Top

Published in:

01-04-2021 | Metastasis | PRECLINICAL STUDIES

Epidermal growth factor-like domain multiple 6 (EGFL6) promotes the migration and invasion of gastric cancer cells by inducing epithelial-mesenchymal transition

Authors: Fu-Chun Huo, Wen-Tao Zhu, Xu Liu, Yun Zhou, Lan-Sheng Zhang, Jie Mou

Published in: Investigational New Drugs | Issue 2/2021

Summary

Epidermal growth factor-like domain multiple 6 (EGFL6) is implicated in tumor growth, metastasis and angiogenesis, and its ectopic alteration has been detected in aggressive malignancies. However, the pathophysiologic roles and molecular mechanisms of EGFL6 in gastric cancer (GC) remain to be elucidated. In this study, we investigated EGFL6 expression in GC cell lines and tissues using western blotting and immunohistochemistry. We found that EGFL6 was elevated expression in GC cell lines and tissues. The high expression of EGFL6 significantly was correlated with histological grade, depth of invasion, lymph node involvement, distant metastasis and TNM stage in GC and predicted poorer prognosis, and it could act an independent prognostic factor for GC patients. EGFL6 enhanced the proliferation, migration and invasion of GC cells. In addition, we identified the possible molecular mechanisms of EGFL6-involved epithelial-mesenchymal transition (EMT). EGFL6 regulated EMT process and induced metastasis partly through FAK/PI3K/AKT/mTOR, Notch and MAPK signaling pathways. In conclusion, EGFL6 confers an oncogenic function in GC progression and may be proposed as a potential therapeutic target for GC.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424. https://doi.org/10.3322/caac.21492CrossRef

Lin MT, Song HJ, Ding XY (2018) Long non-coding RNAs involved in metastasis of gastric cancer. World J Gastroenterol 24(33):3724–3737. https://doi.org/10.3748/wjg.v24.i33.3724CrossRefPubMedPubMedCentral

Tanabe S, Ishido K, Higuchi K, Sasaki T, Katada C, Azuma M, Naruke A, Kim M, Koizumi W (2014) Long-term outcomes of endoscopic submucosal dissection for early gastric cancer: a retrospective comparison with conventional endoscopic resection in a single center. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 17(1):130–136. https://doi.org/10.1007/s10120-013-0241-2CrossRef

Li J, Xu L, Run ZC, Feng W, Liu W, Zhang PJ, Li Z (2018) Multiple cytokine profiling in serum for early detection of gastric cancer. World J Gastroenterol 24(21):2269–2278. https://doi.org/10.3748/wjg.v24.i21.2269CrossRefPubMedPubMedCentral

Yamamoto M, Kurokawa Y, Miyazaki Y, Makino T, Takahashi T, Yamasaki M, Nakajima K, Takiguchi S, Mori M, Doki Y (2016) Usefulness of preoperative plasma fibrinogen versus other prognostic markers for predicting gastric Cancer recurrence. World J Surg 40(8):1904–1909. https://doi.org/10.1007/s00268-016-3474-5CrossRefPubMed

Singh B, Carpenter G, Coffey RJ (2016) EGF receptor ligands: recent advances. F1000Research 5. Doi:https://doi.org/10.12688/f1000research.9025.1

Yeung G, Mulero JJ, Berntsen RP, Loeb DB, Drmanac R, Ford JE (1999) Cloning of a novel epidermal growth factor repeat containing gene EGFL6: expressed in tumor and fetal tissues. Genomics 62(2):304–307. https://doi.org/10.1006/geno.1999.6011CrossRefPubMed

Bai S, Ingram P, Chen YC, Deng N, Pearson A, Niknafs YS, O'Hayer P, Wang Y, Zhang ZY, Boscolo E, Bischoff J, Yoon E, Buckanovich RJ (2016) EGFL6 regulates the asymmetric division, maintenance, and metastasis of ALDH+ ovarian Cancer cells. Cancer Res 76(21):6396–6409. https://doi.org/10.1158/0008-5472.CAN-16-0225CrossRefPubMedPubMedCentral

Lee SH, Jeong EG, Soung YH, Lee JW, Yoo NJ, Lee SH (2008) Absence of GNAS and EGFL6 mutations in common human cancers. Pathology 40(1):95–97. https://doi.org/10.1080/00313020701716375CrossRefPubMed

10.

