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Transient receptor potential ion channel Trpm7 regulates exocrine pancreatic epithelial proliferation by Mg2+-sensitive Socs3a signaling in development and cancer.

Yee NS, Zhou W, Liang IC - Dis Model Mech (2010)

Bottom Line: The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth.TRPM7 is generally overexpressed in human pancreatic adenocarcinoma.Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. nelson-yee@uiowa.edu

ABSTRACT
Genetic analysis of pancreatic development has provided new insights into the mechanisms underlying the formation of exocrine pancreatic neoplasia. Zebrafish sweetbread (swd) mutants develop hypoplastic acini and dysmorphic ducts in the exocrine pancreas, with impeded progression of cell division cycle and of epithelial growth. Positional cloning and allelic complementation have revealed that the swd mutations affect the transient receptor potential melastatin-subfamily member 7 (trpm7) gene, which encodes a divalent cation-permeable channel with kinase activity. Supplementary Mg(2+) partially rescued the exocrine pancreatic defects of the trpm7 mutants by improving cell-cycle progression and growth and repressing the suppressor of cytokine signaling 3a (socs3a) gene. The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth. TRPM7 is generally overexpressed in human pancreatic adenocarcinoma. TRPM7-deficient cells are impaired in proliferation and arrested in the G0-G1 phases of the cell division cycle. Supplementary Mg(2+) rescued the proliferative defect of the TRPM7-deficient cells. Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

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Related in: MedlinePlus

TRPM7 is overexpressed in human pancreatic adenocarcinoma and required for cellular proliferation. (A) Expression of TRPM7 protein in human pancreatic adenocarcinoma (upper panel) and normal pancreatic tissue (lower panel) by immunohistochemistry using anti-TRPM7 antibodies. The images shown are representative of five tumor specimens and five normal control samples. Scale bars: 100 μm. (B) Relative TRPM7 mRNA levels in human pancreatic adenocarcinoma cell lines by quantitative real-time PCR. Each value represents the mean ratio of each pancreatic cancer cell line to that of H6c7 from triplicate samples, and reproducible results were obtained from two independent experiments. (C) Cell morphology at 24 hours post-transfection with siRNA was examined under an inverted microscope with phase contrast. Red arrows point to multinucleated cells with cytoplasmic vacuoles.
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f7-0040240: TRPM7 is overexpressed in human pancreatic adenocarcinoma and required for cellular proliferation. (A) Expression of TRPM7 protein in human pancreatic adenocarcinoma (upper panel) and normal pancreatic tissue (lower panel) by immunohistochemistry using anti-TRPM7 antibodies. The images shown are representative of five tumor specimens and five normal control samples. Scale bars: 100 μm. (B) Relative TRPM7 mRNA levels in human pancreatic adenocarcinoma cell lines by quantitative real-time PCR. Each value represents the mean ratio of each pancreatic cancer cell line to that of H6c7 from triplicate samples, and reproducible results were obtained from two independent experiments. (C) Cell morphology at 24 hours post-transfection with siRNA was examined under an inverted microscope with phase contrast. Red arrows point to multinucleated cells with cytoplasmic vacuoles.

Mentions: Developmental regulators of exocrine pancreas have been shown to play important roles in pancreatic carcinogenesis (Yee and Pack, 2005; Yee, 2010). To test the hypothesis that TRPM7 plays a functional role in pancreatic adenocarcinoma, expression of TRPM7 was analyzed in human pancreatic adenocarcinoma tissues by immunohistochemistry. In contrast to the low level of immunoreactivity at the apical plasma membrane of pancreatic ductal epithelia, TRPM7 was diffusely expressed in the cytoplasm at elevated levels in pancreatic adenocarcinoma (Fig. 7A). Expression of TRPM7 mRNA was then quantified in a panel of established and characterized cell lines by real-time PCR. As compared with human pancreatic ductal epithelia, TRPM7 mRNA was expressed at elevated levels in five of seven human pancreatic adenocarcinoma cell lines examined (Fig. 7B). TRPM7 protein was similarly expressed at relatively high levels in those cell lines, as revealed by immunoblot analysis (N.S.Y., unpublished). Taken together, these data indicate that TRPM7 is overexpressed in human pancreatic adenocarcinoma and suggest a functional role of TRPM7 in the pathogenesis of pancreatic neoplasia.


