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Methylation of CHFR sensitizes esophageal squamous cell cancer to docetaxel and paclitaxel.

Yun T, Liu Y, Gao D, Linghu E, Brock MV, Yin D, Zhan Q, Herman JG, Guo M - Genes Cancer (2015)

Bottom Line: CHFR methylation has been found frequently in different cancers and is regarded as a marker of taxane sensitivity.No difference was found with either cisplatin or VP16 treatment in either group (p>0.05).In CHFR methylated cells, treatment with docetaxel or paclitaxel resulted in almost all cells being suspended in G0/G1 phase of the cell cycle.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing, China.

ABSTRACT
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. Both genetic and epigenetic changes are involved in esophageal carcinogenesis. CHFR methylation has been found frequently in different cancers and is regarded as a marker of taxane sensitivity. CHFR methylation was found in 0% (0/16) of normal mucosa, 2.9% (1/34) of grade I dysplasia, 0% (0/8) of grade II dysplasia, 12.5% (1/8) of grade III dysplasia and 45% (49/109) of invasive cancer. When treated with docetaxel or paclitaxel, cell viability was lower in CHFR methylated esophageal cancer cells than in unmethylated cells (p<0.05). No difference was found with either cisplatin or VP16 treatment in either group (p>0.05). In CHFR methylated cells, treatment with docetaxel or paclitaxel resulted in almost all cells being suspended in G0/G1 phase of the cell cycle. After 5-AZ treatment, there was an increased fraction of CHFR-methylated cells in S and G2/M phases (p<0.05). In conclusion, CHFR is frequently methylated in ESCC and the expression of CHFR is regulated by promoter region methylation. CHFR methylation is a late stage event in ESCC. Methylation of CHFR sensitized ESCC cells to taxanes. 5-AZ may re-sensitize chemotherapy resistant in refractory tumors by inducing cell cycle phase re-distribution.

No MeSH data available.


Related in: MedlinePlus

The flow cytometric assay shows the cell phase distribution in methylated esophageal cancer cells (KYSE70 and KYSE150) Pac: paclitaxel; Doc: docetaxel
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Figure 3: The flow cytometric assay shows the cell phase distribution in methylated esophageal cancer cells (KYSE70 and KYSE150) Pac: paclitaxel; Doc: docetaxel

Mentions: CHFR methylation has been reported to sensitize cancer cells to taxanes. In our study, promoter region methylation sensitized KYSE70 and KYSE150 cells to docetaxel and paclitaxel. To understand the mechanism of promoter region methylation in cheom-sensitivity, we analyzed the cell cycle phase changes in CHFR methylated esophageal cancer cell lines before and after docetaxel/paclitaxel treatment, with or without 5-AZ. In paclitaxel treated KYSE70 cells, cell cycle phase distributions before and after 5-AZ treatment were as follows: 100.00% vs. 39.86% in G0/G1 phase, 0.00% vs. 35.83% in S phase, 0.00% vs. 24.31% in G2/M phase. In docetaxel treated KYSE70 cells, cell cycle phase distributions before and after 5-AZ treatment were as follows: 98.25% vs. 37.90% in G0/G1 phase. 1.75% vs. 38.04% in S phase, 0.00% vs. 24.06% in G2/M phase. In paclitaxel treated KYSE150 cells, cell cycle phase distributions before and after 5-AZ treatment were as follows: 98.11% vs. 36.92% in G0/G1 phase, 1.89% vs. 19.14% in S phase, 0.00% vs. 43.94% in G2/M phase. In docetaxel treated KYSE150 cells, cell cycle phase distributions before and after 5-AZ treatment were as follows: 100.00% vs. 21.06% in G0/G1 phase, 0.00% vs. 17.85% in S phase, 0.00% vs. 61.09% in G2/M phase. In CHFR methylated esophageal cancer cells, under docetaxel or paclitaxel treatment, S and G2/M phase cells were increased with the treatment of 5-AZ (Figure3, all p<0.05). These results may partially explain the mechanism by which 5-AZ can overcome chemotherapy resistance in refractory solid tumors [27]. Apoptosis was analyzed before and after docetaxel/paclitaxel treatment in KYSE70 and KYSE150 cells. The ratio of apoptosis was 16.78 ± 5.42% vs. baseline of 4.39 ± 0.56% and 22.45 ± 3.49% vs. 4.39 ± 0.56% for docetaxel or paclitaxel ( both P<0.05) in KYSE70 cells. In KYSE150 cells, the apoptotic rate was 10.97 ± 0.61% vs. baseline of 5.16 ± 0.51% and 15.78 ± 1.09 vs.5.16 ± 0.51% for docetaxel or paclitaxel (all P<0.05) (Fig.4). No significant changes were found between the docetaxel/paclitaxel treatment groups and the docetaxel/paclitaxel combined with 5-AZ treatment groups.


