Moreover, Beclin-1 forms a complex with Bcl-2 as an anti-apoptotic protein, and when Bcl-2 binds to Beclin-1, it decreases the affinity of Beclin-1 for VPS34 to inhibit autophagy. Beclin-1 is also a trigger of autophagy that interacts with the PI3KC3 complex. During starvation, inhibition of mTORC1 occurs and AMPK signaling induces ULK1 in stimulating autophagy. The interaction between AMPK and ULK1 is crucial for the induction of autophagy, which can be suppressed by mTORC1 when sufficient energy is available in cells. ATG12-ATG5-ATG16L1 and LC3 are involved in the process of autophagosome elongation and maturation. The ULK1 complex is able to induce PI3KC3 to stimulate autophagosome formation, and it also contributes to autophagosome nucleation and recruitment of autophagy-related proteins to the autophagosome membrane. Autophagy is defined by the formation of double-membrane autophagosomes, which may be mediated by the function of the ULK1 complex containing ULK1, ATG13, FIP200, and ATG101. Figure 1 shows a schematic representation of the autophagy mechanism in cells. īecause autophagy is an important mechanism in cells, considerable efforts have been made to understand the molecular pathways that may regulate it. It can induce/inhibit apoptosis and regulates other cellular events. The function of autophagy in diseases varies depending on the concept. The autophagy mechanism has been associated with the pathogenesis of cancer, cardiovascular diseases, neurodegenerative diseases, metabolic diseases and immune diseases. Changes in the internal and external environment of cells may occur during disease initiation and development and trigger autophagy to adapt cells to the new conditions. Therefore, autophagy helps to recover amino acids and macromolecules for the synthesis of proteins and ATP, and improves cell stability and homeostasis by degrading cellular waste. Thus, it can be concluded that autophagy plays an important role in maintaining homeostasis in cells. The basic level of autophagy is required under normal conditions, but its induction can be mediated by metabolic changes, oxidative stress, endoplasmic reticulum stress, mechanical damage, and misfolded protein accumulation. In this review, we focus on macroautophagy and refer to it simply as autophagy. Autophagy is classified into three categories: Macroautophagy, microautophagy, and chaperone-mediated autophagy. There is increasing evidence that autophagy can influence cellular specialization, differentiation, protein trafficking, and unconventional secretion. In addition, autophagy is crucial in the process of eliminating toxic proteins and defective organelles during the aging process. The process of autophagy is dependent on lysosomes and the main goal of autophagy is to provide nutrients and energy, which can be achieved by the degradation of cytoplasmic substituents. Graphical abstractĪutophagy is an evolutionarily conserved mechanism with a potential role in organelle and protein turnover that may also be involved in regulating metabolism and controlling cell quality. In this paper, we comprehensively review the role and mechanisms of autophagy in HCC and discuss the potential benefit of targeting this process in the treatment of the cancer. Moreover, regulation of autophagy (induction or inhibition) by antitumor agents could be suggested for effective treatment of HCC. Of note, a large number of signaling pathways such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs regulate autophagy in HCC. Targeting autophagy impairs growth and metastasis in HCC and improves tumor cell response to therapy. In addition, autophagy is a regulator of stem cell formation in HCC, and pro-survival autophagy leads to cancer cell resistance to chemotherapy and radiotherapy. Induction of autophagy may promote tumor metastasis via induction of EMT. Activation of autophagy may affect apoptosis in HCC and is a regulator of proliferation and glucose metabolism. The function of autophagy in HCC is controversial and may be both tumor suppressive and tumor promoting. Genetic mutations and alterations in molecular processes can exacerbate the progression of HCC. Hepatocellular carcinoma (HCC) is one of the most lethal and common malignancies of the liver, and smoking, infection, and alcohol consumption can lead to its development. Autophagy has reciprocal functions in cancer and may be responsible for either survival or death. However, dysregulation of autophagy is observed in the development of human diseases, especially cancer. Autophagy is an evolutionarily conserved process that plays a role in regulating homeostasis under physiological conditions.
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