Abstract
Autophagy is a catabolic process involved in cellular homeostasis under basal and stressed conditions. Autophagy is crucial for normal liver physiology and the pathogenesis of liver diseases. During the last decade, the function of autophagy in hepatocellular carcinoma (HCC) has been evaluated extensively. Currently, autophagy is thought to play a dual role in HCC, i.e., autophagy is involved in tumorigenesis and tumor suppression. Recent investigations of autophagy have suggested that autophagy biomarkers can facilitate HCC prognosis and the establishment of therapeutic approaches. In this review, we briefly summarize the current understanding of autophagy and discuss recent evidence for its role in HCC.
Highlights
Autophagy is a catabolic process with crucial roles in development, differentiation, homeostasis, and the survival of cells in nutrient-deprived conditions [1,2]
The details of the autophagy process are presented below. (i) The initiation stage is regulated by the adenosine monophosphate-activated protein kinase (AMPK), UNC51-like kinase 1 (ULK1) and mammalian target of rapamycin complex 1 complexes. mTORC1 is the main inhibitor of autophagosome formation by ULK1. Under nutrient starvation such as glucose, the activated AMPK inhibits mTORC1, directly phosphorylates ULK1, and leads to autophagy initiation [29,30]; (ii) Nucleation of the phagophore is mediated by the Beclin-1-class III phosphatidylinositol 3-kinase (PI3K) complex that includes Beclin-1, Vps34, p150, Atg14L/Barkor, and Ambra-1 [4]; (iii) Elongation of the phagophore into a complete autophagosome is regulated by two ubiquitin-like protein conjugated complexes: Atg5-Atg12-Atg16L1 and light chain 3 (LC3)-II
The liver plays a crucial role in metabolism; dysregulation of liver autophagy has great clinical implications
Summary
Autophagy is a catabolic process with crucial roles in development, differentiation, homeostasis, and the survival of cells in nutrient-deprived conditions [1,2]. In addition to preserve intracellular metabolic homeostasis, autophagy is induced in response to starvation, protein aggregation, and other forms of stress such as oxidative and endoplasmic reticulum (ER) stress [6,7]. There is no effective treatment for patients showing advanced- or intermediate-stage HCC [16]. Autophagy-related markers, including microtubule-associated protein 1 light chain 3 (LC3) and beclin-1, are potential prognostic factors for HCC [19,20]. Autophagy-based therapies, such as hydroxychloroquine (HCQ) or chloroquine (CQ), have been examined in mice xenograft models [21,22]. These autophagy-modulating compounds have potential applications in the treatment of HCC in the near future. We provide a brief overview of autophagy and HCC, with focusing on: (1) the current understanding of autophagy pathways; (2) autophagy function in HCC; and (3) prognostic and therapeutic clinical applications in HCC
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