Human giant larvae‑1 promotes migration and invasion of malignant glioma cells by regulating N‑cadherin

Wang,Yan; Zhang,Yu; Sang,Ben; Zhu,Xianlong; Yu,Rutong; Zhou,Xiuping

doi:10.3892/ol.2021.12428

Human giant larvae‑1 promotes migration and invasion of malignant glioma cells by regulating N‑cadherin

Authors:
- Yan Wang
- Yu Zhang
- Ben Sang
- Xianlong Zhu
- Rutong Yu
- Xiuping Zhou
View Affiliations

Affiliations: The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China, Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China
Published online on: January 4, 2021 https://doi.org/10.3892/ol.2021.12428
Article Number: 167
Copyright: © Wang 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

Human giant larvae‑1 (Hugl‑1) is a human homologue of Drosophila tumor suppressor lethal (2)‑giant larvae and has been reported to be involved in the development of human malignancies. Previous studies performed by our group demonstrated that Hugl‑1 inhibits glioma cell proliferation in an intracranial model of nude mice. However, the exact molecular mechanisms underlying the participation of Hugl‑1 in glioma invasion and migration, and in the depolarizing process remain largely unknown. Utilizing the U251‑MG cells with stable expression of Hugl‑1, the present study used wound healing, Transwell invasion and western blot assays to explore the role and specific mechanism of Hugl‑1 in glioma invasion and migration. The results of the present study demonstrated that overexpression of Hugl‑1 decreased cell‑cell adhesion and increased cell‑cell extracellular matrix adhesion. In addition, overexpression of Hugl‑1 promoted pseudopodia formation, glioma cell migration and invasion. The molecular mechanism of action involved the negative regulation of N‑cadherin protein levels by Hugl‑1. Overexpression or knockdown of N‑cadherin partially suppressed or enhanced the effects of Hugl‑1 on glioma cell migration and invasion, respectively. Furthermore, Hugl‑1 inhibited cell proliferation, while promoting cell migration, which suggests that it may serve a two‑sided biological role in cellular processes. Taken together, these results suggest that Hugl‑1 promotes the migration and invasion of malignant glioma cells by decreasing N‑cadherin expression. Thus, Hugl‑1 may be applied in the development of targeted and personalized treatment.

