Abstract
Simple SummaryHepatocellular 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.
Highlights
chaperonemediated autophagy (CMA) is responsible for the degradation of 30% of cytosolic proteins under stress conditions; future investigations could help us gain further insight into whether CMA is responsible for the degradation of autophagic molecules that contribute to macroautophagy inhibition [38]
Recent studies have gained further insight into this mechanism, and they have shown that macroautophagy and the CMA pathway is deeply involved in Hepatocellular carcinoma (HCC) growth [29,69]
Macroautophagy seems to be the first sensor of stressful stimuli; it is probably upregulated during the early stages of carcinogenesis [39]
Summary
Autophagy is an evolutionarily conserved self-digestion process whereby misfolded macromolecules and dysfunctional organelles (referred to as “autophagic cargo”) undergo lysosomal degradation [1]. Autophagy is considered an adaptive process as it could be induced under stressful conditions (“stress-induced autophagy”) by different-molecular signaling pathways in response to stimuli, such as energy deprivation, hypoxia, and inflammation, thereby sustaining cell metabolism and survival [2,3,4,5]. Basal levels of autophagy serve as a mechanism to eliminate dysfunctional organelles and protein aggregates through lysosomal degradation, maintaining energy homeostasis [11,12]. Stress-induced autophagy serves as a substrate-supplying and energy-providing mechanism via recycling of cellular molecules, providing energy and contributing to cell survival under hostile conditions, such as tumor microenvironment [15]
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