Heterozygous deletion of ATG5 in ApcMin/+ mice promotes intestinal adenoma growth and enhances the antitumor efficacy of interferon-gamma
Heterozygous deletion of ATG5 in ApcMin/+ mice promotes intestinal adenoma growth and enhances the antitumor efficacy of interferon-gamma
复制标题
ApcMin/小鼠ATG5杂合缺失促进肠腺瘤生长并增强干扰素-γ的抗肿瘤功效
DOI：
10.1080/15384047.2014.1002331
复制
发表时间：
2015-03-01
影响因子：
3.6
通讯作者：
Qu, Xianjun
中科院分区：
文献类型：
--
作者：
Wang, Lu;Wang, Yan;Qu, Xianjun
自噬相关基因5(ATG5)在23%的结直肠癌(CRC)患者中丢失，其在结直肠癌发病机制中的作用尚不清楚。ATG5在癌细胞中的敲除增强了许多化疗药物的抗肿瘤效果。然而，仍然没有动物模型来验证这些体外观察在体内。在这项研究中，我们发现，与ApcMin/+ATG5+/+小鼠相比，ApcMin/+小鼠ATG5杂合缺失增加了腺瘤的数量和大小。为了探讨干扰素-γ缺陷是否会使肿瘤对化疗药物敏感，我们比较了干扰素-γ在ApcMin/+ATG5+/+和ApcMin/+ATG5+/−小鼠体内的抗肿瘤作用，因为干扰素-γ是一种潜在的结直肠癌抑制因子，并已作为一种有效的肿瘤化疗辅助手段应用于临床。我们发现ATG5杂合性缺失显著增强了干扰素-γ的抗肿瘤效果。早期应用干扰素-γ治疗ApcMin/+ATG5+/ACTH小鼠，肿瘤发生率降至16.7%，腺瘤数量减少95.5%，晚期治疗可使肿瘤消退。此外，干扰素-γ治疗未引起明显的毒性反应。机制分析表明，ATG5杂合缺失激活了ApcMin/+小鼠腺瘤中的EGFR/ERK1/2和Wnt/β-catenin通路，并增强了干扰素-γ对这两条通路的抑制作用。我们的结果表明ATG5在肠道肿瘤的生长中起着重要的作用，联合干扰素-γ和ATG5缺乏或ATG5靶向抑制是预防和治疗结直肠癌的一种有前途的策略。
Autophagy related gene 5 (ATG5) was lost in 23% of the patients with colorectal cancer (CRC) and the role of loss of ATG5 in the pathogenesis of CRC remains unclear. Knockdown of ATG5 in cancer cells enhances the antitumor efficacy of lots of chemotherapeutic agents. However, there is still no animal model to validate these in vitro observations in vivo. In this study, we found that heterozygous deletion of ATG5 in ApcMin/+ mice increased the number and size of adenomas as compared with those in ApcMin/+ATG5+/+ mice. To investigate whether ATG5 deficiency could sensitize tumors to chemotherapies, we compared the antitumor effects of Interferon-gamma (IFN-γ) between ApcMin/+ATG5+/+ and ApcMin/+ATG5+/− mice, as IFN-γ is a potential tumor suppressor for CRC and has been used clinically as an efficient adjuvant to chemotherapy of cancer. We revealed that heterozygous deletion of ATG5 significantly enhanced the antitumor efficacy of IFN-γ. Early treatment of ApcMin/+ATG5+/− mice with IFN-γ decreased tumor incidence rate to 16.7% and reduced the number of adenomas by 95.5% and late treatment led to regression of tumor. Moreover, IFN-γ treatment did not cause any evident toxic reaction. Mechanistic analysis revealed that heterozygous deletion of ATG5 activated EGFR/ERK1/2 and Wnt/β-catenin pathways in adenomas of ApcMin/+ mice and enhanced the effects of IFN-γ-dependent inhibition of these 2 pathways. Our results demonstrate that ATG5 plays important roles in intestinal tumor growth and combination of IFN-γ and ATG5 deficiency or ATG5-targeted inhibition is a promising strategy for prevention and treatment of CRC.