Abstract
The prognosis of hepatocellular carcinoma patients is usually poor, the size of tumors being a limiting factor for surgical treatments. Present results suggest that the overexpression of Gas1 (growth arrest specific 1) gene reduces the size, proliferating activity and malignancy of liver tumors. Mice developing diethylnitrosamine-induced hepatocellular carcinoma were subjected to hydrodynamic gene delivery to overexpress Gas1 in liver. This treatment significantly (p < 0.05) reduced the number of large tumors, while the difference in the total number of lesions was not significant. Moreover, the number of carcinoma foci in the liver and the number of lung metastases were reduced. These results are related with the finding that overexpression of Gas1 in Hepa 1-6 cells arrests cell cycle before S phase, with a significant (p < 0.01) and concomitant reduction in the expression of cyclin E2 gene. In addition, a triangular analysis of microarray data shows that Gas1 overexpression restores the transcription levels of 150 genes whose expression was affected in the diethylnitrosamine-induced tumors, thirteen of which are involved in the hedgehog signaling pathway. Since the in vivo Gas1 gene delivery to livers of mice carrying hepatocellular carcinoma reduces the size and proliferating activity of tumors, partially restoring the transcriptional profile of the liver, the present study opens promising insights towards a therapeutic approach for hepatocellular carcinoma.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third major cause of deaths attributable to cancer [1]
It has long been established that Gas1 overexpression arrests cell cycle before S phase in different cell lines [6], but its role in hepatoma cells remains unknown
Overexpression of Gas1 resulted in the inhibition of the proliferation of Hepa 1–6 cells, which did not progress to S phase (Fig 1E)
Summary
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third major cause of deaths attributable to cancer [1]. The prognosis of HCC patients is usually poor, the size of tumors being a limit to surgical resection and liver transplantation [2] and only patients with small tumors are candidates for resection or local ablation [3]. Attempts to reduce the size and proliferating activity of liver tumors constitute an attractive strategy prior to resection. The localization of human GAS1 to chromosomal bands 9q21.3-q22, often deleted in myeloid malignancies, suggested that this gene could be involved in the suppression of tumor cell proliferation [7]
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