View Figures

View References

1	Gould J: Breaking down the epidemiology of brain cancer. Nature. 561:S40–S41. 2018. View Article : Google Scholar : PubMed/NCBI
2	Meyer MA: Malignant gliomas in adults. N Engl J Med. 359:18502008. View Article : Google Scholar : PubMed/NCBI
3	Osswald M and Morais-de-Sá E: Dealing with apical-basal polarity and intercellular junctions: A multidimensional challenge for epithelial cell division. Curr Opin Cell Biol. 60:75–83. 2019. View Article : Google Scholar : PubMed/NCBI
4	Martin-Belmonte F and Perez-Moreno M: Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer. 12:23–38. 2011. View Article : Google Scholar : PubMed/NCBI
5	Hariharan IK and Bilder D: Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annu Rev Genet. 40:335–361. 2006. View Article : Google Scholar : PubMed/NCBI
6	Kashyap A, Zimmerman T, Ergül N, Bosserhoff A, Hartman U, Alla V, Bataille F, Galle PR, Strand S and Strand D: The human Lgl polarity gene, Hugl-2, induces MET and suppresses Snail tumorigenesis. Oncogene. 32:1396–1407. 2013. View Article : Google Scholar : PubMed/NCBI
7	Zimmermann T, Kashyap A, Hartmann U, Otto G, Galle PR, Strand S and Strand D: Cloning and characterization of the promoter of Hugl-2, the human homologue of Drosophila lethal giant larvae (lgl) polarity gene. Biochem Biophys Res Commun. 366:1067–1073. 2008. View Article : Google Scholar : PubMed/NCBI
8	Grifoni D, Garoia F, Bellosta P, Parisi F, De Biase D, Collina G, Strand D, Cavicchi S and Pession A: aPKCzeta cortical loading is associated with Lgl cytoplasmic release and tumor growth in Drosophila and human epithelia. Oncogene. 26:5960–5965. 2007. View Article : Google Scholar : PubMed/NCBI
9	Ohshiro T, Yagami T, Zhang C and Matsuzaki F: Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature. 408:593–596. 2000. View Article : Google Scholar : PubMed/NCBI
10	Vasioukhin V: Lethal giant puzzle of Lgl. Dev Neurosci. 28:13–24. 2006. View Article : Google Scholar : PubMed/NCBI
11	Lu X, Feng X, Man X, Yang G, Tang L, Du D, Zhang F, Yuan H, Huang Q, Zhang Z, et al: Aberrant splicing of Hugl-1 is associated with hepatocellular carcinoma progression. Clin Cancer Res. 15:3287–3296. 2009. View Article : Google Scholar : PubMed/NCBI
12	Kuphal S, Wallner S, Schimanski CC, Bataille F, Hofer P, Strand S, Strand D and Bosserhoff AK: Expression of Hugl-1 is strongly reduced in malignant melanoma. Oncogene. 25:103–110. 2006. View Article : Google Scholar : PubMed/NCBI
13	Schimanski CC, Schmitz G, Kashyap A, Bosserhoff AK, Bataille F, Schäfer SC, Lehr HA, Berger MR, Galle PR, Strand S and Strand D: Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer. Oncogene. 24:3100–3109. 2005. View Article : Google Scholar : PubMed/NCBI
14	Tsuruga T, Nakagawa S, Watanabe M, Takizawa S, Matsumoto Y, Nagasaka K, Sone K, Hiraike H, Miyamoto Y, Hiraike O, et al: Loss of Hugl-1 expression associates with lymph node metastasis in endometrial cancer. Oncol Res. 16:431–435. 2007. View Article : Google Scholar : PubMed/NCBI
15	Matsuzaki T, Takekoshi S, Toriumi K, Kitatani K, Nitou M, Imamura N, Ogura G, Masuda R, Nakamura N and Iwazaki M: Reduced expression of Hugl 1 contributes to the progression of lung squamous cell carcinoma. Tokai J Exp Clin Med. 40:169–177. 2015.PubMed/NCBI
16	Biesterfeld S, Kauhausen A, Kost C, Gockel I, Schimanski CC and Galle PR: Preservation of HUGL-1 expression as a favourable prognostic factor in pancreatic carcinoma. Anticancer Res. 32:3153–3159. 2012.PubMed/NCBI
17	Liu X, Lu D, Ma P, Liu H, Cao Y, Sang B, Zhu X, Shi Q, Hu J, Yu R and Zhou X: Hugl-1 inhibits glioma cell growth in intracranial model. J Neurooncol. 125:113–121. 2015. View Article : Google Scholar : PubMed/NCBI
18	Massimi P, Narayan N, Thomas M, Gammoh N, Strand S, Strand D and Banks L: Regulation of the hDlg/hScrib/Hugl-1 tumour suppressor complex. Exp Cell Res. 314:3306–3317. 2008. View Article : Google Scholar : PubMed/NCBI
