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Annexin A2 mediates up-regulation of NF-?B, ?-catenin, and stem cell in response to progastrin in mice and HEK-293 cells.

ABSTRACT: BACKGROUND & AIMS:Prograstrin induces proliferation in colon crypts by activating p65nuclear factor-?B (NF-?B) (p65) and ?-catenin. We investigated whether Annexin A2 (AnxA2), a progastrin receptor, activates NF-?B and ?-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-?B, and ?-catenin in cells. RESULTS:Proliferation and activation of p65 and ?-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-?B and ?-catenin, as well as levels of DCAMKL+1. Surprisingly, down-regulation of ?-catenin had no effect on activation of p65NF-?B, whereas down-regulation of p65 significantly reduced activation of ?-catenin in HEK-mGAS clones. Loss of either p65 or ?-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, ?-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-?, ?-catenin, and the putative stem cell markers DCAMKL+1 and CD44. AnxA2 might therefore mediate the hyperproliferative and cocarcinogenic effects of progastrin.

SUBMITTER: Sarkar S

PROVIDER: S-EPMC3031715 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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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 S Swiercz Rafal R Kantara Carla C Hajjar Katherine A KA Singh Pomila P

Gastroenterology 20100906 2

<h4>Background & aims</h4>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.<h4>Methods</h4>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 us ...[more]

PMID: 20826156

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Project description:BackgroundPituitary tumor transforming gene (PTTG), also known as securin, is highly expressed in various tumors including pituitary, thyroid, colon, ovary, testis, lung, and breast. An overexpression of PTTG enhances cell proliferation, induces cellular transformation in vitro, and promotes tumor development in nude mice. PTTG also inhibits separation of sister chromatids leading to aneuploidy and genetic instability. A great amount of work has been undertaken to understand the biology of PTTG and its expression in various tumors. However, mechanisms by which PTTG mediates its tumorigenic function are not fully understood. To utilize this gene for cancer therapy, identification of the downstream signaling genes regulated by PTTG in mediation of its tumorigenic function is necessary. For this purpose, we expressed PTTG in human embryonic kidney (HEK293) cells that do not express PTTG and analyzed the downstream genes using microarray analysis.ResultsA total of 22,277 genes printed on an Affymetrix HG-U133A 2.0 GeneChip array were screened with labeled cRNA prepared from HEK293 cells infected with adenovirus vector expressing PTTG cDNA (AdPTTG cDNA) and compared with labeled cRNA prepared from HEK293 cells infected with control adenovirus (control Ad) or adenovirus vector expressing GFP (AdGFP). Out of 22,277 genes, 71 genes were down-regulated and 35 genes were up-regulated with an FDR corrected p-value of < or = 0.05 and a fold change of > or =2. Most of the altered genes identified are involved in the cell cycle and cell apoptosis; a few are involved in mRNA processing and nitrogen metabolism. Most of the up-regulated genes belong to the histone protein family.ConclusionPTTG is a well-studied oncogene for its role in tumorigenesis. In addition to its importance in regulation of the cell cycle, this gene has also been recently shown to play a role in the induction of cell apoptosis. The microarray analysis in the present study demonstrated that PTTG may induce apoptosis by down-regulation of oncogenes such as v-Jun and v-maf and up-regulation of the histone family of genes.

Dataset Information

Annexin A2 mediates up-regulation of NF-?B, ?-catenin, and stem cell in response to progastrin in mice and HEK-293 cells.

Publications

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

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