A Nucleotide Analog Prevents Colitis-Associated Cancer via Beta-Catenin Independently of Inflammation and Autophagy.,Cellular and Molecular Gastroenterology and Hepatology

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A Nucleotide Analog Prevents Colitis-Associated Cancer via Beta-Catenin Independently of Inflammation and Autophagy.
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2020-06-01 , DOI: 10.1016/j.jcmgh.2020.05.012
Yong Hua Sheng ₁ , Rabina Giri ₂ , Julie Davies ₂ , Veronika Schreiber ₂ , Saleh Alabbas ₂ , Ramya Movva ₂ , Yaowu He ₃ , Andy Wu ₄ , John Hooper ₃ , Brett McWhinney ₅ , Iulia Oancea ₆ , Gregor Kijanka ₇ , Sumaira Hasnain ₈ , Andrew J Lucke ₉ , David P Fairlie ₉ , Michael A McGuckin ₁₀ , Timothy H Florin ₂ , Jakob Begun ₁₁

Affiliation

Inflammatory Bowel Diseases Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland.
Inflammatory Bowel Diseases Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland.
Cancer Biology Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland.
Bones and Immunology Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland.
Queensland Pathology Services, Herston.
School of Clinical Medicine, Faculty of Medicine, University of Queensland.
Immune Profiling & Cancer Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland.
Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland.
ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria.
Inflammatory Bowel Diseases Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland; Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, Queensland; School of Clinical Medicine, Faculty of Medicine, University of Queensland.

Background & Aims

Chronic bowel inflammation increases the risk of colon cancer; colitis-associated cancer (CAC). Thiopurine treatments are associated with a reduction in dysplasia and CAC in inflammatory bowel disease (IBD). Abnormal Wnt/β-catenin signalling is characteristic of >90% of colorectal cancers. Immunosuppression by thiopurines is via Rac1 GTPase, which also affects Wnt/β-catenin signalling. Autophagy is implicated in colonic tumors, and topical delivery of the thiopurine thioguanine (TG) is known to alleviate colitis and augment autophagy. This study investigated the effects of TG in a murine model of CAC and potential mechanisms.

Methods

Colonic dysplasia was induced by exposure to azoxymethane (AOM) and dextran sodium sulfate (DSS) in wild-type (WT) mice and mice harboring intestinal epithelial cell–specific deletion of autophagy related 7 gene (Atg7^ΔIEC). TG or vehicle was administered intrarectally, and the effect on tumor burden and β-catenin activity was assessed. The mechanisms of action of TG were investigated in vitro and in vivo.

Results

TG ameliorated DSS colitis in wild-type but not Atg7^ΔIEC mice, demonstrating that anti-inflammatory effects of locally delivered TG are autophagy-dependent. However, TG inhibited CAC in both wild-type and Atg7^ΔIEC mice. This was associated with decreased β-catenin activation/nuclear translocation demonstrating that TG’s inhibition of tumorigenesis occurred independently of anti-inflammatory and pro-autophagic actions. These results were confirmed in cell lines, and the dependency on Rac1 GTPase was demonstrated by siRNA knockdown and overexpression of constitutively active Rac1.

Conclusions

Our findings provide evidence for a new mechanism that could be exploited to improve CAC chemoprophylactic approaches.

中文翻译：

一种核苷酸类似物通过 β-连环蛋白独立于炎症和自噬预防结肠炎相关癌症。

背景与目标

慢性肠道炎症会增加患结肠癌的风险；结肠炎相关癌症 (CAC)。硫嘌呤治疗与炎症性肠病 (IBD) 中发育不良和 CAC 的减少有关。Wnt/β-catenin 信号异常是 >90% 的结直肠癌的特征。硫嘌呤的免疫抑制是通过 Rac1 GTPase 进行的，这也会影响 Wnt/β-catenin 信号传导。自噬与结肠肿瘤有关，已知局部递送硫嘌呤硫鸟嘌呤 (TG) 可减轻结肠炎并增强自噬。本研究调查了 TG 在 CAC 小鼠模型中的影响和潜在机制。

方法

在野生型 (WT) 小鼠和肠上皮细胞特异性缺失自噬相关 7 基因 ( Atg7 ^ΔIEC ) 的小鼠中，暴露于氧化偶氮甲烷 (AOM) 和葡聚糖硫酸钠 (DSS) 可诱导结肠发育不良。直肠内给予 TG 或载体，并评估对肿瘤负荷和 β-连环蛋白活性的影响。在体外和体内研究了TG的作用机制。

结果

TG 改善了野生型而非Atg7 ^ΔIEC小鼠的DSS 结肠炎，表明局部递送的 TG 的抗炎作用是自噬依赖性的。然而，TG 抑制野生型和Atg7 ^ΔIEC小鼠的CAC 。这与 β-连环蛋白活化/核易位降低有关，表明 TG 对肿瘤发生的抑制作用独立于抗炎和促自噬作用。这些结果在细胞系中得到证实，并且通过 siRNA 敲低和组成型活性 Rac1 的过度表达证明了对 Rac1 GTPase 的依赖性。