Epithelial PIK3R1 (p85) and TP53 Regulate Survivin Expression during Adaptation to Ileocecal Resection

Cohran, V.; Managlia, E.; Bradford, E. M.; Goretsky, T.; Li, T.; Katzman, R. B.; Cheresh, P.; Brown, J. B.; Hawkins, J.; Liu, S. X.; De Plaen, I. G.; Weitkamp, J. H.; Helmrath, M.; Zhang, Z.; Barrett, T. A.

Am J Pathol. 2016 May 10; 186(7):1837-46

Abstract

Intestinal adaptation to small-bowel resection (SBR) after necrotizing enterocolitis expands absorptive surface areas and promotes enteral autonomy. Survivin increases proliferation and blunts apoptosis. The current study examines survivin in intestinal epithelial cells after ileocecal resection. Wild-type and epithelial Pik3r1 (p85alpha)-deficient mice underwent sham surgery or 30% resection. RNA and protein were isolated from small bowel to determine levels of beta-catenin target gene expression, activated caspase-3, survivin, p85alpha, and Trp53. Healthy and post-resection human infant small-bowel sections were analyzed for survivin, Ki-67, and TP53 by immunohistochemistry. Five days after ileocecal resection, epithelial levels of survivin increased relative to sham-operated on mice, which correlated with reduced cleaved caspase-3, p85alpha, and Trp53. At baseline, p85alpha-deficient intestinal epithelial cells had less Trp53 and more survivin, and relative responses to resection were blunted compared with wild-type. In infant small bowel, survivin in transit amplifying cells increased 71% after SBR. Resection increased proliferation and decreased numbers of TP53-positive epithelial cells. Data suggest that ileocecal resection reduces p85alpha, which lowers TP53 activation and releases survivin promoter repression. The subsequent increase in survivin among transit amplifying cells promotes epithelial cell proliferation and lengthens crypts. These findings suggest that SBR reduces p85alpha and TP53, which increases survivin and intestinal epithelial cell expansion during therapeutic adaptation in patients with short bowel syndrome.

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