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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2019

Open Access 01-12-2019 | Colorectal Cancer | Research

FAT4 regulates the EMT and autophagy in colorectal cancer cells in part via the PI3K-AKT signaling axis

Authors: Ran Wei, Yuhong Xiao, Yi Song, Huiping Yuan, Jun Luo, Wei Xu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2019

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Abstract

Background

FAT4 functions as a tumor suppressor, and previous findings have demonstrated that FAT4 can inhibit the epithelial-to-mesenchymal transition (EMT) and the proliferation of gastric cancer cells. However, few studies have investigated the role of FAT4 in the development of colorectal cancer (CRC). The current study aimed to detect the role of FAT4 in the invasion, migration, proliferation and autophagy of CRC and elucidate the probable molecular mechanisms through which FAT4 interacts with these processes.

Methods

Transwell invasion assays, MTT assays, transmission electron microscopy, immunohistochemistry and western blotting were performed to evaluate the migration, invasion, proliferation and autophagy abilities of CRC cells, and the levels of active molecules involved in PI3K/AKT signaling were examined through a western blotting analysis. In addition, the function of FAT4 in vivo was assessed using a tumor xenograft model.

Results

FAT4 expression in CRC tissues was weaker than that in nonmalignant tissues and could inhibit cell invasion, migration, and proliferation by promoting autophagy in vitro. Furthermore, the regulatory effects of FAT4 on autophagy and the EMT were partially attributed to the PI3K-AKT signaling pathway. The results in vivo also showed that FAT4 modulated CRC tumorigenesis.

