Effect of the alteration of Tribbles homologue 3 expression on epithelial‑mesenchymal transition of transforming growth factor β1‑induced mouse alveolar epithelial cells through the Wnt/β‑catenin signaling pathway

Yu,Wencheng; Mi,Liyun; Wang,Feifei

doi:10.3892/mmr.2019.10863

Effect of the alteration of Tribbles homologue 3 expression on epithelial‑mesenchymal transition of transforming growth factor β1‑induced mouse alveolar epithelial cells through the Wnt/β‑catenin signaling pathway

Authors:
- Wencheng Yu
- Liyun Mi
- Feifei Wang
View Affiliations

Affiliations: Department of Pulmonary and Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China, Department of Respiratory Medicine, Qingdao Chest Hospital, Qingdao, Shandong 266043, P.R. China
Published online on: December 5, 2019 https://doi.org/10.3892/mmr.2019.10863
Pages: 615-622
Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aims of the present study were to elucidate the regulatory effect of exogenous Tribbles homologue 3 (TRB3) expression on the Wnt/β‑catenin signaling pathway and epithelial‑mesenchymal transition (EMT) in transforming growth factor‑β1 (TGF‑β1)‑induced mouse alveolar epithelial cells (MLE‑12) and investigate the underlying regulatory mechanisms. TRB3 expression was upregulated and downregulated using gene overexpression and RNA interference techniques, respectively. TGF‑β1‑stimulated MLE‑12 cells were examined for EMT and activation condition of the Wnt/β‑catenin signaling pathway using Cell Counting Kit‑8, flow cytometry, western blotting, reverse transcription‑quantitative PCR, ELISA and immunofluorescence techniques. During TGF‑β1‑induced EMT, TRB3 expression was found to be significantly upregulated (P<0.05). In the TRB3 overexpression group, upregulated expression of β‑catenin and EMT‑related genes and proteins was observed (P<0.05), and an increase in fibrosis‑related factors in the cell culture supernatant was detected (P<0.05); however, the results were the opposite in the TRB3 downregulated group (P<0.05). TRB3 may be involved in the regulation of EMT in TGF‑β1‑induced MLE‑12 cells through the Wnt/β‑catenin signaling pathway.

