Abstract
Autophagy is an evolutionarily conserved lysosomal-dependent pathway for degrading cytoplasmic proteins, macromolecules, and organelles. Autophagy-related genes (Atgs) are the core molecular machinery in the control of autophagy, and several major functional groups of Atgs coordinate the entire autophagic process. Autophagy plays a dual role in liver cancer development via several critical signaling pathways, including the PI3K-AKT-mTOR, AMPK-mTOR, EGF, MAPK, Wnt/β-catenin, p53, and NF-κB pathways. Here, we review the signaling pathways involved in the cross-talk between autophagy and hepatocellular carcinoma (HCC) and analyze the status of the development of novel HCC therapy by targeting the core molecular machinery of autophagy as well as the key signaling pathways. The induction or the inhibition of autophagy by the modulation of signaling pathways can confer therapeutic benefits to patients. Understanding the molecular mechanisms underlying the cross-link of autophagy and HCC may extend to translational studies that may ultimately lead to novel therapy and regimen formation in HCC treatment.
Highlights
Autophagy is a self-degradative process that represents an important physiological catabolic mechanism of the eukaryotic cell
ATG proteins, which play an important role in autophagosome formation and the lysosomal delivery of autophagic cargo, are divided into five complexes (Figure 1): (I) Unc-51-like kinase 1 (ULK1) complex- ULK1, RB1-inducible coiled-coil protein 1 (FIP200), ATG101, and ATG13; (II) class III phosphatidylinositol 3-kinase (PI3K) (PI3KC3) complex, the catalytic subunit vacuolar protein sorting 34 (VPS34), Beclin 1, and p115, joined by ATG14 or UV radiation resistance-associated gene protein (UVRAG); (III) two ubiquitin (Ub)-like proteins and conjugation systems: the ATG12-ATG5–ATG16L conjugation complex and Ub-like ATG8 family proteins (ATG8s), which form conjugates with membrane-resident phosphatidylethanolamine (PE); (IV) ATG18/WIPI (WD repeat domain phosphoinositide-interacting) proteins and ATG2; and (V) ATG9, a sole multi-spanning transmembrane protein which is involved in vesicle trafficking [70,71,72]
Two important mechanisms are involved in hepatocellular carcinoma (HCC) molecular pathogenesis: (1) multiple molecular factors related to the cirrhosis induced by hepatitis infection, environmental or metabolic influences [89]; (2) mutations occurring in oncogenes or tumor suppressor genes [90,91]
Summary
Autophagy is a self-degradative process that represents an important physiological catabolic mechanism of the eukaryotic cell. Autophagy can function as a tumor-suppression mechanism in the early stage of cancer development by inhibiting inflammation and promoting genomic stability [19]. Many autophagy-related genes play an essential role in the suppression function of autophagy tumor development. Evidence has revealed that the suppression or induction of autophagy by the modulation of the mTOR, AMPK, and MAPK pathways plays a critical role in liver tumor development [63,64,65]. We hope to provide a comprehensive view and reference for a deep understanding of the underlying mechanisms in the role of autophagy in liver cancer and a unique visual angle for HCC treatments involving autophagy modulation as an HCC therapeutic regimen strategy
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