Sanderson MP, Dempsey PJ, Dunbar AJ (2006) Control of ErbB signaling through metalloprotease mediated ectodomain shedding of EGF-like factors. Growth Factors 24(2):121–136. https://doi.org/10.1080/08977190600634373CrossRefPubMed

11.

Chang CC, Sung WW, Hsu HT, Yeh CM, Lee CH, Chen YL, Liu TC, Yeh KT (2018) Validation of EGFL6 expression as a prognostic marker in patients with lung adenocarcinoma in Taiwan: a retrospective study. BMJ Open 8(6):e021385. https://doi.org/10.1136/bmjopen-2017-021385CrossRefPubMedPubMedCentral

12.

Chuang CY, Chen MK, Hsieh MJ, Yeh CM, Lin CW, Yang WE, Yang SF, Chou YE (2017) High level of plasma EGFL6 is associated with Clinicopathological characteristics in patients with Oral squamous cell carcinoma. Int J Med Sci 14(5):419–424. https://doi.org/10.7150/ijms.18555CrossRefPubMedPubMedCentral

13.

Zhang QW, Zhang XT, Tang CT, Lin XL, Ge ZZ, Li XB (2019) EGFL6 promotes cell proliferation in colorectal cancer via regulation of the WNT/beta-catenin pathway. Mol Carcinog 58(6):967–979. https://doi.org/10.1002/mc.22985CrossRefPubMed

14.

Zhu Z, Ni H, You B, Shi S, Shan Y, Bao L, Duan B, You Y (2018) Elevated EGFL6 modulates cell metastasis and growth via AKT pathway in nasopharyngeal carcinoma. Cancer medicine 7(12):6281–6289. https://doi.org/10.1002/cam4.1883CrossRefPubMedPubMedCentral

15.

An J, Du Y, Fan X, Wang Y, Ivan C, Zhang XG, Sood AK, An Z, Zhang N (2019) EGFL6 promotes breast cancer by simultaneously enhancing cancer cell metastasis and stimulating tumor angiogenesis. Oncogene 38(12):2123–2134. https://doi.org/10.1038/s41388-018-0565-9CrossRefPubMed

16.

Noh K, Mangala LS, Han HD, Zhang N, Pradeep S, Wu SY, Ma S, Mora E, Rupaimoole R, Jiang D, Wen Y, Shahzad MMK, Lyons Y, Cho M, Hu W, Nagaraja AS, Haemmerle M, Mak CSL, Chen X, Gharpure KM, Deng H, Xiong W, Kingsley CV, Liu J, Jennings N, Birrer MJ, Bouchard RR, Lopez-Berestein G, Coleman RL, An Z, Sood AK (2017) Differential effects of EGFL6 on tumor versus wound angiogenesis. Cell Rep 21(10):2785–2795. https://doi.org/10.1016/j.celrep.2017.11.020CrossRefPubMedPubMedCentral

17.

Oberauer R, Rist W, Lenter MC, Hamilton BS, Neubauer H (2010) EGFL6 is increasingly expressed in human obesity and promotes proliferation of adipose tissue-derived stromal vascular cells. Mol Cell Biochem 343(1–2):257–269. https://doi.org/10.1007/s11010-010-0521-7CrossRefPubMed

18.

Wang X, Gong Y, Wang D, Xie Q, Zheng M, Zhou Y, Li Q, Yang Z, Tang H, Li Y, Hu R, Chen X, Mao Y (2012) Analysis of gene expression profiling in meningioma: deregulated signaling pathways associated with meningioma and EGFL6 overexpression in benign meningioma tissue and serum. PLoS One 7(12):e52707. https://doi.org/10.1371/journal.pone.0052707CrossRefPubMedPubMedCentral

19.

