Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide, and it has been linked to radiation exposure. As a well-defined oncogene, wild-type p53-induced phosphatase 1 (WIP1) plays an inhibitory role in several tumor suppressor pathways, including p53. WIP1 is amplified and overexpressed in many malignancies, including HCC. However, the underlying mechanisms remain largely unknown. Here, we show that low-dose ionizing radiation (IR) induces miR-29c expression in female mouse liver, while inhibiting its expression in HepG2, a human hepatocellular carcinoma cell line which is used as a model system in this study. miR-29c expression is downregulated in human hepatocellular carcinoma cells, which is inversely correlated with WIP1 expression. miR-29c attenuates luciferase activity of a reporter harboring the 3'UTR binding motif of WIP1 mRNA. Ectopic expression of miR-29c significantly represses cell proliferation and induces apoptosis and G1 arrest in HepG2. In contrast, the knockdown of miR-29c greatly enhances HepG2 cell proliferation and suppresses apoptosis. The biological effects of miR-29c may be mediated by its target WIP1 which regulates p53 activity via dephosphorylation at Ser-15. Finally, fluorescence in situ hybridization (FISH) and immunohistochemical analyses indicate that miR-29c is downregulated in 50.6% of liver carcinoma tissues examined, whereas WIP1 is upregulated in 45.4% of these tissues. The expression of miR-29c inversely correlates with that of WIP1 in HCC. Our results suggest that the IR-responsive miR-29c may function as a tumor suppressor that plays a crucial role in the development of liver carcinoma via targeting WIP1, therefore possibly representing a target molecule for therapeutic intervention for this disease.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy in adults and the third most common cause of cancer-related deaths worldwide [1, 2]
Our results suggest that the ionizing radiation (IR)-responsive miR-29c may function as a tumor suppressor that plays a crucial role in the development of liver carcinoma via targeting wild-type p53-induced phosphatase 1 (WIP1), possibly representing a target molecule for therapeutic intervention for this disease
To explore an expression pattern of miR-29c in human hepatocellular carcinoma HepG2 cells in response to low-dose IR, HepG2 cells were exposed to 0.3 Gy X-ray, and the expression of miR-29c was determined. qRT-PCR indicated that low-dose IR had no effect on the expression of miR-29c in HepG2 cells at 96 hours post IR, whereas IR did suppress its expression at 12 and 24 hours after IR (Figure 1D)
Summary
HCC is the most common primary liver malignancy in adults and the third most common cause of cancer-related deaths worldwide [1, 2]. Based on data from the Canadian Cancer Registry, age-adjusted liver cancer incidence rose to 15.4 per 100,000 for the period 2006–2010 [3], three times the incidence for the period 1976–1980. The primary risk factors for HCC may be chronic hepatitis B (HBV) and C virus (HCV) infections and cirrhosis because 78% of HCC cases and. 57% of liver cirrhosis cases are caused by chronic infection with HBV and HCV [4]. Most solid cancers have been linked to radiation [5], including liver cancer. The doseresponse relationship between radiation and liver cancer has been clinically verified in primary liver cancer cases and implicated in histological analyses [6]
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