19	Zhong XL and Rescorla FJ: Cell surface adhesion molecules and adhesion-initiated signaling: Understanding of anoikis resistance mechanisms and therapeutic opportunities. Cell Signal. 24:393–401. 2012. View Article : Google Scholar : PubMed/NCBI
20	Fife CM, McCarroll JA and Kavallaris M: Movers and shakers: Cell cytoskeleton in cancer metastasis. Brit J Pharmacol. 171:5507–5523. 2014. View Article : Google Scholar
21	Gloushankova NA, Rubtsova SN and Zhitnyak IY: Cadherin-mediated cell-cell interactions in normal and cancer cells. Tissue Barriers. 5:e13569002017. View Article : Google Scholar : PubMed/NCBI
22	Pal M, Bhattacharya S, Kalyan G and Hazra S: Cadherin profiling for therapeutic interventions in Epithelial Mesenchymal Transition (EMT) and tumorigenesis. Exp Cell Res. 368:137–146. 2018. View Article : Google Scholar : PubMed/NCBI
23	Nair KS, Naidoo R and Chetty R: Expression of cell adhesion molecules in oesophageal carcinoma and its prognostic value. J Clin Pathol. 58:343–351. 2005. View Article : Google Scholar : PubMed/NCBI
24	Huang C, Kratzer MC, Wedlich D and Kashef J: E-cadherin is required for cranial neural crest migration in Xenopus laevis. Dev Biol. 411:159–171. 2016. View Article : Google Scholar : PubMed/NCBI
25	Bremmer F, Schallenberg S, Jarry H, Küffer S, Kaulfuss S, Burfeind P, Strauß A, Thelen P, Radzun HJ, Ströbel P, et al: Role of N-cadherin in proliferation, migration, and invasion of germ cell tumours. Oncotarget. 6:33426–33437. 2015. View Article : Google Scholar : PubMed/NCBI
26	Mrozik KM, Blaschuk OW, Cheong CM, Zannettino ACW and Vandyke K: N-cadherin in cancer metastasis, its emerging role in haematological malignancies and potential as a therapeutic target in cancer. BMC Cancer. 18:9392018. View Article : Google Scholar : PubMed/NCBI
27	Camand E, Peglion F, Osmani N, Sanson M and Etienne-Manneville S: N-cadherin expression level modulates integrin-mediated polarity and strongly impacts on the speed and directionality of glial cell migration. J Cell Sci. 125:844–857. 2012. View Article : Google Scholar : PubMed/NCBI
28	Gheldof A and Berx G: Cadherins and epithelial-to-mesenchymal transition. Prog Mol Biol Transl Sci. 116:317–336. 2013. View Article : Google Scholar : PubMed/NCBI
29	Kourtidis A, Lu R, Pence LJ and Anastasiadis PZ: A central role for cadherin signaling in cancer. Exp Cell Res. 358:78–85. 2017. View Article : Google Scholar : PubMed/NCBI
30	Kashima T, Kawaguchi J, Takeshita S, Kuroda M, Takanashi M, Horiuchi H, Imamura T, Ishikawa Y, Ishida T, Mori S, et al: Anomalous cadherin expression in osteosarcoma. Possible relationships to metastasis and morphogenesis. Am J Pathol. 155:1549–1555. 1999. View Article : Google Scholar : PubMed/NCBI
31	Han ZX, Wang XX, Zhang SN, Wu JX, Qian HY, Wen YY, Tian H, Pei DS and Zheng JN: Downregulation of PAK5 inhibits glioma cell migration and invasion potentially through the PAK5-Egr1-MMP2 signaling pathway. Brain Tumor Pathol. 31:234–241. 2014. View Article : Google Scholar : PubMed/NCBI
32	Li F, Jin D, Guan L, Zhang CC, Wu T, Wang YJ and Gao DS: CEP55 promoted the migration, invasion and neuroshpere formation of the glioma cell line U251. Neurosci Lett. 705:80–86. 2019. View Article : Google Scholar : PubMed/NCBI
33	Wang T, Liu Y, Xu XH, Deng CY, Wu KY, Zhu J, Fu XQ, He M and Luo ZG: Lgl1 activation of rab10 promotes axonal membrane trafficking underlying neuronal polarization. Dev Cell. 21:431–444. 2011. View Article : Google Scholar : PubMed/NCBI
34	Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D and Christofori G: Tumor invasion in the absence of epithelial-mesenchymal transition: Podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell. 9:261–272. 2006. View Article : Google Scholar : PubMed/NCBI
