AhR‑E2F1‑KGFR signaling is involved in KGF‑induced intestinal epithelial cell proliferation

Yang,Kunqiu; Yin,Jiuheng; Sheng,Baifa; Wang,Qimeng; Han,Bin; Pu,Aimin; Yu,Min; Sun,Lihua; Xiao,Weidong; Yang,Hua

doi:10.3892/mmr.2017.6368

AhR‑E2F1‑KGFR signaling is involved in KGF‑induced intestinal epithelial cell proliferation

Authors:
- Kunqiu Yang
- Jiuheng Yin
- Baifa Sheng
- Qimeng Wang
- Bin Han
- Aimin Pu
- Min Yu
- Lihua Sun
- Weidong Xiao
- Hua Yang
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Affiliations: Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
Published online on: March 23, 2017 https://doi.org/10.3892/mmr.2017.6368
Pages: 3019-3026
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Keratinocyte growth factor (KGF) stimulates intestinal epithelial cell proliferation upon binding to the KGF receptor (KGFR). The activated aryl hydrocarbon receptor (AhR) serves an important role in the development of tissues by promoting the expression of AhR receptors, which can regulate cell proliferation. In the present study, the signaling pathway between AhR and KGFR in investigated with regards to KGF‑induced intestinal epithelial cell proliferation. Male C57BL/6J wild type and AhR‑/‑ mice, were randomized into four groups: Control, KGF, AhR‑/‑ + KGF and AhR‑/‑ (n=6 per group). The small bowel was harvested on day 5 post‑treatment. LoVo cells were used to study signaling pathways in vitro and were divided into the following four treatment groups: DMSO, KGF, KGF + small‑interfering (si)AhR and siAhR. In vivo, knockdown of AhR mRNA transcripts may abolish KGF‑induced intestinal epithelial cell proliferation. Furthermore, KGFR expression was downregulated following knockdown or silencing of AhR expression in vivo and in vitro. The present study identified that the transcription factor E2F1 could regulate KGFR expression, and that siAhR treatment led to reduced expression of E2F1 in the nucleus and inhibited KGF‑induced cell proliferation. In conclusion, the current results demonstrated that the AhR‑E2F1‑KGFR pathway is involved in KGF‑induced intestinal epithelial cell proliferation.

