The Role of Macroautophagy and Chaperone-Mediated Autophagy in the Pathogenesis and Management of Hepatocellular Carcinoma

Simple Summary Hepatocellular carcinoma (HCC) is a major health problem with the second highest mortality among all cancers and a continuous increase worldwide. HCC is highly resistant to available chemotherapeutic agents, leaving patients with no effective therapeutic option and a poor prognosis. Although an increasing number of studies have elucidated the potential role of autophagy underlying HCC, the complete regulation is far from understood. The different forms of autophagy constitute important cell survival mechanisms that could prevent hepatocarcinogenesis by limiting hepatocyte death and the associated hepatitis and fibrosis at early stages of chronic liver diseases. On the other hand, at late stages of hepatocarcinogenesis, they could support the malignant transformation of (pre)neoplastic cells by facilitating their survival. Hepatocarcinogenesis is a long process with a complex pathophysiology. The current therapeutic options for HCC management, during the advanced stage, provide short-term survival ranging from 10-14 months. Autophagy acts as a double-edged sword during this process. Recently, two main autophagic pathways have emerged to play critical roles during hepatic oncogenesis, macroautophagy and chaperone-mediated autophagy. Mounting evidence suggests that upregulation of macroautophagy plays a crucial role during the early stages of carcinogenesis as a tumor suppressor mechanism; however, it has been also implicated in later stages promoting survival of cancer cells. Nonetheless, chaperone-mediated autophagy has been elucidated as a tumor-promoting mechanism contributing to cancer cell survival. Moreover, the autophagy pathway seems to have a complex role during the metastatic stage, while induction of autophagy has been implicated as a potential mechanism of chemoresistance of HCC cells. The present review provides an update on the role of autophagy pathways in the development of HCC and data on how the modulation of the autophagic pathway could contribute to the most effective management of HCC.