Methylation of CHFR sensitizes esophageal squamous cell cancer to docetaxel and paclitaxel.

Yun T, Liu Y, Gao D, Linghu E, Brock MV, Yin D, Zhan Q, Herman JG, Guo M - Genes Cancer (2015)

The flow cytometric assay shows the cell phase distribution in methylated esophageal cancer cells (KYSE70 and KYSE150) Pac: paclitaxel; Doc: docetaxel
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362483&req=5

Figure 3: The flow cytometric assay shows the cell phase distribution in methylated esophageal cancer cells (KYSE70 and KYSE150) Pac: paclitaxel; Doc: docetaxel
Mentions: CHFR methylation has been reported to sensitize cancer cells to taxanes. In our study, promoter region methylation sensitized KYSE70 and KYSE150 cells to docetaxel and paclitaxel. To understand the mechanism of promoter region methylation in cheom-sensitivity, we analyzed the cell cycle phase changes in CHFR methylated esophageal cancer cell lines before and after docetaxel/paclitaxel treatment, with or without 5-AZ. In paclitaxel treated KYSE70 cells, cell cycle phase distributions before and after 5-AZ treatment were as follows: 100.00% vs. 39.86% in G0/G1 phase, 0.00% vs. 35.83% in S phase, 0.00% vs. 24.31% in G2/M phase. In docetaxel treated KYSE70 cells, cell cycle phase distributions before and after 5-AZ treatment were as follows: 98.25% vs. 37.90% in G0/G1 phase. 1.75% vs. 38.04% in S phase, 0.00% vs. 24.06% in G2/M phase. In paclitaxel treated KYSE150 cells, cell cycle phase distributions before and after 5-AZ treatment were as follows: 98.11% vs. 36.92% in G0/G1 phase, 1.89% vs. 19.14% in S phase, 0.00% vs. 43.94% in G2/M phase. In docetaxel treated KYSE150 cells, cell cycle phase distributions before and after 5-AZ treatment were as follows: 100.00% vs. 21.06% in G0/G1 phase, 0.00% vs. 17.85% in S phase, 0.00% vs. 61.09% in G2/M phase. In CHFR methylated esophageal cancer cells, under docetaxel or paclitaxel treatment, S and G2/M phase cells were increased with the treatment of 5-AZ (Figure3, all p<0.05). These results may partially explain the mechanism by which 5-AZ can overcome chemotherapy resistance in refractory solid tumors [27]. Apoptosis was analyzed before and after docetaxel/paclitaxel treatment in KYSE70 and KYSE150 cells. The ratio of apoptosis was 16.78 ± 5.42% vs. baseline of 4.39 ± 0.56% and 22.45 ± 3.49% vs. 4.39 ± 0.56% for docetaxel or paclitaxel ( both P<0.05) in KYSE70 cells. In KYSE150 cells, the apoptotic rate was 10.97 ± 0.61% vs. baseline of 5.16 ± 0.51% and 15.78 ± 1.09 vs.5.16 ± 0.51% for docetaxel or paclitaxel (all P<0.05) (Fig.4). No significant changes were found between the docetaxel/paclitaxel treatment groups and the docetaxel/paclitaxel combined with 5-AZ treatment groups.

Bottom Line: CHFR methylation has been found frequently in different cancers and is regarded as a marker of taxane sensitivity.No difference was found with either cisplatin or VP16 treatment in either group (p>0.05).In CHFR methylated cells, treatment with docetaxel or paclitaxel resulted in almost all cells being suspended in G0/G1 phase of the cell cycle.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing, China.

ABSTRACT
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. Both genetic and epigenetic changes are involved in esophageal carcinogenesis. CHFR methylation has been found frequently in different cancers and is regarded as a marker of taxane sensitivity. CHFR methylation was found in 0% (0/16) of normal mucosa, 2.9% (1/34) of grade I dysplasia, 0% (0/8) of grade II dysplasia, 12.5% (1/8) of grade III dysplasia and 45% (49/109) of invasive cancer. When treated with docetaxel or paclitaxel, cell viability was lower in CHFR methylated esophageal cancer cells than in unmethylated cells (p<0.05). No difference was found with either cisplatin or VP16 treatment in either group (p>0.05). In CHFR methylated cells, treatment with docetaxel or paclitaxel resulted in almost all cells being suspended in G0/G1 phase of the cell cycle. After 5-AZ treatment, there was an increased fraction of CHFR-methylated cells in S and G2/M phases (p<0.05). In conclusion, CHFR is frequently methylated in ESCC and the expression of CHFR is regulated by promoter region methylation. CHFR methylation is a late stage event in ESCC. Methylation of CHFR sensitized ESCC cells to taxanes. 5-AZ may re-sensitize chemotherapy resistant in refractory tumors by inducing cell cycle phase re-distribution.

No MeSH data available.


Related in: MedlinePlus