Luteolin inhibits pancreatitis‑induced acinar‑ductal metaplasia, proliferation and epithelial‑mesenchymal transition of acinar cells

Huang,Xince; Bhugul,Pravin Avinash; Fan,Gang; Ye,Tingting; Huang,Shihao; Dai,Shengjie; Chen,Bicheng; Zhou,Mengtao

doi:10.3892/mmr.2017.8327

Luteolin inhibits pancreatitis‑induced acinar‑ductal metaplasia, proliferation and epithelial‑mesenchymal transition of acinar cells

Authors:
- Xince Huang
- Pravin Avinash Bhugul
- Gang Fan
- Tingting Ye
- Shihao Huang
- Shengjie Dai
- Bicheng Chen
- Mengtao Zhou
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Affiliations: Department of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Zhejiang Provincial Top Key Discipline in Surgery, Wenzhou Key Laboratory of Surgery, Department of Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: December 20, 2017 https://doi.org/10.3892/mmr.2017.8327
Pages: 3681-3689
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Luteolin, a flavone, has been demonstrated to have anti‑cancer properties. In the current study, the effects of luteolin on certain carcinogenesis‑associated changes induced by pancreatitis, which are significant risk factors for pancreatic cancer, were investigated. Male six‑week‑old C57BL6 mice used in the current study were divided into three groups; the control group, acute pancreatitis group and luteolin group. Intra‑peritoneal injection of cearulein was performed in the acute pancreatitis group and luteolin group to induce acute pancreatitis whereas the luteolin group received intra‑peritoneal injection of luteolin. The control group received intra‑peritoneal injection of normal saline. Then, the expression of SOX9, phosphorylated (p‑) STAT3, p‑EGFR, cytokeratin‑19, Ki67 and N‑cadherin were determined by immunohistochemistry. Morphological changes of acinar cells were determined by hematoxylin and eosin staining. The mRNA expression of the epithelial‑mesenchymal transition markers CDH1, CDH2, Slug, Zeb1, EpCAM, ZO1, Vimentin, Snail and Twist was determined by reverse transcription‑quantitative polymerase chain reaction. It was identified that luteolin inhibits the formation of tubular complexes and ectopic expression of cytokeratin‑19 and luteolin also decreased proteins of SOX9, p‑STAT3 and p‑EGFR. In addition, luteolin inhibits proliferation and epithelial‑mesenchymal transition of acinar cells induced by acute pancreatitis. As tubular complex formation and ectopic expression of cytokeratin‑19 were two prominent characters of acinar‑ductal metaplasia, it was concluded that luteolin inhibits acinar‑ductal metaplasia induced by pancreatitis and also inhibits pancreatitis‑induced proliferation and epithelial‑mesenchymal transition of acinar cells. Acinar‑ductal metaplasia and proliferation have close associations with pancreatic carcinogenesis. It is suggested that luteolin has potential anti‑pancreatic carcinogenesis effects and merits further investigation.