Conclusion

FAT4 can regulate the activity of PI3K to promote autophagy and inhibit the EMT in part through the PI3K/AKT/mTOR and PI3K/AKT/GSK-3β signaling pathways.
Literature
1.
Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RG, Barzi A, Jemal A. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67:177–93.CrossRef
2.
Ishiuchi T, Misaki K, Yonemura S, Takeichi M, Tanoue T. Mammalian fat and Dachsous cadherins regulate apical membrane organization in the embryonic cerebral cortex. J Cell Biol. 2009;185:959–67.CrossRef
3.
Katoh Y, Katoh M. Comparative integromics on FAT1, FAT2. FAT3 and FAT4, International Journal of Molecular Medicine. 2006;18:523–8.PubMed
4.
Egan D, Chun MH, Vamos M, Zou H, Rong J, Miller C, Lou HJ, Raveendra-Panickar D, Yang CC, Sheffler D. Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol Cell. 2015;59:285–97.CrossRef
5.
Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, Brabletz T. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008;9:582–9.CrossRef
6.
Zhou D, Vinodh K, Chen X, Li J, Leng X, Zhang J, Xuan S. RBP2 induces stem-like cancer cells by promoting EMT and is a prognostic marker for renal cell carcinoma. Exp Mol Med. 2016;48:e238.CrossRef
7.
Mathew R, Karantzawadsworth V, White E. Role of autophagy in cancer. Medical Recapitulate. 2010;7:961.
8.
Mathew R, Karantza‐Wadsworth V, White E. Assessing metabolic stress and autophagy status in epithelial tumors. Elsevier Science & Technology; 2009.
9.
Karantzawadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, White E. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007;21:1621–35.CrossRef
10.
11.
S. Pankiv, T.H. Clausen, T. Lamark, A. Brech, J.A. Bruun, H. Outzen, A. Øvervatn, G. Bjørkøy, T. Johansen, p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy, AIP Adv (2007).
12.
Gozuacik D, Kimchi A. Autophagy as a cell death and tumor suppressor mechanism. Oncogene. 2004;23:2891–906.CrossRef
13.
Debnath J, Baehrecke EH, Kroemer G. Does autophagy contribute to cell death? Autophagy. 2005;1:66–74.CrossRef
14.
Li J, Yang B, Zhou Q, Wu Y, Shang D, Guo Y, Song Z, Zheng Q, Xiong J. Autophagy promotes hepatocellular carcinoma cell invasion through activation of epithelial-mesenchymal transition. Carcinogenesis. 2013;34:1343–51.CrossRef
15.
Zhu H, Wang D, Zhang L, Xie X, Wu Y, Liu Y, Shao G, Su Z. Upregulation of autophagy by hypoxia-inducible factor-1α promotes EMT and metastatic ability of CD133+ pancreatic cancer stem-like cells during intermittent hypoxia. Oncol Rep. 2014;32:935–42.CrossRef
16.
Gugnoni M, Sancisi V, Gandolfi G, Manzotti G, Ragazzi M, Giordano D, Tamagnini I, Tigano M, Frasoldati A, Piana S. Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy. Oncogene. 2016;36:667.CrossRef
17.
Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497–510.CrossRef
18.
Czech MP. PIP2 and PIP3: complex roles at the cell surface. Cell. 2000;100:603–6.CrossRef
19.
Rheenen JV, Song X, Roosmalen WV, Cammer M, Chen X, Desmarais V, Yip SC, Backer JM, Eddy RJ, Condeelis JS. EGF-induced PIP2 hydrolysis releases and activates cofilin locally in carcinoma cells. J Cell Biol. 2007;179:1247–59.CrossRef
20.
Gravdal K, Halvorsen OJ, Haukaas SA, Akslen LA. A switch from E-cadherin to N-cadherin expression indicates epithelial to Mesenchymal transition and is of strong and independent importance for the Progress of prostate Cancer, clinical Cancer research an official journal of the American association for. Cancer Res. 2007;13:7003.
21.
K. Vuoriluoto, ., H. Haugen, ., S. Kiviluoto, ., M. J-P, J. Nevo, ., C. Gjerdrum, ., C. Tiron, ., J.B. Lorens, J. Ivaska, . Vimentin regulates EMT induction by slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer, Oncogene, 30 (2011) 1436–1448.CrossRef
22.
Shamir ER, Pappalardo E, Jorgens DM, Coutinho K, Tsai WT, Aziz K, Auer M, Tran PT, Bader JS, Ewald AJ. Twist1-induced dissemination preserves epithelial identity and requires E-cadherin. J Cell Biol. 2014;204:839–56.CrossRef
23.
Choi AMK, Ryter SW, Levine B. Autophagy in human health and disease — NEJM. N Engl J Med. 2013;368:651–62.CrossRef
24.
Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40:280–93.CrossRef
25.
Tanida I, Ueno TE. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol. 2004;36:2503–18.CrossRef
26.
Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell. 2008;19:2092–100.CrossRef
27.
Ito H, Daido S, Kanzawa T, Kondo S, Kondo Y. Radiation-induced autophagy is associated with LC3 and its inhibition sensitizes malignant glioma cells. Int J Oncol. 2005;26:1401–10.PubMed
