Effect of the IGF-1/PTEN/Akt/FoxO signaling pathway on the development and healing of water immersion and restraint stress-induced gastric ulcers in rats

Huang,Pan; Zhou,Zhengrong; Wang,Hao; Wei,Quanwei; Zhang,Liang; Zhou,Xin; Hutz,Reinhold  J.; Shi,Fangxiong

doi:10.3892/ijmm.2012.1041

Effect of the IGF-1/PTEN/Akt/FoxO signaling pathway on the development and healing of water immersion and restraint stress-induced gastric ulcers in rats

Authors:
- Pan Huang
- Zhengrong Zhou
- Hao Wang
- Quanwei Wei
- Liang Zhang
- Xin Zhou
- Reinhold J. Hutz
- Fangxiong Shi
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Affiliations: College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, P.R. China, Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
Published online on: June 20, 2012 https://doi.org/10.3892/ijmm.2012.1041
Pages: 650-658

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Abstract

Insulin-like growth factor 1 (IGF-1) and Akt [also known as protein kinase B (PKB)] proteins have been reported to exhibit gastroprotective effects by reducing water immersion and restraint stress (WRS)-induced gastric mucosal cellular apoptosis. To confirm whether the IGF-1/PTEN/Akt/FoxO signaling pathway is effective in protecting against gastric ulcers, our current study was conducted to examine the expression and localization of IGF-1, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), Akt and O subfamily of forkhead box (FoxO) proteins, caspase-3 activity and the number of apoptotic cells in gastric mucosa of rats subjected to WRS. Our results demonstrated that WRS induced gastric ulcers by enhancing cell apoptosis in rat gastric mucosa. In addition, in normal rat gastric mucosa, PTEN, total Akt and FoxO1 were found mainly in the cell cytoplasm of fundic glands in the lamina propria close to the muscularis mucosa. In addition, strong staining of IGF-1, FoxO3a and FoxO4 in the gastric mucosa was primarily concentrated in the cell cytoplasm of the fundic glands in whole lamina propria. However, in rat gastric ulcers, IGF-1, total Akt, FoxO3a and FoxO4 were localized in proximity to the base of the ulcer margin and were also present in the granulation tissues of the gastric ulcers. Moreover, in the rat gastric ulcers, the mRNA transcript levels of IGF-1, PTEN, Akt-1, Akt-2, FoxO3 and FoxO4 were upregulated in the gastric ulcer margin, with a peak between Days 4 and 8 following 7 h of WRS. In conclusion, our results imply that the IGF-1/PTEN/Akt/FoxO signaling pathway plays a certain role(s) in the protection against ulceration through the regulation of cellular apoptosis as observed in the development and healing of rat gastric ulcers.

