Neuregulin 1 enhances cell adhesion molecule L1 like expression levels and promotes malignancy in human glioma

Lin,Wen‑Wen; Ou,Guan‑Yong; Lin,Jia‑Zhe; Yi,San‑Jun; Yao,Wei‑Cheng; Pan,Hong‑Chao; Zhao,Wei‑Jiang

doi:10.3892/ol.2020.11548

Neuregulin 1 enhances cell adhesion molecule L1 like expression levels and promotes malignancy in human glioma

Authors:
- Wen‑Wen Lin
- Guan‑Yong Ou
- Jia‑Zhe Lin
- San‑Jun Yi
- Wei‑Cheng Yao
- Hong‑Chao Pan
- Wei‑Jiang Zhao
View Affiliations

Affiliations: Center for Neuroscience, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China, Neurosurgical Department, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China, Medical Research Center, Sun Yat‑Sen Memorial Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510120, P.R. China
Published online on: April 21, 2020 https://doi.org/10.3892/ol.2020.11548
Pages: 326-336
Copyright: © Lin 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

Neural cell adhesion molecular L1‑like protein (CHL1) is a member of the cell adhesion molecule L1 family and serves an important role in the development and progression of tumors. The cytokine neuregulin 1 (NRG1) has been indicated in the tumorigenesis and promotion of metastasis through the modulation of L1. However, the roles of NRG1 in regulating CHL1 in glioma have not been elucidated. The present study investigated the protein expression levels and roles of CHL1 and the possible correlation between NRG1 and CHL1 protein expression levels in human gliomas, both in vivo and in vitro. Using immunohistochemistry coupled with a human glioma tissue microarray, it was demonstrated that the percentage of CHL1‑positive areas was the highest in grade II glioma tissues. Using immunofluorescence staining, a positive correlation was identified between the expression levels of CHL1 and proliferating cell nuclear antigen. In addition, CHL1 downregulation also resulted in increased senescence of U‑87 MG human glioblastoma cells. In vitro, administration of NRG1α induced a significant increase in CHL1 protein expression levels in human glioma SHG‑44 and U251 cells and in human glioblastoma U‑87 MG cells, whereas NRG1β failed to increase CHL1 expression levels in U251 cells. These findings were further confirmed by the downregulation of NRG1 expression levels using small interfering RNA treatment, which resulted in the reduction of CHL1 protein expression levels in U‑87 MG cells. These data indicate that NRG1 can regulate CHL1 protein expression levels in gliomas, that it is correlated with malignancy, and that NRG1 may contribute to malignancy by upregulating CHL1 protein expression levels in glioma/glioblastoma cells.