28.
Jian X, Xiao-yan Z, Bin H, Yu-feng Z, Bo K, Zhi-nong W, Xin N. MiR-204 regulate cardiomyocyte autophagy induced by hypoxia-reoxygenation through LC3-II. Int J Cardiol. 2011;148:110–2.CrossRef
29.
Joungmok K, Mondira K, Benoit V, Kun-Liang G. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13:132–41.CrossRef
30.
Mizushima N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol. 2010;22:132–9.CrossRef
31.
Alers S, Löffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol. 2012;32:2–11.CrossRef
32.
Dan E, Joungmok K, Shaw RJ, Kun-Liang G. The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy. 2011;7:643–4.CrossRef
33.
Heesun C, Tullia L, Junmin W, Chao L, Thompson CB. Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc Natl Acad Sci U S A. 2011;108:11121–6.CrossRef
34.
Libin S, Xiaodong W. AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation. Autophagy. 2011;7:924–6.CrossRef
35.
Egan DF, Shackelford DB, Mihaylova MM, Sara G, Kohnz RA, William M, Vasquez DS, Aashish J, Gwinn DM, Rebecca T. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011;331:456.CrossRef
36.
Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010;12:213–23.CrossRef
37.
Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007;131:1149–63.CrossRef
38.
Di BS, Nazio F, Cecconi F. The role of autophagy during development in higher eukaryotes. Traffic. 2010;11:1280.CrossRef
39.
Lei Q, Baozhong Z, Mei M, Ning W, Tong-Chuan H, Seungmin H, Andrew T, Yu-Ying H. Regulation of cell proliferation and migration by p62 through stabilization of Twist1. Proc Natl Acad Sci U S A. 2014;111:9241–6.CrossRef
40.
Qiang L, He YY. Autophagy deficiency stabilizes TWIST1 to promote epithelial-mesenchymal transition. Autophagy. 2014;10:1864–5.CrossRef
41.
Saiki S, Sasazawa Y, Imamichi Y, Kawajiri S, Fujimaki T, Tanida I, Kobayashi H, Sato F, Sato S, Ishikawa KI. Caffeine induces apoptosis by enhancement of autophagy via PI3K/Akt/mTOR/p70S6K inhibition. Autophagy. 2011;7:176–87.CrossRef
42.
Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol. 2001;3:1014–9.CrossRef
43.
Gao N, Flynn DC, Zhang Z, Zhong XS, Walker V, Liu KJ, Shi X, Jiang BH. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells. Am J Physiol Cell Physiol. 2004;287:C281.CrossRef
44.
Qian Y, Corum L, Meng Q, Blenis J, Zheng JZ, Shi X, Flynn DC, Jiang BH. PI3K induced actin filament remodeling through Akt and p70S6K1: implication of essential role in cell migration. American Journal of Physiology Cell Physiology. 2004;286:C153.CrossRef
45.
Lee YJ, Han HJ. Troglitazone ameliorates high glucose-induced EMT and dysfunction of SGLTs through PI3K/Akt, GSK-3β, Snail1, and β-catenin in renal proximal tubule cells. Am J Physiol Renal Physiol. 2010;298:F1263.CrossRef
46.
Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, Shen L, Fan Y, Giri U, Tumula PK. An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res. 2013;19:279–90.CrossRef
47.
Qiying X, Zelin S, Meifang C, Qiaoqing Z, Tianlun Y, Jun Y. IL-8 up-regulates proliferative angiogenesis in ischemic myocardium in rabbits through phosphorylation of Akt/GSK-3β(ser9) dependent pathways. Int J Clin Exp Med. 2015;8:12498.
48.
Yang W, Zhang Y, Li Y, Wu Z, Zhu D. Myostatin induces cyclin D1 degradation to cause cell cycle arrest through a phosphatidylinositol 3-kinase/AKT/GSK-3 beta pathway and is antagonized by insulin-like growth factor 1. J Biol Chem. 2007;282:3799.CrossRef
49.
Xu W, Wang Z, Zhang W, Qian K, Li H, Kong D, Li Y, Tang Y. Mutated K-ras activates CDK8 to stimulate the epithelial-to-mesenchymal transition in pancreatic cancer in part via the Wnt/β-catenin signaling pathway. Cancer Lett. 2015;356:613–27.CrossRef
50.
Haraguchi K, Ohsugi M, Abe Y, Semba K, Akiyama T, Yamamoto T. Ajuba negatively regulates the Wnt signaling pathway by promoting GSK-3β-mediated phosphorylation of β-catenin. Oncogene. 2007;27:274.CrossRef
51.
Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3β and β-catenin and promotes GSK-3β-dependent phosphorylation of β-catenin. EMBO J. 1998;17:1371–84.CrossRef
Metadata
Title
FAT4 regulates the EMT and autophagy in colorectal cancer cells in part via the PI3K-AKT signaling axis
Authors
Ran Wei
Yuhong Xiao
Yi Song
Huiping Yuan
Jun Luo
Wei Xu
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2019
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-019-1043-0

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