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1	Boismenu R and Havran WL: Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science. 266:1253–1255. 1994. View Article : Google Scholar : PubMed/NCBI
2	Cai Y, Wang W, Liang H, Sun L, Teitelbaum DH and Yang H: Keratinocyte growth factor pretreatment prevents radiation-induced intestinal damage in a mouse model. Scand J Gastroenterol. 48:419–426. 2013. View Article : Google Scholar : PubMed/NCBI
3	Chen Y, Chou K, Fuchs E, Havran WL and Boismenu R: Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci USA. 99:14338–14343. 2002. View Article : Google Scholar : PubMed/NCBI
4	Burbach KM, Poland A and Bradfield CA: Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci USA. 89:8185–8189. 1992. View Article : Google Scholar : PubMed/NCBI
5	Wormke M, Stoner M, Saville B, Walker K, Abdelrahim M, Burghardt R and Safe S: The aryl hydrocarbon receptor mediates degradation of estrogen receptor through activation of proteasomes. Mol Cell Biol. 23:1843–1855. 2003. View Article : Google Scholar : PubMed/NCBI
6	Cai Y, Wang W, Liang H, Sun L, Teitelbaum DH and Yang H: Keratinocyte growth factor improves epithelial structure and function in a mouse model of intestinal ischemia/reperfusion. PLoS One. 7:e447722012. View Article : Google Scholar : PubMed/NCBI
7	Hankinson O: The aryl hydrocarbon receptor complex. Annu Rev Pharmacol Toxicol. 35:307–340. 1995. View Article : Google Scholar : PubMed/NCBI
8	Tashiro E, Minato Y, Maruki H, Asagiri M and Imoto M: Regulation of FGF receptor-2 expression by transcription factor E2F-1. Oncogene. 22:5630–5635. 2003. View Article : Google Scholar : PubMed/NCBI
9	Tashiro E, Maruki H, Minato Y, Doki Y, Weinstein IB and Imoto M: Overexpression of cyclin D1 contributes to malignancy by up-regulation of fibroblast growth factor receptor 1 via the pRB/E2F pathway. Cancer Res. 63:424–431. 2003.PubMed/NCBI
10	Yang H, Wildhaber BE and Teitelbaum DH: 2003 Harry M. Vars Research Award. Keratinocyte growth factor improves epithelial function after massive small bowel resection. JPEN J Parenter Enteral Nutr. 27:198–207. 2003. View Article : Google Scholar : PubMed/NCBI
11	Liu CJ, Jin JD, Lv TD, Wu ZZ and Ha XQ: Keratinocyte growth factor gene therapy ameliorates ulcerative colitis in rats. World J Gastroenterol. 17:2632–2640. 2011. View Article : Google Scholar : PubMed/NCBI
12	Tsuji N, Fukuda K, Nagata Y, Okada H, Haga A, Hatakeyama S, Yoshida S, Okamoto T, Hosaka M, Sekine K, et al: The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90. FEBS Open Bio. 4:796–803. 2014. View Article : Google Scholar : PubMed/NCBI
13	Hao N and Whitelaw ML: The emerging roles of AhR in physiology and immunity. Biochem Pharmacol. 86:561–570. 2013. View Article : Google Scholar : PubMed/NCBI
14	Furumatsu K, Nishiumi S, Kawano Y, Ooi M, Yoshie T, Shiomi Y, Kutsumi H, Ashida H, Fujii-Kuriyama Y, Azuma T and Yoshida M: A role of the aryl hydrocarbon receptor in attenuation of colitis. Dig Dis Sci. 56:2532–2544. 2011. View Article : Google Scholar : PubMed/NCBI
15	Monteleone I, MacDonald TT, Pallone F and Monteleone G: The aryl hydrocarbon receptor in inflammatory bowel disease: Linking the environment to disease pathogenesis. Curr Opin Gastroenterol. 28:310–313. 2012. View Article : Google Scholar : PubMed/NCBI
16	Lee JS, Cella M, McDonald KG, Garlanda C, Kennedy GD, Nukaya M, Mantovani A, Kopan R, Bradfield CA, Newberry RD and Colonna M: AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat Immunol. 13:144–151. 2011. View Article : Google Scholar : PubMed/NCBI
17	Qiu J, Heller JJ, Guo X, Chen ZE, Fish K, Fu YX and Zhou L: The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity. 36:92–104. 2012. View Article : Google Scholar : PubMed/NCBI
18	Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C and Diefenbach A: Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science. 334:1561–1565. 2011. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Jonas CR, Gu LH, Nkabyo YS, Mannery YO, Avissar NE, Sax HC, Jones DP and Ziegler TR: Glutamine and KGF each regulate extracellular thiol/disulfide redox and enhance proliferation in Caco-2 cells. Am J Physiol Regul Integr Comp Physiol. 285:R1421–R1429. 2003. View Article : Google Scholar : PubMed/NCBI
21	Hille A, Grüger S, Christiansen H, Wolff HA, Volkmer B, Lehmann J, Dörr W and Rave-Fränk M: Effect of tumour-cell-derived or recombinant keratinocyte growth factor (KGF) on proliferation and radioresponse of human epithelial tumour cells (HNSCC) and normal keratinocytes in vitro. Radiat Environ Biophys. 49:261–270. 2010. View Article : Google Scholar : PubMed/NCBI
22	Mehta M, Kesinger JW, Zang XP, Lerner ML, Brackett DJ, Brueggemeier RW, Li PK and Pento JT: Influence of novel KGFR tyrosine kinase inhibitor on KGF-mediated proliferation of breast cancer. Anticancer Res. 30:4883–4889. 2010.PubMed/NCBI
23	Kanai M, Tashiro E, Maruki H, Minato Y and Imoto M: Transcriptional regulation of human fibroblast growth factor receptor 1 by E2F-1. Gene. 438:49–56. 2009. View Article : Google Scholar : PubMed/NCBI
24	Furukawa K, Matsumoto K, Nagayasu T, Yamamoto-Fukuda T, Tobinaga S, Abo T, Yamasaki N, Tsuchiya T, Miyazaki T, Kamohara R, et al: Intratracheal administration of recombinant human keratinocyte growth factor promotes alveolar epithelial cell proliferation during compensatory lung growth in rat. Acta Histochem Cytochem. 46:179–185. 2013. View Article : Google Scholar : PubMed/NCBI
25	Hirobe T, Hasegawa K, Furuya R, Fujiwara R and Sato K: Effects of fibroblast-derived factors on the proliferation and differentiation of human melanocytes in culture. J Dermatol Sci. 71:45–57. 2013. View Article : Google Scholar : PubMed/NCBI
26	Li GJ, Jiang DY, Zong XL and Xu X: Keratinocyte growth factor phage model peptides can promote human oral mucosal epithelial cell proliferation. Oral Surg Oral Med Oral Pathol Oral Radiol. 116:e92–e97. 2013. View Article : Google Scholar : PubMed/NCBI
27	Playford RJ, Marchbank T, Mandir N, Higham A, Meeran K, Ghatei MA, Bloom SR and Goodlad RA: Effects of keratinocyte growth factor (KGF) on gut growth and repair. J Pathol. 184:316–322. 1998. View Article : Google Scholar : PubMed/NCBI
28	Kadow S, Jux B, Zahner SP, Wingerath B, Chmill S, Clausen BE, Hengstler J and Esser C: Aryl hydrocarbon receptor is critical for homeostasis of invariant gammadelta T cells in the murine epidermis. J Immunol. 187:3104–3110. 2011. View Article : Google Scholar : PubMed/NCBI
29	Koga H, Yang H, Haxhija EQ and Teitelbaum DH: The role of angiotensin II type 1a receptor on intestinal epithelial cells following small bowel resection in a mouse model. Pediatr Surg Int. 24:1279–1286. 2008. View Article : Google Scholar : PubMed/NCBI
30	D'Amici S, Ceccarelli S, Vescarelli E, Romano F, Frati L, Marchese C and Angeloni A: TNFα modulates fibroblast growth factor receptor 2 gene expression through the pRB/E2F1 pathway: Identification of a non-canonical E2F binding motif. PLoS One. 8:e614912013. View Article : Google Scholar : PubMed/NCBI