Targeting and regulation of autophagy in hepatocellular carcinoma: revisiting the molecular interactions and mechanisms for new therapy approaches

Abstract

Autophagy is an evolutionarily conserved process that plays a role in regulating homeostasis under physiological conditions. However, dysregulation of autophagy is observed in the development of human diseases, especially cancer. Autophagy has reciprocal functions in cancer and may be responsible for either survival or death. 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. Genetic mutations and alterations in molecular processes can exacerbate the progression of HCC. The function of autophagy in HCC is controversial and may be both tumor suppressive and tumor promoting. Activation of autophagy may affect apoptosis in HCC and is a regulator of proliferation and glucose metabolism. Induction of autophagy may promote tumor metastasis via induction of EMT. 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. Targeting autophagy impairs growth and metastasis in HCC and improves tumor cell response to therapy. Of note, a large number of signaling pathways such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs regulate autophagy in HCC. Moreover, regulation of autophagy (induction or inhibition) by antitumor agents could be suggested for effective treatment of HCC. 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. Video Abstract.

Keywords: Autophagy; Chemoresistance; Hepatocellular carcinoma; Metastasis; Stemness.

Fig. 1

Regulation of autophagy in cells. ULK1, mTOR, ATGs, and Beclin-1 are the best known regulators of the autophagy mechanism in cells and therefore their targeting is of importance in the regulation of this molecular mechanism. In addition, oxidative stress, metabolic changes, and misfolded proteins are among the factors that can regulate the autophagy mechanism

Fig. 2

An overview of the risk factors for HCC and the pathways associated with progression

Fig. 3

Targeting autophagy to regulate the survival rate of HCC cells. PD-L1 is involved in the process of immunosuppression, while autophagy inhibits PD-L1 in enhancing cancer immunity in HCC. More importantly, pro-survival autophagy can lead to the activation of Wnt signaling by mediating the nuclear translocation of β-catenin, which induces glycolysis and promotes HCC progression

Fig. 4

Targeting autophagy to regulate metastasis in HCC. Anoikis resistance and EMT as the two most important factors in regulating HCC cell invasion are influenced by autophagy mechanism. When autophagy has an oncogenic function, its induction by Beclin-1 and AMPK/mTOR signaling pathway may lead to EMT induction, which promotes tumor metastasis

Fig. 5

Autophagy, drug resistance, and radioresistance in HCC. Based on the function of autophagy in regulating proliferation and metastasis of HCC cells, this metabolic pathway may be involved in regulating radio- and chemoresistance of HCC cells. The resistance of HCC cells to sorafenib and oxaliplatin is tightly regulated by the autophagy mechanism. Moreover, activation of autophagy by NEAT1 may lead to radioresistance. More importantly, autophagy can reduce the levels of ROS in triggering radioresistance

Fig. 6

Regulation of autophagy by anti-cancer agents in the treatment of HCC. Molecular pathways related to autophagy, such as PI3K/Akt/mTOR, AMPK, and LC3II, are regulated by anticancer drugs. Of note, induction of autophagy by antitumor agents not only has a pro-death function, but sometimes also a pro-survival function, so in this case, inhibition of autophagy increases the potential of antitumor agents to induce apoptosis