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1.	DH CastrillonL MiaoR KolliparaJW HornerRA DePinhoSuppression of ovarian follicle activation in mice by the transcription factor Foxo3aScience301215218200310.1126/science.108633612855809
2.	A CarneroC Blanco-AparicioO RennerW LinkJF LealThe PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implicationsCurr Cancer Drug Targets8187198200810.2174/15680090878429365918473732
3.	P ReddyL LiuD AdhikariOocyte-specific deletion of Pten causes premature activation of the primordial follicle poolScience319611613200810.1126/science.115225718239123
4.	PV CarrollTreatment with growth hormone and insulin-like growth factor-I in critical illnessBest Pract Res Clin Endocrinol Metab15435451200110.1053/beem.2001.016211800516
5.	G SongG OuyangS BaoThe activation of Akt/PKB signaling pathway and cell survivalJ Cell Mol Med95971200510.1111/j.1582-4934.2005.tb00337.x15784165
6.	M CullyH YouAJ LevineTW MakBeyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesisNat Rev Cancer6184192200610.1038/nrc181916453012
7.	JA Fresno VaraE CasadoJ de CastroP CejasC Belda-IniestaM Gonzalez-BaronPI3K/Akt signalling pathway and cancerCancer Treat Rev30193204200415023437
8.	NR LeslieCP DownesPTEN function: how normal cells control it and tumour cells lose itBiochem J382111200410.1042/BJ2004082515193142
9.	DA CrossDR AlessiP CohenM AndjelkovichBA HemmingsInhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase BNature378785789199510.1038/378785a08524413
10.	A SenguptaJD MolkentinJH PaikRA DePinhoKE YutzeyFoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stressJ Biol Chem28674687478201110.1074/jbc.M110.17924221159781
11.	BM BurgeringGJ KopsCell cycle and death control: long live ForkheadsTrends Biochem Sci27352360200210.1016/S0968-0004(02)02113-812114024
12.	M AdachiG HoriuchiN IkematsuIntragastrically administered lysophosphatidic acids protect against gastric ulcer in rats under water-immersion restraint stressDig Dis Sci5622522261201110.1007/s10620-011-1595-0
13.	SX YiY PengXR ChangN PengJ YanYP LinEffect of pre-moxibustion on apoptosis and proliferation of gastric mucosa cellsWorld J Gastroenterol1321742178200710.3748/wjg.v13.i15.217417465496
14.	SN NieXM QianXH WuRole of TFF in healing of stress-induced gastric lesionsWorld J Gastroenterol917721776200312918118
15.	YM LiGM LuXP ZouZS LiGY PengDC FangDynamic functional and ultrastructural changes of gastric parietal cells induced by water immersion-restraint stress in ratsWorld J Gastroenterol12336833722006
16.	P JiangL ChangCS PanYF QiCS TangProtective role of metallothionein in stress-induced gastric ulcer in ratsWorld J Gastroenterol1127392743200510.3748/wjg.v11.i18.273915884113
17.	T NguyenJ ChaiA LiT AkahoshiT TanigawaAS TarnawskiNovel roles of local insulin-like growth factor-1 activation in gastric ulcer healing: promotes actin polymerization, cell proliferation, re-epithelialization, and induces cyclooxygenase-2 in a phosphatidylinositol 3-kinase-dependent mannerAm J Pathol17012191228200710.2353/ajpath.2007.060745
18.	N HaradaK OkajimaH KuriharaN NakagataStimulation of sensory neurons by capsaicin increases tissue levels of IGF-I, thereby reducing reperfusion-induced apoptosis in miceNeuropharmacology5213031311200710.1016/j.neuropharm.2007.01.016
19.	MA DaemenC van ‘t VeerG DeneckerInhibition of apoptosis induced by ischemia-reperfusion prevents inflammationJ Clin Invest104541549199910.1172/JCI697410487768
20.	S WatanabeXE WangM HiroseInsulin-like growth factor I plays a role in gastric wound healing: evidence using a zinc derivative, polaprezinc, and an in vitro rabbit wound repair modelAliment Pharmacol Ther1211311138199810.1046/j.1365-2036.1998.00408.x
21.	SN NieHC SunXH WuXM QianCyclooxygenase 2, pS2, inducible nitric oxide synthase and transforming growth factor alpha in gastric adaptation to stressWorld J Gastroenterol1035373541200415526382
22.	J ZhaoN HaradaK SobueH KatsuyaK OkajimaInsulin-like growth factor-I reduces stress-induced gastric mucosal injury by inhibiting neutrophil activation in miceGrowth Horm IGF Res19136145200910.1016/j.ghir.2008.08.00318809348
23.	P HuangZQ ZhouRH HuangB ZhouQW WeiFX ShiAge-dependent expression of forkhead box O proteins in the duodenum of ratsJ Zhejiang Univ Sci B12730735201110.1631/jzus.B100029821887848
24.	ZQ ZhouT WangLM PanRH HuangFX ShiFoxO4 is the main forkhead transcriptional factor localized in the gastrointestinal tracts of pigsJ Zhejiang Univ Sci B83944200710.1631/jzus.2007.B003917173361
25.	N ShimozawaK OkajimaN HaradaContribution of sensory neurons to sex difference in the development of stress-induced gastric mucosal injury in miceGastroenterology13118261834200610.1053/j.gastro.2006.09.00517087955
