Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
Cell Death Dis. 2020 May 7;11(5):333. doi: 10.1038/s41419-020-2536-7.
Autophagy is an intracellular lysosomal degradative pathway important for tumor surveillance. Autophagy deficiency can lead to tumorigenesis. Autophagy is also known to be important for the aggressive growth of tumors, yet the mechanism that sustains the growth of autophagy-deficient tumors is not unclear. We previously reported that progression of hepatic tumors developed in autophagy-deficient livers required high mobility group box 1 (HMGB1), which was released from autophagy-deficient hepatocytes. In this study we examined the pathological features of the hepatic tumors and the mechanism of HMGB1-mediated tumorigenesis. We found that in liver-specific autophagy-deficient (Atg7) mice the tumors cells were still deficient in autophagy and could also release HMGB1. Histological analysis using cell-specific markers suggested that fibroblast and ductular cells were present only outside the tumor whereas macrophages were present both inside and outside the tumor. Genetic deletion of Hmgb1 or one of its receptors, receptor for advanced glycated end product (Rage), retarded liver tumor development. HMGB1 and RAGE enhanced the proliferation capability of the autophagy-deficient hepatocytes and tumors. However, RAGE expression was only found on ductual cells and Kupffer's cells but not on hepatoctyes, suggesting that HMGB1 might promote hepatic tumor growth through a paracrine mode, which altered the tumor microenvironment. Finally, RNAseq analysis of the tumors indicated that HMGB1 induced a much broad changes in tumors. In particular, genes related to mitochondrial structures or functions were enriched among those differentially expressed in tumors in the presence or absence of HMGB1, revealing a potentially important role of mitochondria in sustaining the growth of autophagy-deficient liver tumors via HMGB1 stimulation.
自噬是一种重要的细胞内溶酶体降解途径，对肿瘤监测至关重要。自噬缺陷可导致肿瘤发生。自噬也被认为对肿瘤的侵袭性生长很重要，但维持自噬缺陷肿瘤生长的机制尚不清楚。我们之前报道过，自噬缺陷肝脏中发展的肝肿瘤的进展需要高迁移率族蛋白 B1（HMGB1），它是从自噬缺陷的肝细胞中释放出来的。在这项研究中，我们检查了肝肿瘤的病理特征和 HMGB1 介导的肿瘤发生机制。我们发现，在肝特异性自噬缺陷（Atg7）小鼠中，肿瘤细胞仍然缺乏自噬，也可以释放 HMGB1。使用细胞特异性标志物进行组织学分析表明，成纤维细胞和胆管细胞仅存在于肿瘤外部，而巨噬细胞存在于肿瘤内部和外部。Hmgb1 或其受体（晚期糖基化终产物受体）的遗传缺失会延迟肝肿瘤的发展。HMGB1 和 RAGE 增强了自噬缺陷的肝细胞和肿瘤的增殖能力。然而，RAGE 表达仅在胆管细胞和库普弗细胞上发现，而不在肝细胞上发现，这表明 HMGB1 可能通过旁分泌模式促进肝肿瘤生长，从而改变肿瘤微环境。最后，对肿瘤的 RNAseq 分析表明，HMGB1 诱导了肿瘤中广泛的变化。特别是，与线粒体结构或功能相关的基因在存在或不存在 HMGB1 的情况下在肿瘤中差异表达的基因中富集，这揭示了线粒体在通过 HMGB1 刺激维持自噬缺陷肝肿瘤生长方面的潜在重要作用。