View Figures

View References

1	Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI
2	Sathornsumetee S, Reardon DA, Desjardins A, Quinn JA, Vredenburgh JJ and Rich JN: Molecularly targeted therapy for malignant glioma. Cancer. 110:13–24. 2007. View Article : Google Scholar : PubMed/NCBI
3	Davis ME: Glioblastoma: Overview of disease and treatment. Clin J Oncol Nurs. 20 (5 Suppl):S2–S8. 2016. View Article : Google Scholar : PubMed/NCBI
4	Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, et al: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10:459–466. 2009. View Article : Google Scholar : PubMed/NCBI
5	Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, Pekmezci M, Schwartzbaum JA, Turner MC, Walsh KM, et al: The epidemiology of glioma in adults: A ‘state of the science’ review. Neuro Oncol. 16:896–913. 2014. View Article : Google Scholar : PubMed/NCBI
6	Morgan MA and Canman CE: Replication stress: An achilles' heel of glioma cancer stem-like cells. Cancer Res. 78:6713–6716. 2018. View Article : Google Scholar : PubMed/NCBI
7	Weller M, van den Bent M, Tonn JC, Stupp R, Preusser M, Cohen-Jonathan-Moyal E, Henriksson R, Rhun EL, Balana C, Chinot O, et al: European association for neuro-oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol. 18:e315–e329. 2017. View Article : Google Scholar : PubMed/NCBI
8	Nilsson P, Gedda L, Sjöström A and Carlsson J: Effects of dextranation on the uptake of peptides in micrometastases: Studies on binding of EGF in tumor spheroids. Tumour Biol. 22:229–238. 2001. View Article : Google Scholar : PubMed/NCBI
9	Thuringer D, Hammann A, Benikhlef N, Fourmaux E, Bouchot A, Wettstein G, Solary E and Garrido C: Transactivation of the epidermal growth factor receptor by heat shock protein 90 via Toll-like receptor 4 contributes to the migration of glioblastoma cells. J Biol Chem. 286:3418–3428. 2011. View Article : Google Scholar : PubMed/NCBI
10	O-charoenrat P, Rhys-Evans P, Court WJ, Box GM and Eccles SA: Differential modulation of proliferation, matrix metalloproteinase expression and invasion of human head and neck squamous carcinoma cells by c-ErbB ligands. Clin Exp Metastasis. 17:631–639. 1999. View Article : Google Scholar : PubMed/NCBI
11	Forster JA, Paul AB, Harnden P and Knowles MA: Expression of NRG1 and its receptors in human bladder cancer. Br J Cancer. 104:1135–1143. 2011. View Article : Google Scholar : PubMed/NCBI
12	Cheng H, Terai M, Kageyama K, Ozaki S, McCue PA, Sato T and Aplin AE: Paracrine effect of NRG1 and HGF drives resistance to MEK inhibitors in metastatic uveal melanoma. Cancer Res. 75:2737–2748. 2015. View Article : Google Scholar : PubMed/NCBI
13	Yarden Y and Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2:127–137. 2001. View Article : Google Scholar : PubMed/NCBI
14	Buonanno A and Fischbach GD: Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr Opin Neurobiol. 11:287–296. 2001. View Article : Google Scholar : PubMed/NCBI
15	Ritch PS, Carroll SL and Sontheimer H: Neuregulin-1 enhances survival of human astrocytic glioma cells. Glia. 51:217–228. 2005. View Article : Google Scholar : PubMed/NCBI
16	Senchenko VN, Krasnov GS, Dmitriev AA, Kudryavtseva AV, Anedchenko EA, Braga EA, Pronina IV, Kondratieva TT, Ivanov SV, Zabarovsky ER and Lerman MI: Differential expression of CHL1 gene during development of major human cancers. PLoS One. 6:e156122011. View Article : Google Scholar : PubMed/NCBI
17	Schmid RS and Maness PF: L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth. Curr Opin Neurobiol. 18:245–250. 2008. View Article : Google Scholar : PubMed/NCBI
18	Panicker AK, Buhusi M, Thelen K and Maness PF: Cellular signalling mechanisms of neural cell adhesion molecules. Front Biosci. 8:d900–d911. 2003. View Article : Google Scholar : PubMed/NCBI
19	Sasaki H, Yoshida K, Ikeda E, Asou H, Inaba M, Otani M and Kawase T: Expression of the neural cell adhesion molecule in astrocytic tumors: An inverse correlation with malignancy. Cancer. 82:1921–1931. 1998. View Article : Google Scholar : PubMed/NCBI
20	Long MJ, Wu FX, Li P, Liu M, Li X and Tang H: MicroRNA-10a targets CHL1 and promotes cell growth, migration and invasion in human cervical cancer cells. Cancer Lett. 324:186–196. 2012. View Article : Google Scholar : PubMed/NCBI
