Annexin A2 mediates Up-regulation of NF-κB, β-catenin, and stem cell in response to progastrin in mice and HEK-293 cells

Shubhashish Sarkar, Rafal Swiercz, Carla Kantara, Katherine A. Hajjar, Pomila Singh

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Background & Aims Prograstrin induces proliferation in colon crypts by activating p65nuclear factor-κB (NF-κB) (p65) and β-catenin. We investigated whether Annexin A2 (AnxA2), a progastrin receptor, activates NF-κB and β-catenin in vivo. Methods ANXA2-null (ANXA2-/-) and wild-type (ANXA2+/+) mice were studied, along with clones of progastrin-responsive HEK-293 cells that stably expressed full-length progastrin (HEK-mGAS) or an empty vector (HEK-C). Small interfering RNA was used to down-regulate AnxA2, p65NF-κB, and β-catenin in cells. Results Proliferation and activation of p65 and β-catenin increased significantly in HEK-mGAS compared with HEK-C clones. HEK-mGAS cells had a 2- to 4-fold increase in relative levels of c-Myc, cyclooxygenase (COX)-2, CyclinD1, double cortin CAM kinase-like 1 (DCAMKL+1), and CD44, compared with HEK-C clones. Down-regulation of AnxA2 in HEK-mGAS clones reduced activation of NF-κB and β-catenin, as well as levels of DCAMKL+1. Surprisingly, down-regulation of β-catenin had no effect on activation of p65NF-κB, whereas down-regulation of p65 significantly reduced activation of β-catenin in HEK-mGAS clones. Loss of either p65 or β-catenin significantly reduced proliferation of HEK-mGAS clones, indicating that both factors are required for the proliferative effects of progastrin. Lengths of colon crypts and levels of p65, β-catenin, DCAMKL+1, and CD44 were significantly higher in ANXA2 +/+ mice compared with either ANXA2-/- mice given progastrin or ANXA2+/+ and ANXA2-/- mice given saline. Conclusions AnxA2 expression is required for the biologic effects of progastrin in vivo and in vitro and mediates the stimulatory effect of progastrin on p65NF-κ, β-catenin, and the putative stem cell markers DCAMKL+1 and CD44. AnxA2 might therefore mediate the hyperproliferative and cocarcinogenic effects of progastrin.

Original languageEnglish (US)
Pages (from-to)583-595
Number of pages13
JournalGastroenterology
Volume140
Issue number2
DOIs
StatePublished - Feb 2011

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Annexins
Catenins
HEK293 Cells
Up-Regulation
Stem Cells
Annexin A2
Clone Cells
Down-Regulation
Colon
big gastrin
Cyclooxygenase 2
Small Interfering RNA
Phosphotransferases

Keywords

  • CD44
  • Colorectal Cancer
  • DCAMKL+1
  • Signaling

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Annexin A2 mediates Up-regulation of NF-κB, β-catenin, and stem cell in response to progastrin in mice and HEK-293 cells. / Sarkar, Shubhashish; Swiercz, Rafal; Kantara, Carla; Hajjar, Katherine A.; Singh, Pomila.

In: Gastroenterology, Vol. 140, No. 2, 02.2011, p. 583-595.

Research output: Contribution to journalArticle

Sarkar, Shubhashish ; Swiercz, Rafal ; Kantara, Carla ; Hajjar, Katherine A. ; Singh, Pomila. / Annexin A2 mediates Up-regulation of NF-κB, β-catenin, and stem cell in response to progastrin in mice and HEK-293 cells. In: Gastroenterology. 2011 ; Vol. 140, No. 2. pp. 583-595.
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abstract = "Background & Aims Prograstrin induces proliferation in colon crypts by activating p65nuclear factor-κB (NF-κB) (p65) and β-catenin. We investigated whether Annexin A2 (AnxA2), a progastrin receptor, activates NF-κB and β-catenin in vivo. Methods ANXA2-null (ANXA2-/-) and wild-type (ANXA2+/+) mice were studied, along with clones of progastrin-responsive HEK-293 cells that stably expressed full-length progastrin (HEK-mGAS) or an empty vector (HEK-C). Small interfering RNA was used to down-regulate AnxA2, p65NF-κB, and β-catenin in cells. Results Proliferation and activation of p65 and β-catenin increased significantly in HEK-mGAS compared with HEK-C clones. HEK-mGAS cells had a 2- to 4-fold increase in relative levels of c-Myc, cyclooxygenase (COX)-2, CyclinD1, double cortin CAM kinase-like 1 (DCAMKL+1), and CD44, compared with HEK-C clones. Down-regulation of AnxA2 in HEK-mGAS clones reduced activation of NF-κB and β-catenin, as well as levels of DCAMKL+1. Surprisingly, down-regulation of β-catenin had no effect on activation of p65NF-κB, whereas down-regulation of p65 significantly reduced activation of β-catenin in HEK-mGAS clones. Loss of either p65 or β-catenin significantly reduced proliferation of HEK-mGAS clones, indicating that both factors are required for the proliferative effects of progastrin. Lengths of colon crypts and levels of p65, β-catenin, DCAMKL+1, and CD44 were significantly higher in ANXA2 +/+ mice compared with either ANXA2-/- mice given progastrin or ANXA2+/+ and ANXA2-/- mice given saline. Conclusions AnxA2 expression is required for the biologic effects of progastrin in vivo and in vitro and mediates the stimulatory effect of progastrin on p65NF-κ, β-catenin, and the putative stem cell markers DCAMKL+1 and CD44. AnxA2 might therefore mediate the hyperproliferative and cocarcinogenic effects of progastrin.",
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T1 - Annexin A2 mediates Up-regulation of NF-κB, β-catenin, and stem cell in response to progastrin in mice and HEK-293 cells