Transient receptor potential ion channel Trpm7 regulates exocrine pancreatic epithelial proliferation by Mg2+-sensitive Socs3a signaling in development and cancer.

Yee NS, Zhou W, Liang IC - Dis Model Mech (2010)

TRPM7 is overexpressed in human pancreatic adenocarcinoma and required for cellular proliferation. (A) Expression of TRPM7 protein in human pancreatic adenocarcinoma (upper panel) and normal pancreatic tissue (lower panel) by immunohistochemistry using anti-TRPM7 antibodies. The images shown are representative of five tumor specimens and five normal control samples. Scale bars: 100 μm. (B) Relative TRPM7 mRNA levels in human pancreatic adenocarcinoma cell lines by quantitative real-time PCR. Each value represents the mean ratio of each pancreatic cancer cell line to that of H6c7 from triplicate samples, and reproducible results were obtained from two independent experiments. (C) Cell morphology at 24 hours post-transfection with siRNA was examined under an inverted microscope with phase contrast. Red arrows point to multinucleated cells with cytoplasmic vacuoles.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3046099&req=5

f7-0040240: TRPM7 is overexpressed in human pancreatic adenocarcinoma and required for cellular proliferation. (A) Expression of TRPM7 protein in human pancreatic adenocarcinoma (upper panel) and normal pancreatic tissue (lower panel) by immunohistochemistry using anti-TRPM7 antibodies. The images shown are representative of five tumor specimens and five normal control samples. Scale bars: 100 μm. (B) Relative TRPM7 mRNA levels in human pancreatic adenocarcinoma cell lines by quantitative real-time PCR. Each value represents the mean ratio of each pancreatic cancer cell line to that of H6c7 from triplicate samples, and reproducible results were obtained from two independent experiments. (C) Cell morphology at 24 hours post-transfection with siRNA was examined under an inverted microscope with phase contrast. Red arrows point to multinucleated cells with cytoplasmic vacuoles.
Mentions: Developmental regulators of exocrine pancreas have been shown to play important roles in pancreatic carcinogenesis (Yee and Pack, 2005; Yee, 2010). To test the hypothesis that TRPM7 plays a functional role in pancreatic adenocarcinoma, expression of TRPM7 was analyzed in human pancreatic adenocarcinoma tissues by immunohistochemistry. In contrast to the low level of immunoreactivity at the apical plasma membrane of pancreatic ductal epithelia, TRPM7 was diffusely expressed in the cytoplasm at elevated levels in pancreatic adenocarcinoma (Fig. 7A). Expression of TRPM7 mRNA was then quantified in a panel of established and characterized cell lines by real-time PCR. As compared with human pancreatic ductal epithelia, TRPM7 mRNA was expressed at elevated levels in five of seven human pancreatic adenocarcinoma cell lines examined (Fig. 7B). TRPM7 protein was similarly expressed at relatively high levels in those cell lines, as revealed by immunoblot analysis (N.S.Y., unpublished). Taken together, these data indicate that TRPM7 is overexpressed in human pancreatic adenocarcinoma and suggest a functional role of TRPM7 in the pathogenesis of pancreatic neoplasia.

Bottom Line: The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth.TRPM7 is generally overexpressed in human pancreatic adenocarcinoma.Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. nelson-yee@uiowa.edu

ABSTRACT
Genetic analysis of pancreatic development has provided new insights into the mechanisms underlying the formation of exocrine pancreatic neoplasia. Zebrafish sweetbread (swd) mutants develop hypoplastic acini and dysmorphic ducts in the exocrine pancreas, with impeded progression of cell division cycle and of epithelial growth. Positional cloning and allelic complementation have revealed that the swd mutations affect the transient receptor potential melastatin-subfamily member 7 (trpm7) gene, which encodes a divalent cation-permeable channel with kinase activity. Supplementary Mg(2+) partially rescued the exocrine pancreatic defects of the trpm7 mutants by improving cell-cycle progression and growth and repressing the suppressor of cytokine signaling 3a (socs3a) gene. The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth. TRPM7 is generally overexpressed in human pancreatic adenocarcinoma. TRPM7-deficient cells are impaired in proliferation and arrested in the G0-G1 phases of the cell division cycle. Supplementary Mg(2+) rescued the proliferative defect of the TRPM7-deficient cells. Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

Show MeSH
Related in: MedlinePlus