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Low molecular weight protein tyrosine phosphatase (LMWPTP) upregulation mediates malignant potential in colorectal cancer.

Hoekstra E, Kodach LL, Das AM, Ruela-de-Sousa RR, Ferreira CV, Hardwick JC, van der Woude CJ, Peppelenbosch MP, Ten Hagen TL, Fuhler GM - Oncotarget (2015)

Bottom Line: In the present study, we show that LMWPTP expression is not only significantly increased in colorectal cancer (CRC), but also follows a step-wise increase in different levels of dysplasia.Chemical inhibition of LMWPTP significantly reduces CRC growth.In conclusion, this study shows that LMWPTP is not only overexpressed in colorectal cancer, but it is correlated with the malignant potential of this cancer, suggesting that this phosphatase may act as a predictive biomaker of CRC stage and represents a rational novel target in the treatment of this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, 's Gravendijkwa, Rotterdam, The Netherlands.

ABSTRACT
Phosphatases have long been regarded as tumor suppressors, however there is emerging evidence for a tumor initiating role for some phosphatases in several forms of cancer. Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP; acid phosphatase 1 [ACP1]) is an 18 kDa enzyme that influences the phosphorylation of signaling pathway mediators involved in cancer and is thus postulated to be a tumor-promoting enzyme, but neither unequivocal clinical evidence nor convincing mechanistic actions for a role of LMWPTP have been identified. In the present study, we show that LMWPTP expression is not only significantly increased in colorectal cancer (CRC), but also follows a step-wise increase in different levels of dysplasia. Chemical inhibition of LMWPTP significantly reduces CRC growth. Furthermore, downregulation of LMWPTP in CRC leads to a reduced migration ability in both 2D- and 3D-migration assays, and sensitizes tumor cells to the chemotherapeutic agent 5-FU. In conclusion, this study shows that LMWPTP is not only overexpressed in colorectal cancer, but it is correlated with the malignant potential of this cancer, suggesting that this phosphatase may act as a predictive biomaker of CRC stage and represents a rational novel target in the treatment of this disease.

No MeSH data available.


Related in: MedlinePlus

LMWPTP protein expression is increased in CRC as compared to paired normal adjacent tissue, and expression increases during the canonical progression sequence from normal tissue via adenoma to carcinoma(A) Freshly frozen paired tumor (T) and normal adjacent (N) colonic tissue samples of 6 patients were lysed in Laemmli buffer, and LMWPTP expression was determined using western blot analysis. β-Actin served as loading control. (B) Quantification of western blot results using Li-Cor Odyssey software presented as boxplot of mean, as well as comparisons of individual patient's samples (*P < 0.05; **P < 0.01). (C) IHC analysis of LMWPTP on a tissue micro array (TMA) of patients with colorectal cancer (n = 65), colorectal adenoma (n = 25), and healthy adjacent tissue (n = 62). Representative stainings (20x and 40X inset) of tissue cores from carcinoma, adenoma and healthy tissue are shown. (D–E) Staining was scored for percentage of LMWPTP positive intestinal epithelial cells as well as intensity of staining. Statistical analysis was performed using Mann-Whitney t-test. (F) Percentage of LMWPTP positive IEC were compared in patients from whom normal, adenoma and CRC tissue were all available (n = 15, Wilkinson paired t-test) (*P < 0.05; **P < 0.01; ***P < 0.001).
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Figure 2: LMWPTP protein expression is increased in CRC as compared to paired normal adjacent tissue, and expression increases during the canonical progression sequence from normal tissue via adenoma to carcinoma(A) Freshly frozen paired tumor (T) and normal adjacent (N) colonic tissue samples of 6 patients were lysed in Laemmli buffer, and LMWPTP expression was determined using western blot analysis. β-Actin served as loading control. (B) Quantification of western blot results using Li-Cor Odyssey software presented as boxplot of mean, as well as comparisons of individual patient's samples (*P < 0.05; **P < 0.01). (C) IHC analysis of LMWPTP on a tissue micro array (TMA) of patients with colorectal cancer (n = 65), colorectal adenoma (n = 25), and healthy adjacent tissue (n = 62). Representative stainings (20x and 40X inset) of tissue cores from carcinoma, adenoma and healthy tissue are shown. (D–E) Staining was scored for percentage of LMWPTP positive intestinal epithelial cells as well as intensity of staining. Statistical analysis was performed using Mann-Whitney t-test. (F) Percentage of LMWPTP positive IEC were compared in patients from whom normal, adenoma and CRC tissue were all available (n = 15, Wilkinson paired t-test) (*P < 0.05; **P < 0.01; ***P < 0.001).

Mentions: To validate these results using a different technique, we examined LMWPTP expression in 6 paired freshly frozen tumor and normal adjacent tissues by Western blotting, again demonstrating a significant increase in the total levels of this phosphatase in the tumor tissue (Figure 2A, 2B).


