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A suppressive role of ionizing radiation-responsive miR-29c in the development of liver carcinoma via targeting WIP1.

Wang B, Li D, Sidler C, Rodriguez-Juarez R, Singh N, Heyns M, Ilnytskyy Y, Bronson RT, Kovalchuk O - Oncotarget (2015)

Bottom Line: Ectopic expression of miR-29c significantly represses cell proliferation and induces apoptosis and G1 arrest in HepG2.The biological effects of miR-29c may be mediated by its target WIP1 which regulates p53 activity via dephosphorylation at Ser-15.The expression of miR-29c inversely correlates with that of WIP1 in HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada.

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.

No MeSH data available.


Related in: MedlinePlus

A model for the suppressive role of miR-29c in liver carcinoma(A) In normal liver cells, the normally expressed miR-29c may contribute to the maintenance of normal p53 activity via targeting WIP1 phosphatase, thus maintaining a normal growth, proliferation, and apoptosis. (B) In liver carcinoma cells, miR-29c is downregulated due to promoter hypermethylation, leading to the overexpression of WIP1 that inactivates p53 by dephosphorylating p53 at Ser-15, which results in the promotion in cell proliferation and reduction in apoptosis that may contribute to the development of liver carcinoma.
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Figure 5: A model for the suppressive role of miR-29c in liver carcinoma(A) In normal liver cells, the normally expressed miR-29c may contribute to the maintenance of normal p53 activity via targeting WIP1 phosphatase, thus maintaining a normal growth, proliferation, and apoptosis. (B) In liver carcinoma cells, miR-29c is downregulated due to promoter hypermethylation, leading to the overexpression of WIP1 that inactivates p53 by dephosphorylating p53 at Ser-15, which results in the promotion in cell proliferation and reduction in apoptosis that may contribute to the development of liver carcinoma.

Mentions: In summary, low-dose IR-responsive miR-29c is downregulated in liver carcinoma cells and tissues. miR-29c functions as a tumor suppressor that plays a crucial role in the development of hepatocellular carcinoma via targeting WIP1 (Figure 5A and 5B), and it may represent a target molecule for therapeutic intervention for this disease.


A suppressive role of ionizing radiation-responsive miR-29c in the development of liver carcinoma via targeting WIP1.

Wang B, Li D, Sidler C, Rodriguez-Juarez R, Singh N, Heyns M, Ilnytskyy Y, Bronson RT, Kovalchuk O - Oncotarget (2015)

A model for the suppressive role of miR-29c in liver carcinoma(A) In normal liver cells, the normally expressed miR-29c may contribute to the maintenance of normal p53 activity via targeting WIP1 phosphatase, thus maintaining a normal growth, proliferation, and apoptosis. (B) In liver carcinoma cells, miR-29c is downregulated due to promoter hypermethylation, leading to the overexpression of WIP1 that inactivates p53 by dephosphorylating p53 at Ser-15, which results in the promotion in cell proliferation and reduction in apoptosis that may contribute to the development of liver carcinoma.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496408&req=5

Figure 5: A model for the suppressive role of miR-29c in liver carcinoma(A) In normal liver cells, the normally expressed miR-29c may contribute to the maintenance of normal p53 activity via targeting WIP1 phosphatase, thus maintaining a normal growth, proliferation, and apoptosis. (B) In liver carcinoma cells, miR-29c is downregulated due to promoter hypermethylation, leading to the overexpression of WIP1 that inactivates p53 by dephosphorylating p53 at Ser-15, which results in the promotion in cell proliferation and reduction in apoptosis that may contribute to the development of liver carcinoma.
Mentions: In summary, low-dose IR-responsive miR-29c is downregulated in liver carcinoma cells and tissues. miR-29c functions as a tumor suppressor that plays a crucial role in the development of hepatocellular carcinoma via targeting WIP1 (Figure 5A and 5B), and it may represent a target molecule for therapeutic intervention for this disease.

Bottom Line: Ectopic expression of miR-29c significantly represses cell proliferation and induces apoptosis and G1 arrest in HepG2.The biological effects of miR-29c may be mediated by its target WIP1 which regulates p53 activity via dephosphorylation at Ser-15.The expression of miR-29c inversely correlates with that of WIP1 in HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada.

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.

No MeSH data available.


Related in: MedlinePlus