过依赖STAT3和DKK1的方式抑制β-连环蛋白信号传导来诱导细胞凋亡。这一发现证明了干扰素与β-连环蛋白信号传导之间的联系，这可能为开发针对肺癌的新型治疗措施提供潜力。