View Figures

View References

1	Sgalla G, Biffi A and Richeldi L: Idiopathic pulmonary fibrosis: Diagnosis, epidemiology and natural history. Respirology. 21:427–437. 2016. View Article : Google Scholar : PubMed/NCBI
2	Su Y, Yu L, Liu N, Guo Z, Wang G, Zheng J, Wei M, Wang H, Yang AG, Qin W and Wen W: PSMA specific single chain antibody-mediated targeted knockdown of Notch1 inhibits human prostate cancer cell proliferation and tumor growth. Cancer Lett. 338:282–291. 2013. View Article : Google Scholar : PubMed/NCBI
3	Carew RM, Wang B and Kantbaridis P: The role of EMT in renal fibrosis. Cell Tissue Res. 347:103–116. 2012. View Article : Google Scholar : PubMed/NCBI
4	Qi X, Zhang L and Lu X: New insights into the epithelial-to-mesenchymal transition in cancer. Trends Pharmacol Sci. 37:246–248. 2016. View Article : Google Scholar : PubMed/NCBI
5	Kretzschmar K and Watt FM: Lineage tracing. Cell. 148:33–45. 2012. View Article : Google Scholar : PubMed/NCBI
6	Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D and Chapman HA: Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA. 103:13180–13185. 2006. View Article : Google Scholar : PubMed/NCBI
7	Huang C, Ma R, Xu Y, Li N, Li Z, Yue J, Li H, Guo Y and Qi D: Wnt2 promotes non-small cell lung cancer progression by activating WNT/β-catenin pathway. Am J Cancer Res. 5:1032–1046. 2015.PubMed/NCBI
8	Kim TH, Kim SH, Seo JY, Chung H, Kwak HJ, Lee SK, Yoon HJ, Shin DH, Park SS and Sohn JW: Blockade of the Wnt/β-catenin pathway attenuates bleomycin-induced pulmonary fibrosis. Tohoku J Exp Med. 223:45–54. 2011. View Article : Google Scholar : PubMed/NCBI
9	Meuten T, Hickey A, Franklin K, Grossi B, Tobias J, Newman DR, Jennings SH, Correa M and Sannes PL: WNT7B in fibroblastic fociof idiopathic pulmonary fibrosis. Respir Res. 13:622012. View Article : Google Scholar : PubMed/NCBI
10	Wang W, Cheng J, Sun A, Lv S, Liu H, Liu X, Guan G and Liu G: TRB3 mediates renal tubular cell apoptosis associated with proteinuria. Clin Exp Med. 15:167–177. 2015. View Article : Google Scholar : PubMed/NCBI
11	Ti Y, Xie GL, Wang ZH, Bi XL, Ding WY, Wang J, Jiang GH, Bu PL, Zhang Y, Zhong M and Zhang W: TRB3 gene silencing alleviates diabetic cardiomyopathy in a type 2 diabetic rat model. Diabetes. 60:2963–2974. 2011. View Article : Google Scholar : PubMed/NCBI
12	Lampiasi N, Azzolina A, Umezawa K, Montalto G, McCubrey JA and Cervello M: The novel NF-κB inhibitor DHMEQ synergizes with celecoxib to exert antitumor effects on human liver cancer cells by a ROS-dependent mechanism. Cancer Lett. 322:35–44. 2012. View Article : Google Scholar : PubMed/NCBI
13	Pardo A and Selman M: Role of matrix metaloproteases in idiopathic pulmonary fibrosis. Fibrogenesis Tissue Repair. 5 (Suppl 1):S92012. View Article : Google Scholar : PubMed/NCBI
14	Sakai N and Tager AM: Fibrosis of Two: Epithelial cell-fibmblast interactions inpulmonary fibrosis. Biochim Biophys Acta. 1832:911–921. 2013. View Article : Google Scholar : PubMed/NCBI
15	Ferrarotto R, Goonatilake R, Yoo SY, Tong P, Giri U, Peng S, Minna J, Girard L, Wang Y, Wang L, et al: Epithelial-mesenchymal transition predicts polo-like kinase 1 inhibitor-mediated apoptosis in non-small cell lung cancer. Clin Cancer Res. 22:1674–1686. 2016. View Article : Google Scholar : PubMed/NCBI
16	Zhou B, Liu Y, Kahn M, Ann DK, Han A, Wang H, Nguyen C, Flodby P, Zhong Q, Krishnaveni MS, et al: Interactions between β-catenin and transforming growth factor-β signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem. 287:7026–7038. 2012. View Article : Google Scholar : PubMed/NCBI
17	Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis P, Zerr P, Horn A, Kireva T, Beyer C, Zwerina J, et al: Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis. Nat Commun. 3:7352012. View Article : Google Scholar : PubMed/NCBI
18	Ohoka N, Yoshii S, Hattori T, Onozaki K and Hayashi H: TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J. 24:1243–1255. 2005. View Article : Google Scholar : PubMed/NCBI
19	Tomcik M, Palumbo-Zerr K, Zerr P, Sumova B, Avouac J, Dees C, Distler A, Becvar R, Distler O, Schett G, et al: Tribbles homologue 3 stimulates canonical TGF-β signalling to regulate fibroblast activation and tissue fibrosis. Ann Rheum Dis. 75:609–616. 2016. View Article : Google Scholar : PubMed/NCBI
20	Zhang L, Zhang J, Liu X, Liu S and Tian J: Tribbles 3 regulates the fibrosis cytokine TGF-β1 through ERK1/2-MAPK signaling pathway in diabetic nephropathy. J Immunol Res. 2014:2403962014. View Article : Google Scholar : PubMed/NCBI
21	Xu L, Cui WH, Zhou WC, Li DL, Li LC, Zhao P, Mo XT, Zhang Z and Gao J: Activation of Wnt/β-catenin signalling is required for TGF-β/Smad2/3 signalling during myofibroblast proliferation. J Cell Mol Med. 21:1545–1554. 2017. View Article : Google Scholar : PubMed/NCBI
22	Kim MK, Maeng YI, Sung WJ, Oh HK, Park JB, Yoon GS, Cho CH and Park KK: The differential expression of TGF-β1, ILK and wnt signaling inducing epithelial to mesenchymal transition in human renal fibrogenesis: An immunohistochemical study. Int J Clin Exp Pathol. 6:1747–1758. 2013.PubMed/NCBI