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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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FBP1 gene was downregulated and hypermethylated in primary tumor tissues.(A) The expression of FBP1 in liver, gastric and colon tumor tissues and adjacent non-tumor tissues were determined by Real-Time RT-PCR. 1∼10 T/N: liver cancer, 11–15 T/N: gastric cancer, 16∼20 T/N: colon cancer. (B) The methylation status of FBP1 promoter in primary liver, gastric and colon tumor tissues and adjacent non-tumor tissues was detected by MSP. Representative results were shown. 1∼3 T/N: liver cancer, 4∼5 T/N: colon cancer, 6∼9 T/N: gastric cancer. “T” indicates tumor tissues and “N” represents adjacent non-tumor tissues.
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pone-0025564-g003: FBP1 gene was downregulated and hypermethylated in primary tumor tissues.(A) The expression of FBP1 in liver, gastric and colon tumor tissues and adjacent non-tumor tissues were determined by Real-Time RT-PCR. 1∼10 T/N: liver cancer, 11–15 T/N: gastric cancer, 16∼20 T/N: colon cancer. (B) The methylation status of FBP1 promoter in primary liver, gastric and colon tumor tissues and adjacent non-tumor tissues was detected by MSP. Representative results were shown. 1∼3 T/N: liver cancer, 4∼5 T/N: colon cancer, 6∼9 T/N: gastric cancer. “T” indicates tumor tissues and “N” represents adjacent non-tumor tissues.

Mentions: To further confirm the relevance of FBP1 promoter CGI hypermethylation in mediating its silencing in human liver, gastric and colon cancer, FBP1 expression and promoter methylation in primary hepatocellular carcinoma, gastric and colon tumor tissues and adjacent non-tumor tissues were analyzed by Real-Time RT-PCR and MSP, respectively. FBP1 expression was significantly downregulated in 80% (8/10) human liver tumor tissues, 100% (5/5) in gastric and 80% (4/5) colon tumor tissues (Figure 3A) when compared with adjacent non-tumor tissues. In addition, promoter methylation was frequently detected by using MSP in tumor samples but not non-tumor tissues (Figure 3B), indicating that downregulation of FBP1 was involved in the carcinogenesis of human liver and other digestive cancers.


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)

FBP1 gene was downregulated and hypermethylated in primary tumor tissues.(A) The expression of FBP1 in liver, gastric and colon tumor tissues and adjacent non-tumor tissues were determined by Real-Time RT-PCR. 1∼10 T/N: liver cancer, 11–15 T/N: gastric cancer, 16∼20 T/N: colon cancer. (B) The methylation status of FBP1 promoter in primary liver, gastric and colon tumor tissues and adjacent non-tumor tissues was detected by MSP. Representative results were shown. 1∼3 T/N: liver cancer, 4∼5 T/N: colon cancer, 6∼9 T/N: gastric cancer. “T” indicates tumor tissues and “N” represents adjacent non-tumor tissues.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0025564-g003: FBP1 gene was downregulated and hypermethylated in primary tumor tissues.(A) The expression of FBP1 in liver, gastric and colon tumor tissues and adjacent non-tumor tissues were determined by Real-Time RT-PCR. 1∼10 T/N: liver cancer, 11–15 T/N: gastric cancer, 16∼20 T/N: colon cancer. (B) The methylation status of FBP1 promoter in primary liver, gastric and colon tumor tissues and adjacent non-tumor tissues was detected by MSP. Representative results were shown. 1∼3 T/N: liver cancer, 4∼5 T/N: colon cancer, 6∼9 T/N: gastric cancer. “T” indicates tumor tissues and “N” represents adjacent non-tumor tissues.
Mentions: To further confirm the relevance of FBP1 promoter CGI hypermethylation in mediating its silencing in human liver, gastric and colon cancer, FBP1 expression and promoter methylation in primary hepatocellular carcinoma, gastric and colon tumor tissues and adjacent non-tumor tissues were analyzed by Real-Time RT-PCR and MSP, respectively. FBP1 expression was significantly downregulated in 80% (8/10) human liver tumor tissues, 100% (5/5) in gastric and 80% (4/5) colon tumor tissues (Figure 3A) when compared with adjacent non-tumor tissues. In addition, promoter methylation was frequently detected by using MSP in tumor samples but not non-tumor tissues (Figure 3B), indicating that downregulation of FBP1 was involved in the carcinogenesis of human liver and other digestive cancers.

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