Abstract

Although inhibition of autophagy has been implicated in the onset and progression of cancer cells, it is still unclear whether its dysregulation at early stages of tumorigenesis plays an oncogenic or a tumor suppressor role. To address this question, we employed the Resistant-Hepatocyte rat model to study the very early stages of hepatocellular carcinoma (HCC) development. We detected a different autophagy-related gene expression and changes in the ultrastructural profile comparing the most aggressive preneoplastic lesions, namely those positive for the putative progenitor cell marker cytokeratin-19 (KRT-19) with the negative ones. The ultrastructural and immunohistochemical analyses of KRT-19-positive preneoplastic hepatocytes showed the presence of autophagic vacuoles which was associated with p62, Ambra1 and Beclin1 protein accumulation suggesting that a differential modulation of autophagy occurs at early stages of the oncogenesis in KRT-19-positive vs negative lesions. We observed an overall decrease of the autophagy-related genes transcripts and a strong up-regulation of miR-224 in the KRT-19-positive nodules. Interestingly, the treatment with the autophagy inducer, Amiodarone, caused a marked increase in the proliferation of KRT-19 positive preneoplastic lesions associated with a strong increase of their size; by contrast, Chloroquine, an inhibitor of the autophagic process, led to their reduction. These results show that autophagy modulation is a very early event in hepatocarcinogenesis and is restricted to a hepatocytes subset in the most aggressive preneoplastic lesions. Our findings highlight the induction of autophagy as a permissive condition favouring cancer progression indicating in its inhibition a therapeutic goal to interfere with the development of HCC.

Highlights

  • The term autophagy identifies the basic selfdegradative physiological process by which the cell removes worn-out or damaged components, such as protein aggregates, mitochondria, Endoplasmic Reticulum (ER), peroxisomes and intracellular pathogens [1,2,3]

  • Differential autophagy modulation takes place in early preneoplastic nodules The R-H model allows dissecting the different steps of the carcinogenic process, as phenotypically distinct lesions can be identified at well-defined timings [19]

  • Most hepatocytes in the nodules displayed abnormal mitochondria (Figure 1C), which appeared swollen with loss of cristae and ruptures of the outer membrane

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Summary

Introduction

The term autophagy identifies the basic selfdegradative physiological process by which the cell removes worn-out or damaged components, such as protein aggregates, mitochondria, Endoplasmic Reticulum (ER), peroxisomes and intracellular pathogens [1,2,3]. Autophagy is evolutionarily conserved and involves the double-membrane sequestration and lysosomal breakdown of the cargo [1,2,3]. Defects in the autophagy machinery have been associated with the pathogenesis of the major human diseases including cancer [1,4]. Three major forms of autophagy have been described: micro-, macroand chaperone-mediated autophagy, all involving the lysosomal breakdown of sequestered material [4,5]. Autophagy is a multistep process involving its induction, the development of an www.impactjournals.com/oncotarget isolation membrane, the completion and maturation of an ‘autophagosome’ containing cytosolic components for recycling and the ultimate fusion with a lysosome (forming the autophagolysosome) for degradation by lysosomal enzymes [1,2,3]

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