Tumour Suppressor Gene Linked to Liver Cancer

by Rajshri on  June 5, 2008 at 6:35 PM Cancer News
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 Tumour Suppressor Gene Linked to Liver Cancer
A link between tumour suppressor gene and liver cancer has been found by researchers at Cold Spring Harbor Laboratory (CSHL).

In the study, the researchers have not only confirmed that a gene called DLC1 is a tumour suppressor but they have also demonstrated in living mice that its deletion, inactivation or loss precipitates events culminating in an aggressive type of liver cancer closely related to common human epithelial cancers of the liver (also known as hepatocellular carcinoma, or HCC).

The team's success in identifying the intricate pathway by which DLC1 functions in both healthy and pathological states suggests a highly specific new target for future anticancer drugs.

Tumour suppressor genes play a vital role in intracellular signalling networks that protect against uncontrolled cell growth and proliferation.

Such genes can be rendered inactive by a variety of DNA alterations, including deletions, mutations and so-called epigenetic changes in DNA's chemical configuration.

DLC1, a gene whose acronym reflects prior suspicions that it was 'deleted in liver cancer,' was known to be located in a region of chromosome 8 that has been observed to be missing in past studies of mammalian liver cancer cells.

"The region in question is a large one that may harbour more than one tumour suppressor. We set out to conclusively identify DLC1 as a tumour suppressor, which had not been done before, and to show at the molecular level how the absence of this gene produces pathology in cells that can lead to liver cancer. Interestingly, loss of DLC1 is observed in a range of epithelial cancers, which suggests that DLC1 may a play common role in many types of human cancer," Dr. Scott W. Lowe said.

In order to prove that DLC1 was causally implicated in specific cancers, the researchers genetically engineered mouse liver cells in which the gene was not expressed.

Short-hairpin RNAs (shRNAs) were designed to 'knock down' DLC1 expression in vivo. When the DLC1 shRNAs are introduced into normal mouse liver cells, the production of DLC1 protein is blocked, or 'silenced.'

The researchers found that nearly all of the mice whose livers had been transplanted with the engineered cells developed liver cancer, and that the gene's reintroduction stopped the cancer.

However, it is not simply the absence of the DLC1 protein that causes tumorigenesis. In fact, abnormally low levels of the protein, or its complete absence, induces a complex series of interrelated events.

The protein encoded by the DLC1 gene belongs to regulators of a large family of enzymes called small Rho GTPases that act as molecular switches.

Following the Signalling Pathway Using a mechanism called RNA interference to control the expression of specific genes, the researchers effectively turned the DLC1 'switch' on and off in living mice cells, and in so doing was able to isolate one particular signalling intermediary whose presence was both necessary and sufficient to set the cell on an uncontrolled growth path.

This essential molecular intermediary is called RhoA. When the DLC1 gene is absent in a cell, RhoA is activated, effectively removing a brake on tumour initiation. Whether the experimenters knocked down the DLC1 gene or in separate experiments activated RhoA, the result was the same: the promotion of liver cancer.

Specifically, the researchers demonstrated that RhoA is required for maintaining the tumour-formation process stimulated by deletion of the DLC1 gene.

The study appears in the June 1 issue of Genes and Development.

Source: ANI

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