AU - Sarkar, Shubhashish

AU - Swiercz, Rafal

AU - Kantara, Carla

AU - Hajjar, Katherine A.

AU - Singh, Pomila

PY - 2011/2

Y1 - 2011/2

N2 - Background & Aims Prograstrin induces proliferation in colon crypts by activating p65nuclear factor-κB (NF-κB) (p65) and β-catenin. We investigated whether Annexin A2 (AnxA2), a progastrin receptor, activates NF-κB and β-catenin in vivo. Methods ANXA2-null (ANXA2-/-) and wild-type (ANXA2+/+) mice were studied, along with clones of progastrin-responsive HEK-293 cells that stably expressed full-length progastrin (HEK-mGAS) or an empty vector (HEK-C). Small interfering RNA was used to down-regulate AnxA2, p65NF-κB, and β-catenin in cells. Results Proliferation and activation of p65 and β-catenin increased significantly in HEK-mGAS compared with HEK-C clones. HEK-mGAS cells had a 2- to 4-fold increase in relative levels of c-Myc, cyclooxygenase (COX)-2, CyclinD1, double cortin CAM kinase-like 1 (DCAMKL+1), and CD44, compared with HEK-C clones. Down-regulation of AnxA2 in HEK-mGAS clones reduced activation of NF-κB and β-catenin, as well as levels of DCAMKL+1. Surprisingly, down-regulation of β-catenin had no effect on activation of p65NF-κB, whereas down-regulation of p65 significantly reduced activation of β-catenin in HEK-mGAS clones. Loss of either p65 or β-catenin significantly reduced proliferation of HEK-mGAS clones, indicating that both factors are required for the proliferative effects of progastrin. Lengths of colon crypts and levels of p65, β-catenin, DCAMKL+1, and CD44 were significantly higher in ANXA2 +/+ mice compared with either ANXA2-/- mice given progastrin or ANXA2+/+ and ANXA2-/- mice given saline. Conclusions AnxA2 expression is required for the biologic effects of progastrin in vivo and in vitro and mediates the stimulatory effect of progastrin on p65NF-κ, β-catenin, and the putative stem cell markers DCAMKL+1 and CD44. AnxA2 might therefore mediate the hyperproliferative and cocarcinogenic effects of progastrin.

AB - Background & Aims Prograstrin induces proliferation in colon crypts by activating p65nuclear factor-κB (NF-κB) (p65) and β-catenin. We investigated whether Annexin A2 (AnxA2), a progastrin receptor, activates NF-κB and β-catenin in vivo. Methods ANXA2-null (ANXA2-/-) and wild-type (ANXA2+/+) mice were studied, along with clones of progastrin-responsive HEK-293 cells that stably expressed full-length progastrin (HEK-mGAS) or an empty vector (HEK-C). Small interfering RNA was used to down-regulate AnxA2, p65NF-κB, and β-catenin in cells. Results Proliferation and activation of p65 and β-catenin increased significantly in HEK-mGAS compared with HEK-C clones. HEK-mGAS cells had a 2- to 4-fold increase in relative levels of c-Myc, cyclooxygenase (COX)-2, CyclinD1, double cortin CAM kinase-like 1 (DCAMKL+1), and CD44, compared with HEK-C clones. Down-regulation of AnxA2 in HEK-mGAS clones reduced activation of NF-κB and β-catenin, as well as levels of DCAMKL+1. Surprisingly, down-regulation of β-catenin had no effect on activation of p65NF-κB, whereas down-regulation of p65 significantly reduced activation of β-catenin in HEK-mGAS clones. Loss of either p65 or β-catenin significantly reduced proliferation of HEK-mGAS clones, indicating that both factors are required for the proliferative effects of progastrin. Lengths of colon crypts and levels of p65, β-catenin, DCAMKL+1, and CD44 were significantly higher in ANXA2 +/+ mice compared with either ANXA2-/- mice given progastrin or ANXA2+/+ and ANXA2-/- mice given saline. Conclusions AnxA2 expression is required for the biologic effects of progastrin in vivo and in vitro and mediates the stimulatory effect of progastrin on p65NF-κ, β-catenin, and the putative stem cell markers DCAMKL+1 and CD44. AnxA2 might therefore mediate the hyperproliferative and cocarcinogenic effects of progastrin.

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