Debebe A, Medina V, Chen C-Y, Mahajan I M, Jia C, Fu D, He L, Zeng N, Stiles B W, Chen C-L, Wang M, Aggarwal K-R, Peng Z, Huang J, Chen J, Li M, Dong T, Atkins S, Borok Z, Yuan W, Machida K, Ju C, Kahn M, Johnson D, Stiles B L
Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
Department of Nuclear medicine, Shanghai 10th people's hospital, Tongji University, Shanghai, China.
Oncogene. 2017 Oct 26;36(43):6020-6029. doi: 10.1038/onc.2017.207. Epub 2017 Jul 3.
Obesity confers an independent risk for carcinogenesis. In the liver, steatosis often proceeds cancer formation; however, the mechanisms by which steatosis promotes carcinogenesis is unknown. We hypothesize that steatosis alters the microenvironment to promote proliferation of tumor initiating cells (TICs) and carcinogenesis. We used several liver cancer models to address the mechanisms underlying the role of obesity in cancer and verified these findings in patient populations. Using bioinformatics analysis and verified by biochemical assays, we identified that hepatosteatosis resulting from either Pten deletion or transgenic expression of HCV core/NS5A proteins, promotes the activation of Wnt/β-catenin. We verified that high fat diet lipid accumulation is also capable of inducing Wnt/β-catenin. Caloric restriction inhibits hepatosteatosis, reduces Wnt/β-catenin activation and blocks the expansion of TICs leading to complete inhibition of tumorigenesis without affecting the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) loss regulated protein kinase B (AKT) activation. Pharmacological inhibition or loss of the Wnt/β-catenin signal represses TIC growth in vitro, and decreases the accumulation of TICs in vivo. In human liver cancers, ontology analysis of gene set enrichment analysis (GSEA)-defined Wnt signature genes indicates that Wnt signaling is significantly induced in tumor samples compared with healthy livers. Indeed, Wnt signature genes predict 90% of tumors in a cohort of 558 patient samples. Selective depletion of macrophages leads to reduction of Wnt and suppresses tumor development, suggesting infiltrating macrophages as a key source for steatosis-induced Wnt expression. These data established Wnt/β-catenin as a novel signal produced by infiltrating macrophages induced by steatosis that promotes growth of tumor progenitor cells, underlying the increased risk of liver tumor development in obese individuals.
肥胖是致癌的独立危险因素。在肝脏中，脂肪变性往往先于癌症形成；然而，脂肪变性促进致癌作用的机制尚不清楚。我们假设脂肪变性会改变微环境，以促进肿瘤起始细胞（TICs）的增殖和致癌作用。我们使用了几种肝癌模型来探讨肥胖在癌症中作用的潜在机制，并在患者群体中验证了这些发现。通过生物信息学分析并经生化分析验证，我们发现由Pten缺失或HCV核心/NS5A蛋白的转基因表达导致的肝脂肪变性会促进Wnt/β-连环蛋白的激活。我们证实高脂饮食引起的脂质积累也能够诱导Wnt/β-连环蛋白。热量限制可抑制肝脂肪变性，减少Wnt/β-连环蛋白的激活，并阻断TICs的扩增，从而完全抑制肿瘤发生，而不影响10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）缺失调节的蛋白激酶B（AKT）激活。Wnt/β-连环蛋白信号的药理学抑制或缺失会抑制体外TICs的生长，并减少体内TICs的积累。在人类肝癌中，基因集富集分析（GSEA）定义的Wnt特征基因的本体分析表明，与健康肝脏相比，肿瘤样本中的Wnt信号被显著诱导。事实上，Wnt特征基因在558例患者样本队列中可预测90%的肿瘤。巨噬细胞的选择性耗竭会导致Wnt减少并抑制肿瘤发展，这表明浸润性巨噬细胞是脂肪变性诱导的Wnt表达的关键来源。这些数据确立了Wnt/β-连环蛋白是由脂肪变性诱导的浸润性巨噬细胞产生的一种新信号，它促进肿瘤祖细胞的生长，这是肥胖个体肝肿瘤发生风险增加的基础。
