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