21	Liu Y, Yu Y, Schachner M and Zhao W: Neuregulin 1-β regulates cell adhesion molecule L1 expression in the cortex and hippocampus of mice. Biochem Biophys Res Commun. 441:7–12. 2013. View Article : Google Scholar : PubMed/NCBI
22	Zhao WJ and Schachner M: Neuregulin 1 enhances cell adhesion molecule l1 expression in human glioma cells and promotes their migration as a function of malignancy. J Neuropathol Exp Neurol. 72:244–255. 2013. View Article : Google Scholar : PubMed/NCBI
23	Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella- Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P and Ellison DW: The 2016 world health organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 131:803–820. 2016. View Article : Google Scholar : PubMed/NCBI
24	Ritch PA, Carroll SL and Sontheimer H: Neuregulin-1 enhances motility and migration of human astrocytic glioma cells. J Biol Chem. 278:20971–20978. 2003. View Article : Google Scholar : PubMed/NCBI
25	Demyanenko GP, Schachner M, Anton E, Schmid R, Feng G, Sanes J and Maness PF: Close homolog of L1 modulates area-specific neuronal positioning and dendrite orientation in the cerebral cortex. Neuron. 44:423–437. 2004. View Article : Google Scholar : PubMed/NCBI
26	Sytnyk V, Leshchyns'ka I and Schachner M: Neural cell adhesion molecules of the immunoglobulin superfamily regulate synapse formation, maintenance, and function. Trends Neurosci. 40:295–308. 2017. View Article : Google Scholar : PubMed/NCBI
27	He LH, Ma Q, Shi YH, Ge J, Zhao HM, Li SF and Tong ZS: CHL1 is involved in human breast tumorigenesis and progression. Biochem Biophys Res Commun. 438:433–438. 2013. View Article : Google Scholar : PubMed/NCBI
28	Yang Z, Xie Q, Hu CL, Jiang Q, Shen HF, Schachner M and Zhao WJ: CHL1 is expressed and functions as a malignancy promoter in glioma cells. Front Mol Neurosci. 10:3242017. View Article : Google Scholar : PubMed/NCBI
29	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
30	Fan HC, Chen CM, Chi CS, Tsai JD, Chiang KL, Chang YK, Lin SZ and Harn HJ: Targeting telomerase and ATRX/DAXX inducing tumor senescence and apoptosis in the malignant glioma. Int J Mol Sci. 20(pii): E2002019. View Article : Google Scholar : PubMed/NCBI
31	Debacq-Chainiaux F, Erusalimsky JD, Campisi J and Toussaint O: Protocols to detect senescence-associated beta-galactosidase (SA-beta gal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc. 4:1798–1806. 2009. View Article : Google Scholar : PubMed/NCBI
32	Alver TN, Lavelle TJ, Longva AS, Øy GF, Hovig E and Bøe SL: MITF depletion elevates expression levels of ERBB3 receptor and its cognate ligand NRG1-beta in melanoma. Oncotarget. 7:55128–55140. 2016. View Article : Google Scholar : PubMed/NCBI
33	Asati V, Mahapatra DK and Bharti SK: PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur J Med Chem. 109:314–341. 2016. View Article : Google Scholar : PubMed/NCBI
34	Zhao HF, Wang J, Shao W, Wu CP, Chen ZP, To ST and Li WP: Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: Current preclinical and clinical development. Mol Cancer. 16:1002017. View Article : Google Scholar : PubMed/NCBI
35	Li X, Wu C, Chen N, Gu H, Yen A, Cao L, Wang E and Wang L: PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget. 7:33440–33450. 2016.PubMed/NCBI
36	Rodon J, Dienstmann R, Serra V and Tabernero J: Development of PI3K inhibitors: Lessons learned from early clinical trials. Nat Rev Clin Oncol. 10:143–153. 2013. View Article : Google Scholar : PubMed/NCBI
37	Yin F, Zhang JN, Wang SW, Zhou CH, Zhao MM, Fan WH, Fan M and Liu S: MiR-125a-3p regulates glioma apoptosis and invasion by regulating Nrg1. PLoS One. 10:e01167592015. View Article : Google Scholar : PubMed/NCBI
38	Li Y, Li Y, Ge P and Ma C: MiR-126 regulates the ERK pathway via targeting KRAS to inhibit the glioma cell proliferation and invasion. Mol Neurobiol. 54:137–145. 2017. View Article : Google Scholar : PubMed/NCBI
39	Li B, Wang F, Liu N, Shen W and Huang T: Astragaloside IV inhibits progression of glioma via blocking MAPK/ERK signaling pathway. Biochem Biophys Res Commun. 491:98–103. 2017. View Article : Google Scholar : PubMed/NCBI