Chim SM, Qin A, Tickner J, Pavlos N, Davey T, Wang H, Guo Y, Zheng MH, Xu J (2011) EGFL6 promotes endothelial cell migration and angiogenesis through the activation of extracellular signal-regulated kinase. J Biol Chem 286(25):22035–22046. https://doi.org/10.1074/jbc.M110.187633CrossRefPubMedPubMedCentral

20.

Pastushenko I, Blanpain C (2019) EMT transition states during tumor progression and metastasis. Trends Cell Biol 29(3):212–226. https://doi.org/10.1016/j.tcb.2018.12.001CrossRefPubMed

21.

Wang Y, Lin Z, Sun L, Fan S, Huang Z, Zhang D, Yang Z, Li J, Chen W (2014) Akt/Ezrin Tyr353/NF-kappaB pathway regulates EGF-induced EMT and metastasis in tongue squamous cell carcinoma. Br J Cancer 110(3):695–705. https://doi.org/10.1038/bjc.2013.770CrossRefPubMed

22.

Sheng W, Chen C, Dong M, Wang G, Zhou J, Song H, Li Y, Zhang J, Ding S (2017) Calreticulin promotes EGF-induced EMT in pancreatic cancer cells via integrin/EGFR-ERK/MAPK signaling pathway. Cell Death Dis 8(10):e3147. https://doi.org/10.1038/cddis.2017.547CrossRefPubMedPubMedCentral

23.

Wang XH, He X, Jin HY, Liang JX, Li N (2018) Effect of hypoxia on the Twist1 in EMT of cervical cancer cells. European review for medical and pharmacological sciences 22(20):6633–6639. https://doi.org/10.26355/eurrev_201810_16138CrossRefPubMed

24.

Zhang YC, Huo FC, Wei LL, Gong CC, Pan YJ, Mou J, Pei DS (2017) PAK5-mediated phosphorylation and nuclear translocation of NF-kappaB-p65 promotes breast cancer cell proliferation in vitro and in vivo. Journal of experimental & clinical cancer research : CR 36(1):146. https://doi.org/10.1186/s13046-017-0610-5CrossRef

25.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45(W1):W98–W102. https://doi.org/10.1093/nar/gkx247CrossRefPubMedPubMedCentral

26.

Huo FC, Pan YJ, Li TT, Mou J, Pei DS (2019) PAK5 promotes the migration and invasion of cervical cancer cells by phosphorylating SATB1. Cell Death Differ 26(6):994–1006. https://doi.org/10.1038/s41418-018-0178-4CrossRefPubMed

27.

Nieto MA, Huang RY, Jackson RA, Thiery JP (2016) Emt: 2016. Cell 166(1):21–45. https://doi.org/10.1016/j.cell.2016.06.028CrossRefPubMed

28.

Luo J, Yao JF, Deng XF, Zheng XD, Jia M, Wang YQ, Huang Y, Zhu JH (2018) 14, 15-EET induces breast cancer cell EMT and cisplatin resistance by up-regulating integrin alphavbeta3 and activating FAK/PI3K/AKT signaling. Journal of experimental & clinical cancer research : CR 37(1):23. https://doi.org/10.1186/s13046-018-0694-6CrossRef

29.

Cheng Y, Pan Y, Pan Y, Wang O (2019) MNX1-AS1 is a functional oncogene that induces EMT and activates the AKT/mTOR pathway and MNX1 in breast cancer. Cancer Manag Res 11:803–812. https://doi.org/10.2147/CMAR.S188007CrossRefPubMedPubMedCentral

30.

Wang Y, Zhong Y, Hou T, Liao J, Zhang C, Sun C, Wang G (2019) PM2.5 induces EMT and promotes CSC properties by activating notch pathway in vivo and vitro. Ecotoxicol Environ Saf 178:159–167. https://doi.org/10.1016/j.ecoenv.2019.03.086CrossRefPubMed

31.

