Liver Regeneration Associated Protein (ALR) Exhibits Antimetastatic 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.

Augmenter of liver regeneration: A key protein in liver regeneration and pathophysiology

“…These findings seem contradictory, however, evidence suggests that overexpression of sfALR in cancerous HepG2 cells leads to a reduced invasiveness and cell migration. There is still increased cell growth, but of the epithelial cell types, with a reduced expression of SNAIL and an upregulation of epithelial markers E‐cadherin and Zona occludens‐1 signifying a reduction in EMT . This implies that ALR might indeed have a crucial role to play in the development and progression of HCC.…”

Augmenter of liver regeneration enhances cell proliferation through the microRNA‐26a/Akt/cyclin D1 pathway in hepatic cells

“…Previously, it was shown that liver‐specific deletion of ALR resulted in the development of steatohepatitis and hepatocellular carcinoma in mice . ALR was also shown to act as an anti‐metastatic regulator in hepatocellular carcinoma . Although, these studies showed the effect of ALR, there was a paucity of data on the molecular mechanisms of ALR regulating the proliferation.…”

Augmenter of Liver Regeneration Links Mitochondrial Function to Steatohepatitis and Hepatocellular Carcinoma

“…[15][16][17][18] Despite the advance in our understanding of NASHinduced HCC provided by the present study, there are questions that remain unaddressed. Although data for the latter are preliminary owing to the low number of patients examined, a role of reduced ALR expression in steatohepatitis seems to be evident.…”