Liver regeneration associated protein ALR exhibits anti-metastatic potential in hepatocellular carcinoma

Abstract

Augmenter of liver regeneration (ALR), which is critically important in liver regeneration and hepatocyte proliferation, is highly expressed in cirrhotic livers and hepatocellular carcinomas (HCC). In the current study, the functional role of ALR in hepatocancerogenesis was analyzed in more detail. HepG2 cells, in which the cytosolic 15 kDa ALR isoform was reexpressed stably, (HepG2-ALR) were used in migration and invasion assays using modified Boyden chambers. Epithelial-mesenchymal transition (EMT) markers were determined in HepG2-ALR cells in vitro and in HepG2-ALR tumors grown in nude mice. ALR protein was quantified in HCC and nontumorous tissues by immunohistochemistry. HepG2-ALR, compared with HepG2 cells, demonstrated reduced cell motility and increased expression of the epithelial cell markers E-cadherin and Zona occludens-1 (ZO-1), whereas SNAIL, a negative regulator of E-cadherin, was diminished. Matrix metalloproteinase MMP1 and MMP3 mRNA expression and activity were reduced. HepG2-ALR cell-derived subcutaneously grown tumors displayed fewer necrotic areas, more epithelial-like cell growth and fewer polymorphisms and atypical mitotic figures than tumors derived from HepG2 cells. Analysis of tumor tissues of 53 patients with HCC demonstrated an inverse correlation of ALR protein with histological angioinvasion and grading. The 15 kDa ALR isoform was found mainly in HCC tissues without histological angioinvasion 0. In summary the present data indicate that cytosolic ALR reduces hepatoma cell migration, augments epithelial growth and, therefore, may act as an antimetastatic and EMT reversing protein.

Clinical Implications of Augmenter of Liver Regeneration in Cancer: A Systematic Review

“…In HCC tissue, ALR typically demonstrates cytoplasmic localization with a granular quality on immunostaining (20). Dayoub and colleagues, however, observe the short ALR isoform of 15 kDa to be expressed at lower levels in HCC overall, compared to normal liver tissue (11). Furthermore, this study found ALR expression to be inversely correlated with tumor grade and histologic angioinvasion.…”

“…Full-text review eliminated one article that was an editorial and did not contain original data. Ultimately, 12 articles were included in the present review (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Study characteristics are summarized in Table I.…”

“…The majority of included studies observe ALR to be upregulated in malignant cells. In frozen and paraffin-embedded HCC tissue, ALR expression is consistently altered when compared to normal para-tumoral tissue and/or healthy controls (10,11,13,20,21). The majority of studies suggest ALR mRNA and protein levels to be higher in HCC tissue relative to normal tissue.…”

Mice overexpression of <i>human augmenter of liver regeneration</i> (hALR) in male germ cells shows abnormal spermatogenesis and reduced fertility

“…For the analysis of the testes at defined time points after birth, the testes were collected and single-cell cells [11]. The full-length 23kDa mammalian ALR is predominant and localized in the mitochondrial intermembrane space, and is an important component of a disulfide-redox relay system [12].…”

Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia–Reperfusion Injury by Improving Mitochondrial Function

“…In practice, administration of an HSS-bearing plasmid by hydrodynamic tail vein injection protects mice from hepatic failure, implying its potential role in clinical application. It has been demonstrated that alterations in HSS gene expression could be observed in relation to pathological states, such as acute liver failure (Li et al, 2011), liver cirrhosis (Gribilas et al, 2009), and hepatocellular carcinoma (Thasler et al, 2005;Dayoub et al, 2011). HSS seems to have additional clinical implications because exogenous HSS administration to rats with thioacetamide-induced liver fibrosis/cirrhosis is able to significantly decrease fibrosis and suppress the onset of cirrhosis (Gribilas et al, 2009).…”