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Promoter hypermethylation mediated downregulation of FBP1 in human hepatocellular carcinoma and colon cancer.

Chen M, Zhang J, Li N, Qian Z, Zhu M, Li Q, Zheng J, Wang X, Shi G - PLoS ONE (2011)

Bottom Line: Restoring FBP1 expression in low expressed cells significantly inhibited cell growth and colony formation ability through the induction of G2-M phase cell cycle arrest.Moreover, the observed effects coincided with an increase in reactive oxygen species (ROS) generation.In summary, epigenetic inactivation of FBP1 is also common in human liver and colon cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.

ABSTRACT
FBP1, fructose-1,6-bisphosphatase-1, a gluconeogenesis regulatory enzyme, catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate. The mechanism that it functions to antagonize glycolysis and was epigenetically inactivated through NF-kappaB pathway in gastric cancer has been reported. However, its role in the liver carcinogenesis still remains unknown. Here, we investigated the expression and DNA methylation of FBP1 in primary HCC and colon tumor. FBP1 was lowly expressed in 80% (8/10) human hepatocellular carcinoma, 66.7% (6/9) liver cancer cell lines and 100% (6/6) colon cancer cell lines, but was higher in paired adjacent non-tumor tissues and immortalized normal cell lines, which was well correlated with its promoter methylation status. Methylation was further detected in primary HCCs, gastric and colon tumor tissues, but none or occasionally in paired adjacent non-tumor tissues. Detailed methylation analysis of 29 CpG sites at a 327-bp promoter region by bisulfite genomic sequencing confirmed its methylation. FBP1 silencing could be reversed by chemical demethylation treatment with 5-aza-2'-deoxycytidine (Aza), indicating direct epigenetic silencing. Restoring FBP1 expression in low expressed cells significantly inhibited cell growth and colony formation ability through the induction of G2-M phase cell cycle arrest. Moreover, the observed effects coincided with an increase in reactive oxygen species (ROS) generation. In summary, epigenetic inactivation of FBP1 is also common in human liver and colon cancer. FBP1 appears to be a functional tumor suppressor involved in the liver and colon carcinogenesis.

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Related in: MedlinePlus

Exogenous FBP1 increased ROS levels in liver and colon cancer cells.The effect of ectopic FBP1 expression on oxidative stress was determined by flow cytometry assay as shown in (A) and (B). Stable cells were stained with DCFH-DA and then the redox state of cells was measured by flow cytometry.
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pone-0025564-g006: Exogenous FBP1 increased ROS levels in liver and colon cancer cells.The effect of ectopic FBP1 expression on oxidative stress was determined by flow cytometry assay as shown in (A) and (B). Stable cells were stained with DCFH-DA and then the redox state of cells was measured by flow cytometry.

Mentions: The ROS levels were measured in cancer cells untransfected and transfected with pcDNA-FBP1 expressing vector. Exogenous FBP1 expression clearly increased intracellular ROS levels in SMMC-7721 and SW480 cells (Figure 6A and 6B). Therefore, FBP1 could increase ROS production which exert cytotoxic and proapoptotic functions and limit tumorigenicity and malignant progression.


Promoter hypermethylation mediated downregulation of FBP1 in human hepatocellular carcinoma and colon cancer.

Chen M, Zhang J, Li N, Qian Z, Zhu M, Li Q, Zheng J, Wang X, Shi G - PLoS ONE (2011)

Exogenous FBP1 increased ROS levels in liver and colon cancer cells.The effect of ectopic FBP1 expression on oxidative stress was determined by flow cytometry assay as shown in (A) and (B). Stable cells were stained with DCFH-DA and then the redox state of cells was measured by flow cytometry.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198434&req=5

pone-0025564-g006: Exogenous FBP1 increased ROS levels in liver and colon cancer cells.The effect of ectopic FBP1 expression on oxidative stress was determined by flow cytometry assay as shown in (A) and (B). Stable cells were stained with DCFH-DA and then the redox state of cells was measured by flow cytometry.
Mentions: The ROS levels were measured in cancer cells untransfected and transfected with pcDNA-FBP1 expressing vector. Exogenous FBP1 expression clearly increased intracellular ROS levels in SMMC-7721 and SW480 cells (Figure 6A and 6B). Therefore, FBP1 could increase ROS production which exert cytotoxic and proapoptotic functions and limit tumorigenicity and malignant progression.

Bottom Line: Restoring FBP1 expression in low expressed cells significantly inhibited cell growth and colony formation ability through the induction of G2-M phase cell cycle arrest.Moreover, the observed effects coincided with an increase in reactive oxygen species (ROS) generation.In summary, epigenetic inactivation of FBP1 is also common in human liver and colon cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.

ABSTRACT
FBP1, fructose-1,6-bisphosphatase-1, a gluconeogenesis regulatory enzyme, catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate. The mechanism that it functions to antagonize glycolysis and was epigenetically inactivated through NF-kappaB pathway in gastric cancer has been reported. However, its role in the liver carcinogenesis still remains unknown. Here, we investigated the expression and DNA methylation of FBP1 in primary HCC and colon tumor. FBP1 was lowly expressed in 80% (8/10) human hepatocellular carcinoma, 66.7% (6/9) liver cancer cell lines and 100% (6/6) colon cancer cell lines, but was higher in paired adjacent non-tumor tissues and immortalized normal cell lines, which was well correlated with its promoter methylation status. Methylation was further detected in primary HCCs, gastric and colon tumor tissues, but none or occasionally in paired adjacent non-tumor tissues. Detailed methylation analysis of 29 CpG sites at a 327-bp promoter region by bisulfite genomic sequencing confirmed its methylation. FBP1 silencing could be reversed by chemical demethylation treatment with 5-aza-2'-deoxycytidine (Aza), indicating direct epigenetic silencing. Restoring FBP1 expression in low expressed cells significantly inhibited cell growth and colony formation ability through the induction of G2-M phase cell cycle arrest. Moreover, the observed effects coincided with an increase in reactive oxygen species (ROS) generation. In summary, epigenetic inactivation of FBP1 is also common in human liver and colon cancer. FBP1 appears to be a functional tumor suppressor involved in the liver and colon carcinogenesis.

Show MeSH
Related in: MedlinePlus