26.	KJ KellyRM SandovalKW DunnBA MolitorisPC DagherA novel method to determine specificity and sensitivity of the TUNEL reaction in the quantitation of apoptosisAm J Physiol Cell Physiol284C1309C1318200310.1152/ajpcell.00353.200212676658
27.	W WangJ XuL LiNeuroprotective effect of morroniside on focal cerebral ischemia in ratsBrain Res Bull83196201201010.1016/j.brainresbull.2010.07.00320637265
28.	L SongB ZhangY FengX LuoX WeiX XiaoA role for forkhead box A1 in acute lung injuryInflammation32322332200910.1007/s10753-009-9139-x19649697
29.	W DingW WangB ZhouFormation of primordial follicles and immunolocalization of PTEN, PKB and FOXO3A proteins in the ovaries of fetal and neonatal pigsJ Reprod Dev56162168201010.1262/jrd.09-094H19996554
30.	WM LiuFX ShiLZ LuEffects of linoleic acid and eicosapentaenoic acid on cell proliferation and lipid-metabolism gene expression in primary duck hepatocytesMol Cell Biochem3521924201110.1007/s11010-011-0735-321274596
31.	T BrzozowskiPC KonturekS ChlopickiTherapeutic potential of 1-methylnicotinamide against acute gastric lesions induced by stress: role of endogenous prostacyclin and sensory nervesJ Pharmacol Exp Ther326105116200810.1124/jpet.108.136457
32.	T BrzozowskiK Zwirska-KorczalaPC KonturekRole of circadian rhythm and endogenous melatonin in pathogenesis of acute gastric bleeding erosions induced by stressJ Physiol Pharmacol58Suppl 6S53S64200718212400
33.	P CeranowiczZ WarzechaA DembinskiTreatment with ghrelin accelerates the healing of acetic acid-induced gastric and duodenal ulcers in ratsJ Physiol Pharmacol608798200919439811
34.	CY ChenTL KuoSY SheuTF KuoPreventive effects of Chinese herb chai-hu-gui-zhi-tang extract on water immersion restraint stress-induced acute gastric ulceration in ratsJ Vet Med Sci72679685201010.1292/jvms.09-028420086327
35.	Z SunX WangR WallenThe influence of apoptosis on intestinal barrier integrity in ratsScand J Gastroenterol33415422199810.1080/003655298501710539605264
36.	PC KonturekT BrzozowskiA DudaEpidermal growth factor and prostaglandin E(2) accelerate mucosal recovery from stress-induced gastric lesions via inhibition of apoptosisJ Physiol Paris95361367200110.1016/S0928-4257(01)00049-311595461
37.	PC KonturekT BrzozowskiSJ KonturekApoptosis in gastric mucosa with stress-induced gastric ulcersJ Physiol Pharmacol50211225199910424718
38.	EM CreaghH ConroySJ MartinCaspase-activation pathways in apoptosis and immunityImmunol Rev1931021200310.1034/j.1600-065X.2003.00048.x12752666
39.	N HaradaK OkajimaM UchibaT KatsuragiContribution of capsaicin-sensitive sensory neurons to stress-induced increases in gastric tissue levels of prostaglandins in ratsAm J Physiol Gastrointest Liver Physiol285G1214G1224200310.1152/ajpgi.00364.200212893632
40.	ED RabinovskyThe multifunctional role of IGF-1 in peripheral nerve regenerationNeurol Res26204210200410.1179/01616410422501385115072640
41.	OP ChaurasiaSP MarcuardER SeidelInsulin-like growth factor I in human gastrointestinal exocrine secretionsRegul Pept50113119199410.1016/0167-0115(94)90026-48190912
42.	RP KorolkiewiczK TashimaA FujitaS KatoK TakeuchiExogenous insulin-like growth factor (IGF)-1 improves the impaired healing of gastric mucosal lesions in diabetic ratsPharmacol Res41221229200010.1006/phrs.1999.058110623490
43.	S KatoA TanakaY OgawaEffect of polaprezinc on impaired healing of chronic gastric ulcers in adjuvant-induced arthritic rats - role of insulin-like growth factors (IGF)-1Med Sci Monit72025200111208487
44.	S CoerperS WolfS von KiparskiInsulin-like growth factor I accelerates gastric ulcer healing by stimulating cell proliferation and by inhibiting gastric acid secretionScand J Gastroenterol36921927200110.1080/00365520175030542211521981
45.	D AlvaroVD MetalliG AlpiniThe intrahepatic biliary epithelium is a target of the growth hormone/insulin-like growth factor 1 axisJ Hepatol43875883200510.1016/j.jhep.2005.04.01116083987
46.	X XiongHZ RenMH LiJH MeiJF WenCL ZhengDown-regulated miRNA-214 induces a cell cycle G1 arrest in gastric cancer cells by up-regulating the PTEN proteinPathol Oncol Res17931937201110.1007/s12253-011-9406-721688200
47.	X WangY XieQ XiaoLentivirus-mediated RNA interference targeting E2F-1 inhibits human gastric cancer MGC-803 cell growth in vivoExp Mol Med43638645201110.3858/emm.2011.43.11.07221869593
48.	X LiuWJ GuoXW ZhangX CaiS TianJ LiCetuximab enhances the activities of irinotecan on gastric cancer cell lines through downregulating the EGFR pathway upregulated by irinotecanCancer Chemother Pharmacol68871878201110.1007/s00280-011-1559-221286718
49.	J NakaeWH Biggs IIIT KitamuraRegulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1Nat Genet32245253200210.1038/ng89012219087
50.	Y LiuY WangT ShanJ GuoC XuJ LiuThe tissue-specific and developmental expression patterns of the forkhead transcription factor FoxO1 gene in pigsJ Anim Feed Sci171821902008