Limits...
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 influences cell adhesion and cell morphology(A) CRC cell adhesion was determined by MTT assay of adherent cells after indicated time points, with fibronectin (FN) coating serving as control. CACO-2 LMWPTP knockdown cells adhere less than control cells (*P < 0.05; **P < 0.01). (B, C) Confocal microscopy of Phalloidin-rhodamine stained cells was employed to examine cell morphology. Immunofluorescence reveals a more elongated morphology in HCT116 LMWPTP knockdown cells as compared to control (B). To quantify the changes in morphology, the ratio between the length and width of the cells was calculated, with a higher ratio indicating a more elongated shape. Non-target control cells have a significantly lower ratio compared to LMWPTP knockdown cells. (1.1 ± 0.02 vs 1.7 ± 0.18, n = 26; P < 0.0001) (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4480753&req=5

Figure 6: LMWPTP influences cell adhesion and cell morphology(A) CRC cell adhesion was determined by MTT assay of adherent cells after indicated time points, with fibronectin (FN) coating serving as control. CACO-2 LMWPTP knockdown cells adhere less than control cells (*P < 0.05; **P < 0.01). (B, C) Confocal microscopy of Phalloidin-rhodamine stained cells was employed to examine cell morphology. Immunofluorescence reveals a more elongated morphology in HCT116 LMWPTP knockdown cells as compared to control (B). To quantify the changes in morphology, the ratio between the length and width of the cells was calculated, with a higher ratio indicating a more elongated shape. Non-target control cells have a significantly lower ratio compared to LMWPTP knockdown cells. (1.1 ± 0.02 vs 1.7 ± 0.18, n = 26; P < 0.0001) (C).

Mentions: As both CACO-2 and HCT116 cell lines demonstrated reduced FAK activity and subsequent migration upon LMWPTP knock down, we next set out to further examine the underlying mechanism of this reduced migration. First we investigated the adhesive capacity of these cell lines, adhesion being indispensable for proper migration, and FAK being a major regulator of this process. As shown in Figure 6A, full adherence of CACO-2 non-target cells to the glass surface was reached after 30 minutes and 1 h, while only 50% of the knockdown cells adhered to the bottom of the wells within these time points (P > 0.05). In contrast, HCT116 cells were much slower to adhere, and no differences could be observed between LMWPTP knock down and control cells (Figure S5A).


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 influences cell adhesion and cell morphology(A) CRC cell adhesion was determined by MTT assay of adherent cells after indicated time points, with fibronectin (FN) coating serving as control. CACO-2 LMWPTP knockdown cells adhere less than control cells (*P < 0.05; **P < 0.01). (B, C) Confocal microscopy of Phalloidin-rhodamine stained cells was employed to examine cell morphology. Immunofluorescence reveals a more elongated morphology in HCT116 LMWPTP knockdown cells as compared to control (B). To quantify the changes in morphology, the ratio between the length and width of the cells was calculated, with a higher ratio indicating a more elongated shape. Non-target control cells have a significantly lower ratio compared to LMWPTP knockdown cells. (1.1 ± 0.02 vs 1.7 ± 0.18, n = 26; P < 0.0001) (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: LMWPTP influences cell adhesion and cell morphology(A) CRC cell adhesion was determined by MTT assay of adherent cells after indicated time points, with fibronectin (FN) coating serving as control. CACO-2 LMWPTP knockdown cells adhere less than control cells (*P < 0.05; **P < 0.01). (B, C) Confocal microscopy of Phalloidin-rhodamine stained cells was employed to examine cell morphology. Immunofluorescence reveals a more elongated morphology in HCT116 LMWPTP knockdown cells as compared to control (B). To quantify the changes in morphology, the ratio between the length and width of the cells was calculated, with a higher ratio indicating a more elongated shape. Non-target control cells have a significantly lower ratio compared to LMWPTP knockdown cells. (1.1 ± 0.02 vs 1.7 ± 0.18, n = 26; P < 0.0001) (C).
Mentions: As both CACO-2 and HCT116 cell lines demonstrated reduced FAK activity and subsequent migration upon LMWPTP knock down, we next set out to further examine the underlying mechanism of this reduced migration. First we investigated the adhesive capacity of these cell lines, adhesion being indispensable for proper migration, and FAK being a major regulator of this process. As shown in Figure 6A, full adherence of CACO-2 non-target cells to the glass surface was reached after 30 minutes and 1 h, while only 50% of the knockdown cells adhered to the bottom of the wells within these time points (P > 0.05). In contrast, HCT116 cells were much slower to adhere, and no differences could be observed between LMWPTP knock down and control cells (Figure S5A).

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