The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors

Abstract

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 (Atg7ΔHep) 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.