35	Li N, Chen G, Liu J, Xia Y, Chen H, Tang H, Zhang F and Gu N: Effect of surface topography and bioactive properties on early adhesion and growth behavior of mouse preosteoblast MC3T3-E1 cells. ACS Appl Mater Interfaces. 6:17134–17143. 2014. View Article : Google Scholar : PubMed/NCBI
36	Lewczuk Ł, Pryczynicz A and Guzińska-Ustymowicz K: Cell adhesion molecules in endometrial cancer-A systematic review. Adv Med Sci. 64:423–429. 2019. View Article : Google Scholar : PubMed/NCBI
37	McKeown SJ, Wallace AS and Anderson RB: Expression and function of cell adhesion molecules during neural crest migration. Dev Biol. 373:244–257. 2013. View Article : Google Scholar : PubMed/NCBI
38	Zhan T, Rindtorff N and Boutros M: Wnt signaling in cancer. Oncogene. 36:1461–1473. 2017. View Article : Google Scholar : PubMed/NCBI
39	Taciak B, Pruszynska I, Kiraga L, Bialasek M and Krol M: Wnt signaling pathway in development and cancer. J Physiol Pharmacol. 69:2018.PubMed/NCBI
40	Li ZH, Zhou Y, Ding YX, Guo QL and Zhao L: Roles of integrin in tumor development and the target inhibitors. Chin J Nat Med. 17:241–251. 2019.PubMed/NCBI
41	Li JC, Cheng LC and Jiang HY: Cell shape and intercellular adhesion regulate mitotic spindle orientation. Mol Biol Cell. 30:2458–2468. 2019. View Article : Google Scholar : PubMed/NCBI
42	Mack NA and Georgiou M: The interdependence of the Rho GTPases and apicobasal cell polarity. Small GTPases. 5:102014. View Article : Google Scholar : PubMed/NCBI
43	Bonastre E, Brambilla E and Sanchez-Cespedes M: Cell adhesion and polarity in squamous cell carcinoma of the lung. J Pathol. 238:606–616. 2016. View Article : Google Scholar : PubMed/NCBI
44	Waghmare I and Kango-Singh M: Loss of cell adhesion increases tumorigenic potential of polarity deficient scribble mutant cells. PLoS One. 11:e01580812016. View Article : Google Scholar : PubMed/NCBI
45	Wan S, Meyer AS, Weiler SME, Rupp C, Tóth M, Sticht C, Singer S, Thomann S, Roessler S, Schorpp-Kistner M, et al: Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness. Hepatology. 67:1842–1856. 2018. View Article : Google Scholar : PubMed/NCBI
46	Bhattacharya S: Cell polarity: A link to epithelial-mesenchymal transition and vascular mimicry. Crit Rev Eukar Gene. 28:101–105. 2018. View Article : Google Scholar
47	Song J, Peng XL, Ji MY, Ai MH, Zhang JX and Dong WG: Hugl-1 induces apoptosis in esophageal carcinoma cells both in vitro and in vivo. World J Gastroenterol. 19:4127–4136. 2013. View Article : Google Scholar : PubMed/NCBI
48	Ke LD, Shi YX and Yung WK: VEGF(121), VEGF(165) overexpression enhances tumorigenicity in U251 MG but not in NG-1 glioma cells. Cancer Res. 62:1854–1861. 2002.PubMed/NCBI
49	Painter KJ, Armstrong NJ and Sherratt JA: The impact of adhesion on cellular invasion processes in cancer and development. J Theor Biol. 264:1057–1067. 2010. View Article : Google Scholar : PubMed/NCBI
50	Cavallaro U and Christofori G: Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer. 4:118–132. 2004. View Article : Google Scholar : PubMed/NCBI
51	Grifoni D, Garoia F, Schimanski CC, Schmitz G, Laurenti E, Galle PR, Pession A, Cavicchi S and Strand D: The human protein Hugl-1 substitutes for Drosophila lethal giant larvae tumour suppressor function in vivo. Oncogene. 23:8688–8694. 2004. View Article : Google Scholar : PubMed/NCBI
52	Yu FX, Zhao B and Guan KL: Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 163:811–828. 2015. View Article : Google Scholar : PubMed/NCBI
53	Asano K, Duntsch CD, Zhou Q, Weimar JD, Bordelon D, Robertson JH and Pourmotabbed T: Correlation of N-cadherin expression in high grade gliomas with tissue invasion. J Neurooncol. 70:3–15. 2004. View Article : Google Scholar : PubMed/NCBI
54	Jossin Y, Lee M, Klezovitch O, Kon E, Cossard A, Lien WH, Fernandez TE, Cooper JA and Vasioukhin V: Llgl1 connects cell polarity with cell-cell adhesion in embryonic neural stem cells. Dev Cell. 41:481–495.e5. 2017. View Article : Google Scholar : PubMed/NCBI