Low molecular weight protein tyrosine phosphatase (LMWPTP) upregulation mediates malignant potential in colorectal cancer.

Hoekstra E, Kodach LL, Das AM, Ruela-de-Sousa RR, Ferreira CV, Hardwick JC, van der Woude CJ, Peppelenbosch MP, Ten Hagen TL, Fuhler GM - Oncotarget (2015)

LMWPTP protein expression is increased in CRC as compared to paired normal adjacent tissue, and expression increases during the canonical progression sequence from normal tissue via adenoma to carcinoma(A) Freshly frozen paired tumor (T) and normal adjacent (N) colonic tissue samples of 6 patients were lysed in Laemmli buffer, and LMWPTP expression was determined using western blot analysis. β-Actin served as loading control. (B) Quantification of western blot results using Li-Cor Odyssey software presented as boxplot of mean, as well as comparisons of individual patient's samples (*P < 0.05; **P < 0.01). (C) IHC analysis of LMWPTP on a tissue micro array (TMA) of patients with colorectal cancer (n = 65), colorectal adenoma (n = 25), and healthy adjacent tissue (n = 62). Representative stainings (20x and 40X inset) of tissue cores from carcinoma, adenoma and healthy tissue are shown. (D–E) Staining was scored for percentage of LMWPTP positive intestinal epithelial cells as well as intensity of staining. Statistical analysis was performed using Mann-Whitney t-test. (F) Percentage of LMWPTP positive IEC were compared in patients from whom normal, adenoma and CRC tissue were all available (n = 15, Wilkinson paired t-test) (*P < 0.05; **P < 0.01; ***P < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4480753&req=5

Figure 2: LMWPTP protein expression is increased in CRC as compared to paired normal adjacent tissue, and expression increases during the canonical progression sequence from normal tissue via adenoma to carcinoma(A) Freshly frozen paired tumor (T) and normal adjacent (N) colonic tissue samples of 6 patients were lysed in Laemmli buffer, and LMWPTP expression was determined using western blot analysis. β-Actin served as loading control. (B) Quantification of western blot results using Li-Cor Odyssey software presented as boxplot of mean, as well as comparisons of individual patient's samples (*P < 0.05; **P < 0.01). (C) IHC analysis of LMWPTP on a tissue micro array (TMA) of patients with colorectal cancer (n = 65), colorectal adenoma (n = 25), and healthy adjacent tissue (n = 62). Representative stainings (20x and 40X inset) of tissue cores from carcinoma, adenoma and healthy tissue are shown. (D–E) Staining was scored for percentage of LMWPTP positive intestinal epithelial cells as well as intensity of staining. Statistical analysis was performed using Mann-Whitney t-test. (F) Percentage of LMWPTP positive IEC were compared in patients from whom normal, adenoma and CRC tissue were all available (n = 15, Wilkinson paired t-test) (*P < 0.05; **P < 0.01; ***P < 0.001).
Mentions: To validate these results using a different technique, we examined LMWPTP expression in 6 paired freshly frozen tumor and normal adjacent tissues by Western blotting, again demonstrating a significant increase in the total levels of this phosphatase in the tumor tissue (Figure 2A, 2B).

Bottom Line: In the present study, we show that LMWPTP expression is not only significantly increased in colorectal cancer (CRC), but also follows a step-wise increase in different levels of dysplasia.Chemical inhibition of LMWPTP significantly reduces CRC growth.In conclusion, this study shows that LMWPTP is not only overexpressed in colorectal cancer, but it is correlated with the malignant potential of this cancer, suggesting that this phosphatase may act as a predictive biomaker of CRC stage and represents a rational novel target in the treatment of this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, 's Gravendijkwa, Rotterdam, The Netherlands.

ABSTRACT
Phosphatases have long been regarded as tumor suppressors, however there is emerging evidence for a tumor initiating role for some phosphatases in several forms of cancer. Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP; acid phosphatase 1 [ACP1]) is an 18 kDa enzyme that influences the phosphorylation of signaling pathway mediators involved in cancer and is thus postulated to be a tumor-promoting enzyme, but neither unequivocal clinical evidence nor convincing mechanistic actions for a role of LMWPTP have been identified. In the present study, we show that LMWPTP expression is not only significantly increased in colorectal cancer (CRC), but also follows a step-wise increase in different levels of dysplasia. Chemical inhibition of LMWPTP significantly reduces CRC growth. Furthermore, downregulation of LMWPTP in CRC leads to a reduced migration ability in both 2D- and 3D-migration assays, and sensitizes tumor cells to the chemotherapeutic agent 5-FU. In conclusion, this study shows that LMWPTP is not only overexpressed in colorectal cancer, but it is correlated with the malignant potential of this cancer, suggesting that this phosphatase may act as a predictive biomaker of CRC stage and represents a rational novel target in the treatment of this disease.

No MeSH data available.


Related in: MedlinePlus