Document Type

Article

Publication Date

2017

Abstract

Background/Aim: Hepatocellular carcinoma is a substantial healthcare burden with high prevalence and poor prognosiS. As such, efforts are continually made to uncover molecules relevant in cancer biology, that are exploitable as targets for therapy. The mitochondrion is the powerhouse of the cell and exhibits altered functionality in the malignant state, including aberrant regulation of apoptosis and cellular respiration. Augmenter of liver regeneration (ALR) is a multifunctional mitochondrial protein that demonstrates antioxidative and anti-apoptotic properties and plays a key role in liver regeneration. Materials and Methods: The present study systematically reviews the available literature on the role of ALR in cancer. Results: Systematic search of PubMed resulted in 12 studies discussing ALR in multiple types of cancer. More specifically, ALR appears to be up-regulated in malignant cells and tissueS. Furthermore, treatment of cells with exogenous ALR shows an anti-apoptotic effect while silencing or inhibiting ALR decreases cell and tumor survival. Conclusion: ALR clearly plays a role in cancer biology and demonstrates potential as a therapeutic target. Hepatocellular carcinoma (HCC) is a common oncologic condition with a poor prognosis that poses as a global burden on medical care (1). Between 2002 and 2012 the mortality rate of HCC rose by 34.8% in the United States and liver cancer, with HCC estimated as 70 to 90% of cases, was considered to be the second leading cause of cancer-related deaths among males on a global scale in 2012 (2, 3). Considering the metabolic aspect of several known risk factors for HCC, such as obesity, diabetes, and non-alcoholic fatty liver disease, a common underlying feature of mitochondrial dysfunction is of growing interest in molecular oncology. The regulation of specific mitochondrial proteins is of particular interest, as these proteins demonstrate potential as therapeutic targets for HCC (4). Augmenter of liver regeneration (ALR) is one particular protein of interest that localizes in the intermembrane space of the mitochondria of humans and has a prokaryotic homolog, Erv1, sharing 42% identical amino acid residueS. ALR/Erv1 has been known to contribute to mitochondrial biogenesis and function as a sulfhydryl oxidase in mitochondrial disulfide relay systems (5). It functions to oxidize the import receptor Mia40, both of which conjunctively import small translocase inner membrane (Tim) proteins through an oxidative-folding pathway (6). In turn, cytochrome c (cyt c), which constitutes an important member of the electron transport chain, oxidizes ALR through locomotion of electrons via FAD, thus connecting this redox regulated import pathway to electron transport (5, 7). During specific unfavorable conditions, cells must reprogram to undergo apoptosis during which cyt c activates a series of activated-caspase pathways that lead to cell suicide (8). It is a trademark of cancer cells to down-regulate apoptotic mechanisms and alter mitochondrial respiratory function, resulting in uncontrolled growth and eventual metastasis of cancerous cellS. ALR manifests anti-oxidative and anti-apoptotic properties and is known to support liver regeneration in cases of hepatic injury (9). Considering these properties, early investigations have suggested a role for ALR in cancer (particularly hepatocellular) pathogenesis, growth and progression. In this study, we systematically review the literature discussing ALR in cancer. Clinical implications including oncogenesis and targeted therapy are explored.

Original Publication Citation

Nguyen KH, Nguyen AH, Dabir DV. Clinical Implications of Augmenter of Liver Regeneration in Cancer: A Systematic Review. Anticancer Res. 2017 Jul;37(7):3379-3383. doi: 10.21873/anticanres.11704. PMID: 28668825.

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