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. Graphical abstract

Inhibition of UBA52 induces autophagy via EMC6 to suppress hepatocellular carcinoma tumorigenesis and progression

“…Recently, accumulating studies have suggested that autophagy is involved in the development and progression of HCC 30–32 . In our study, we first identified the UBA52 gene, one of the most highly expressed autophagy‐related genes in HCC in the GEPIA database.…”

“…Recently, accumulating studies have suggested that autophagy is involved in the development and progression of HCC. 30 , 31 , 32 In our study, we first identified the UBA52 gene, one of the most highly expressed autophagy‐related genes in HCC in the GEPIA database. Then, we collected tissue samples from HCC patients and verified that the UBA52 expression was significantly increased in HCC samples.…”

OVOL2 induces autophagy-mediated epithelial-mesenchymal transition by the ERK1/2 MAPK signaling in lung adenocarcinoma

“… 26 EMT is the mechanism most closely associated with tumor cell invasion and metastasis and is characterized by morphological and physiological changes, such as loss of cell polarity, disruption of intracellular junctions, and increased growth and invasion. 27 Multiple studies have shown that OVOL2, as a transcription factor, inhibits EMT in tumor cells. 22 , 28 , 29 This result is consistent with our research results.…”

Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

“…A detailed overview of the autophagy mechanisms involved in HCC development and progression have been recently published [ 264 , 265 ].…”