Hu X, Zhai Y, Kong P, Cui H, Yan T, Yang J, Qian Y, Ma Y, Wang F, Li H, Cheng C, Zhang L, Jia Z, Li Y, Yang B, Xu E, Wang J, Yang J, Bi Y, Chang L, Wang Y, Zhang Y, Song B, Li G, Shi R, Liu J, Zhang M, Cheng X, Cui Y (2017) FAT1 prevents epithelial mesenchymal transition (EMT) via MAPK/ERK signaling pathway in esophageal squamous cell cancer. Cancer Lett 397:83–93. https://doi.org/10.1016/j.canlet.2017.03.033CrossRefPubMed

32.

Zhang PF, Li KS, Shen YH, Gao PT, Dong ZR, Cai JB, Zhang C, Huang XY, Tian MX, Hu ZQ, Gao DM, Fan J, Ke AW, Shi GM (2016) Galectin-1 induces hepatocellular carcinoma EMT and sorafenib resistance by activating FAK/PI3K/AKT signaling. Cell Death Dis 7:e2201. https://doi.org/10.1038/cddis.2015.324CrossRefPubMedPubMedCentral

33.

Zhou Q, Yu B, Anderson C, Huang ZP, Hanus J, Zhang W, Han Y, Bhattacharjee PS, Srinivasan S, Zhang K, Wang DZ, Wang S (2019) LncEGFL7OS regulates human angiogenesis by interacting with MAX at the EGFL7/miR-126 locus. eLife 8. https://doi.org/10.7554/eLife.40470

34.

Usuba R, Pauty J, Soncin F, Matsunaga YT (2019) EGFL7 regulates sprouting angiogenesis and endothelial integrity in a human blood vessel model. Biomaterials 197:305–316. https://doi.org/10.1016/j.biomaterials.2019.01.022CrossRefPubMed

35.

Brabletz T, Kalluri R, Nieto MA, Weinberg RA (2018) EMT in cancer. Nat Rev Cancer 18(2):128–134. https://doi.org/10.1038/nrc.2017.118CrossRefPubMed

36.

Wang Y, Zhou BP (2011) Epithelial-mesenchymal transition in breast cancer progression and metastasis. Chinese journal of cancer 30(9):603–611. https://doi.org/10.5732/cjc.011.10226CrossRefPubMedPubMedCentral

37.

Wang H, Lian Z, Lerch MM, Chen Z, Xie W, Ullrich A (1996) Characterization of PCP-2, a novel receptor protein tyrosine phosphatase of the MAM domain family. Oncogene 12(12):2555–2562PubMed

38.

Xu S, Ge J, Zhang Z, Zhou W (2017) MiR-129 inhibits cell proliferation and metastasis by targeting ETS1 via PI3K/AKT/mTOR pathway in prostate cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 96:634-641. doi:https://doi.org/10.1016/j.biopha.2017.10.037

39.

Osada A, Kiyozumi D, Tsutsui K, Ono Y, Weber CN, Sugimoto N, Imai T, Okada A, Sekiguchi K (2005) Expression of MAEG, a novel basement membrane protein, in mouse hair follicle morphogenesis. Exp Cell Res 303(1):148–159. https://doi.org/10.1016/j.yexcr.2004.04.053CrossRefPubMed

Title: Epidermal growth factor-like domain multiple 6 (EGFL6) promotes the migration and invasion of gastric cancer cells by inducing epithelial-mesenchymal transition
Authors: Fu-Chun Huo
Wen-Tao Zhu
Xu Liu
Yun Zhou
Lan-Sheng Zhang
Jie Mou
Publication date: 01-04-2021
Publisher: Springer US
Keywords: Metastasis
Gastric Cancer
Gastric Cancer
Published in: Investigational New Drugs / Issue 2/2021
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-020-01004-2

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Summary

Please log in to get access to this content

Other articles of this Issue 2/2021

Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type epidermal growth factor receptor (TORG1320)

Determinants of pain in advanced HCC patients recieving hepatic artery infusion chemotherapy

A phase II study of Mirvetuximab Soravtansine in triple-negative breast cancer

Discovery of oxyepiberberine as a novel tubulin polymerization inhibitor and an anti-colon cancer agent against LS-1034 cells

Absorption of the orally active multikinase inhibitor axitinib as a therapeutic index to guide dose titration in metastatic renal cell carcinoma

A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer