Development of Liver Cancer Linked to an Inactive Tumor Suppressor Gene

Cancer researchers have found that mice with mutated and inactive tumor suppressor gene Nf2 (neurofibromatosis type 2) in their liver cells produce large numbers of undifferentiated progenitor stem cells that ultimately mature into the two major types of human liver cancer.

The human tumor suppressor gene Nf2 is located on chromosome 22, where it encodes the 595 amino acid (70-kDa molecular weight) protein merlin (Moesin-Ezrin-Radixin-Like protein). In mice, a similar gene resides on chromosome 11.

Merlin is a membrane-cytoskeleton scaffolding protein that links actin filaments to cell membrane or membrane glycoproteins. Human merlin is predominantly found in nervous tissue, but also in several other fetal tissues. A mutated form of Nf2 that results in phosphorylation of serine 518 alters the functional state of merlin, which causes the human autosomal dominant disease neurofibromatosis type 2.

To examine further the role of Nf2/merlin in tumor suppression investigators at Harvard Medical School (Cambridge, MA, USA) genetically engineered a line of mice lacking Nf2 in their liver cells. They reported in the July 30, 2010, online edition of the journal Genes & Development that liver-specific deletion of the Nf2 gene in the developing or adult mouse specifically yielded a dramatic, progressive expansion of progenitor cells throughout the liver without affecting differentiated hepatocytes. All surviving mice eventually developed both cholangiocellular and hepatocellular carcinoma, suggesting that Nf2-null progenitors can be a cell of origin for these tumors.

"We found that mutation of the Nf2 tumor suppressor gene in the mouse liver led to a dramatic over proliferation of liver stem cells – the cells that contribute to the liver's remarkable ability to regenerate,” said senior author Dr. Andrea McClatchey, associate professor of pathology at Harvard Medical School. "These mice go on to develop the two forms of liver cancer that are most common in humans, suggesting that liver stem cells may be the cells of origin of these tumors.”

"We also showed that merlin's role in cell-to-cell communication is essential for cells to stop growing when they fill the appropriate space. Since liver progenitors need to be poised to regenerate in case of injury, they may be particularly sensitive to the loss of merlin's regulatory function,” said Dr. McClatchey.

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