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1	Vincent A, Herman J, Schulick R, Hruban RH and Goggins M: Pancreatic cancer. Lancet. 378:607–620. 2011. View Article : Google Scholar : PubMed/NCBI
2	Ekbom A, McLaughlin JK and Nyrén O: Pancreatitis and the risk of pancreatic cancer. N Engl J Med. 329:1502–1503. 1993. View Article : Google Scholar : PubMed/NCBI
3	Guerra C, Schuhmacher AJ, Cañamero M, Grippo PJ, Verdaguer L, Pérez-Gallego L, Dubus P, Sandgren EP and Barbacid M: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 11:291–302. 2007. View Article : Google Scholar : PubMed/NCBI
4	Morris JP IV, Cano DA, Sekine S, Wang SC and Hebrok M: Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J Clin Invest. 120:508–520. 2010. View Article : Google Scholar : PubMed/NCBI
5	Hruban RH, Wilentz RE and Maitra A: Identification and analysis of precursors to invasive pancreatic cancer. Methods Mol Med. 103:1–13. 2005.PubMed/NCBI
6	De La OJP, Emerson LL, Goodman JL, Froebe SC, Illum BE, Curtis AB and Murtaugh LC: Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci USA. 105:pp. 18907–18912. 2008; View Article : Google Scholar : PubMed/NCBI
7	Shih HP, Kopp JL, Sandhu M, Dubois CL, Seymour PA, Grapin-Botton A and Sander M: A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation. Development. 139:2488–2499. 2012. View Article : Google Scholar : PubMed/NCBI
8	Kopp JL, von Figura G, Mayes E, Liu FF, Dubois CL, Morris JP IV, Pan FC, Akiyama H, Wright CV, Jensen K, et al: Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell. 22:737–750. 2012. View Article : Google Scholar : PubMed/NCBI
9	Prévot PP, Simion A, Grimont A, Colletti M, Khalaileh A, Van den Steen G, Sempoux C, Xu X, Roelants V, Hald J, et al: Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia. Gut. 61:1723–1732. 2012. View Article : Google Scholar : PubMed/NCBI
10	Grimont A, Pinho AV, Cowley MJ, Augereau C, Mawson A, Giry-Laterrière M, Van den Steen G, Waddell N, Pajic M, Sempoux C, et al: SOX9 regulates ERBB signalling in pancreatic cancer development. Gut. 64:1790–1799. 2015. View Article : Google Scholar : PubMed/NCBI
11	Ardito CM, Grüner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, Delgiorno KE, Carpenter ES, Halbrook CJ, Hall JC, et al: EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell. 22:304–317. 2012. View Article : Google Scholar : PubMed/NCBI
12	Navas C, Hernández-Porras I, Schuhmacher AJ, Sibilia M, Guerra C and Barbacid M: EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell. 22:318–330. 2012. View Article : Google Scholar : PubMed/NCBI
13	Collins MA, Yan W, Sebolt-Leopold JS and Pasca di Magliano M: MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice. Gastroenterology. 146:822–834.e7. 2014. View Article : Google Scholar : PubMed/NCBI
14	Wu CY, Carpenter ES, Takeuchi KK, Halbrook CJ, Peverley LV, Bien H, Hall JC, DelGiorno KE, Pal D, Song Y, et al: PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. Gastroenterology. 147:1405–1416.e7. 2014. View Article : Google Scholar : PubMed/NCBI
15	Corcoran RB, Contino G, Deshpande V, Tzatsos A, Conrad C, Benes CH, Levy DE, Settleman J, Engelman JA and Bardeesy N: STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 71:5020–5029. 2011. View Article : Google Scholar : PubMed/NCBI
16	Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Klöppel G, Yoshimura A, Reindl W, Sipos B, Akira S, et al: Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 19:456–469. 2011. View Article : Google Scholar : PubMed/NCBI
17	Fukuda A, Wang SC, Morris JP IV, Folias AE, Liou A, Kim GE, Akira S, Boucher KM, Firpo MA, Mulvihill SJ, et al: Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell. 19:441–455. 2011. View Article : Google Scholar : PubMed/NCBI
18	Zhang Y, Morris JP IV, Yan W, Schofield HK, Gurney A, Simeone DM, Millar SE, Hoey T, Hebrok M and Pasca di Magliano M: Canonical wnt signaling is required for pancreatic carcinogenesis. Cancer Res. 73:4909–4922. 2013. View Article : Google Scholar : PubMed/NCBI
19	Pasca di Magliano M, Sekine S, Ermilov A, Ferris J, Dlugosz AA and Hebrok M: Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev. 20:3161–3173. 2006. View Article : Google Scholar : PubMed/NCBI
20	Brabletz S, Bajdak K, Meidhof S, Burk U, Niedermann G, Firat E, Wellner U, Dimmler A, Faller G, Schubert J and Brabletz T: The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells. EMBO J. 30:770–782. 2011. View Article : Google Scholar : PubMed/NCBI
21	Wang F, Sloss C, Zhang X, Lee SW and Cusack JC: Membrane-bound heparin-binding epidermal growth factor like growth factor regulates E-cadherin expression in pancreatic carcinoma cells. Cancer Res. 67:8486–8493. 2007. View Article : Google Scholar : PubMed/NCBI
22	Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, et al: EMT and dissemination precede pancreatic tumor formation. Cell. 148:349–361. 2012. View Article : Google Scholar : PubMed/NCBI
23	Middleton E Jr, Kandaswami C and Theoharides TC: The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacol Rev. 52:673–751. 2000.PubMed/NCBI
24	Kandaswami C, Lee LT, Lee PP, Hwang JJ, Ke FC, Huang YT and Lee MT: The antitumor activities of flavonoids. In Vivo. 19:895–909. 2005.PubMed/NCBI
25	Jia Z, Nallasamy P, Liu D, Shah H, Li JZ, Chitrakar R, Si H, McCormick J, Zhu H, Zhen W and Li Y: Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IΚBα/NF-κB signaling pathway. J Nutr Biochem. 26:293–302. 2015. View Article : Google Scholar : PubMed/NCBI
26	Shi RX, Ong CN and Shen HM: Luteolin sensitizes tumor necrosis factor-alpha-induced apoptosis in human tumor cells. Oncogene. 23:7712–7721. 2004. View Article : Google Scholar : PubMed/NCBI
27	Hong Z, Cao X, Li N, Zhang Y, Lan L, Zhou Y, Pan X, Shen L, Yin Z and Luo L: Luteolin is effective in the non-small cell lung cancer model with L858R/T790M EGF receptor mutation and erlotinib resistance. Br J Pharmacol. 171:2842–2853. 2014. View Article : Google Scholar : PubMed/NCBI
28	Huang X, Dai S, Dai J, Xiao Y, Bai Y, Chen B and Zhou M: Luteolin decreases invasiveness, deactivates STAT3 signaling, and reverses interleukin-6 induced epithelial-mesenchymal transition and matrix metalloproteinase secretion of pancreatic cancer cells. Onco Targets Ther. 8:2989–3001. 2015. View Article : Google Scholar : PubMed/NCBI
29	Seymour PA, Freude KK, Tran MN, Mayes EE, Jensen J, Kist R, Scherer G and Sander M: SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci USA. 104:pp. 1865–1870. 2007; View Article : Google Scholar : PubMed/NCBI
30	Rau B, Paszkowski A, Lillich S, Baumgart K, Möller P and Beger HG: Differential effects of caspase-1/interleukin-1beta-converting enzyme on acinar cell necrosis and apoptosis in severe acute experimental pancreatitis. Lab Invest. 81:1001–1013. 2001. View Article : Google Scholar : PubMed/NCBI
31	Reid LE and Walker NI: Acinar cell apoptosis and the origin of tubular complexes in caerulein-induced pancreatitis. Int J Exp Pathol. 80:205–215. 1999. View Article : Google Scholar : PubMed/NCBI
32	Bagli E, Stefaniotou M, Morbidelli L, Ziche M, Psillas K, Murphy C and Fotsis T: Luteolin inhibits vascular endothelial growth factor-induced angiogenesis: Inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3′-kinase activity. Cancer Res. 64:7936–7946. 2004. View Article : Google Scholar : PubMed/NCBI