Antiapoptotic Activity of Autocrine Mterleukin-22 and Therapeutic Effects of Interleukin-22-Small Interfering RNA on Human Lung Cancer Xenografts
Antiapoptotic Activity of Autocrine Mterleukin-22 and Therapeutic Effects of Interleukin-22-Small Interfering RNA on Human Lung Cancer Xenografts
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自分泌Mterleukin-22的抗凋亡活性及IL-22-小干扰RNA对人肺癌异种移植瘤的治疗作用
DOI：
10.1158/1078-0432.ccr-07-4401
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发表时间：
2008-10-15
影响因子：
11.5
通讯作者：
Tian, Zhigang
中科院分区：
文献类型：
--
作者：
Zhang, Weici;Chen, Yongyan;Tian, Zhigang
目的：非小细胞肺癌（NSCLC）是最常见的恶性疾病之一，通常对凋亡诱导化疗具有耐药性。本研究旨在探讨白细胞介素(IL)-22在人肺癌中的抗凋亡机制。实验设计：收集19例I ~ III期NSCLC患者，检测IL-22的表达。将人IL-22 cDNA稳定转染到A549和PG细胞中，并转染IL-22 rna干扰（RNAi）到这些癌细胞中，以揭示IL-22的分子机制。结果：发现IL-22在非小细胞肺癌患者的原发肿瘤组织、恶性胸腔积液及血清中高表达。在肺癌组织和肺癌细胞系中也检测到IL-22R1 mRNA。IL-22的过表达通过激活STAT3及其下游抗凋亡蛋白如Bcl-2和Bcl-xL以及细胞外信号调节激酶1/2的失活，保护肺癌细胞系免受血清饥饿诱导和化疗药物诱导的凋亡。暴露于IL-22R1阻断抗体或转染IL-22-RNAi质粒可通过STAT3和细胞外信号调节激酶1/2通路导致肺癌细胞凋亡。此外，一项体内异种移植研究表明，给予IL-22-RNAi质粒可显著抑制BALB/c裸鼠的人肿瘤细胞生长。结论：我们的研究表明，自分泌IL-22通过上调抗凋亡蛋白参与人肺癌细胞存活和化疗耐药。
Purpose: Non-small cell lung carcinoma (NSCLC) is one of most common malignant diseases and usually is resistant against apoptosis-inducing chemotherapy. This study is to explore the antiapoptotic mechanisms of interleukin (IL)-22 in human lung cancer.Experimental Design: Nineteen cases with stage I to III NSCLC were collected to determine the expression of IL-22. Stable transfection of human IL-22 cDNA into A549 and PG cells and transfection of IL-22-RNA interference (RNAi) into these cancer cell lines were done to reveal the molecular mechanisms of IL-22.Results: It was found that IL-22 was highly expressed in primary tumor tissue, malignant pleural effusion, and serum of patients with NSCLC. IL-22R1 mRNA was also detected in lung cancer tissues as well as lung cancer cell lines. Overexpression of IL-22 protected lung cancer cell lines from serum starvation-induced and chemotherapeutic drug-induced apoptosis via activation of STAT3 and its downstream antiapoptotic proteins such as Bcl-2 and Bcl-xL and inactivation of extracellular signal-regulated kinase 1/2. Exposure to blocking antibodies against IL-22R1 or transfection with the IL-22-RNAi plasmid in vitro resulted in apoptosis of these lung cancer cells via STAT3 and extracellular signal-regulated kinase 1/2 pathways. Furthermore, an in vivo xenograft study showed that administration of IL-22-RNAi plasmids significantly inhibited the human tumor cell growth in BALB/c nude mice.Conclusions: Our study indicates that autocrine production of IL-22 contributes to human lung cancer cell survival and resistance to chemotherapy through the up-regulation of antiapoptotic proteins.