Annexin A2 regulates glioma cell proliferation through the STAT3‑cyclin D1 pathway

Chen,Ling; Lin,Ling; Xian,Na; Zheng,Zhihong

doi:10.3892/or.2019.7155

Annexin A2 regulates glioma cell proliferation through the STAT3‑cyclin D1 pathway

Authors:
- Ling Chen
- Ling Lin
- Na Xian
- Zhihong Zheng
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Affiliations: Department of Biochemistry and Molecular Biology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China, Department of Cell Biology and Genetics, The School of Basic Medical Sciences; 3Fujian Provincial Key Laboratory of Neuroglia and Disease, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
Published online on: May 9, 2019 https://doi.org/10.3892/or.2019.7155
Pages: 399-413

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Abstract

Annexin A2 (ANXA2) acts as a calcium‑dependent phospholipid‑binding protein that is widely expressed in vertebrate cells and has abnormally high expression in various tumor cells. However, the detailed molecular mechanism underlying the effects of ANXA2 on glioma cells remains unclear. The present study aimed to investigate the role and underlying molecular mechanisms of ANXA2 in glioma cell proliferation. The results revealed that knockdown of ANXA2 inhibited the proliferation of U251 and U87 glioma cell lines and decreased phosphorylated (p) signal transducer and activator of transcription 3 (STAT3)(Y705) and cyclin D1 expression, leading to impedance of the G1‑to‑S phase transition. Furthermore, it was suggested that ANXA2 may regulate pSTAT3(Y705) levels through direct binding with STAT3, thereby affecting STAT3‑cyclin D1 pathway‑mediated cell proliferation. When ANXA2 was re‑expressed in ANXA2‑knockdown cells, the expression of pSTAT3(Y705) and cyclin D1 was restored. Furthermore, overexpression of ANXA2 significantly promoted the proliferation of U251 cells, as determined by an MTT assay and a tumor formation assay in nude mice, but had no statistically significant effect on colony formation rate, cell cycle progression or the STAT3‑cyclin D1 pathway, suggesting that endogenous ANXA2 may be redundant. Additionally, the present study provided evidence that the overexpression of ANXA2 enhanced the expression of pSTAT3(Y705) in the presence of epidermal growth factor (EGF), indicating that the proliferation‑promoting effect of ANXA2 may be due to the accumulation and synergistic effect of paracrine EGF. Taken together, the present results indicated that ANXA2 may affect the proliferation of human glioma cells through the STAT3‑cyclin D1 pathway via direct interaction with STAT3 in U251 and U87 glioma cells. ANXA2 was redundant in this pathway, but positive synergy was revealed to exist between ANXA2 and EGF.

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1	Ohgaki H: Epidemiology of brain tumors. Methods Mol Biol. 472:323–342. 2009. View Article : Google Scholar : PubMed/NCBI
2	Ohgaki H and Kleihues P: Epidemiology and etiology of gliomas. Acta Neuropathol. 109:93–108. 2005. View Article : Google Scholar : PubMed/NCBI
3	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
4	Stylli SS and Kaye AH: Photodynamic therapy of cerebral glioma-a review. Part II-clinical studies. J Clin Neurosci. 13:709–717. 2006. View Article : Google Scholar : PubMed/NCBI
5	Pan DS, Feng SZ, Cao P and Li JJ: Endothelin B receptor promotes the proliferation and immune escape of malignant gliomas. Artif Cells Nanomed Biotechnol. 46:1230–1235. 2018. View Article : Google Scholar : PubMed/NCBI
6	Ruokun C, Yake X, Fengdong Y, Xinting W, Laijun S and Xianzhi L: Lentivirus-mediated silencing of HSDL2 suppresses cell proliferation in human gliomas. Tumour Biol. 37:15065–15077. 2016. View Article : Google Scholar : PubMed/NCBI
7	Jiang L, Wang C, Lei F, Zhang L, Zhang X, Liu A, Wu G, Zhu J and Song L: miR-93 promotes cell proliferation in gliomas through activation of PI3K/Akt signaling pathway. Oncotarget. 6:8286–8299. 2015.PubMed/NCBI
8	Pan Y, Liang W, Zhao X, Liu L, Qing Y and Li Y: miR-548b inhibits the proliferation and invasion of malignant gliomas by targeting metastasis tumor-associated protein-2. Neuroreport. 27:1266–1273. 2016. View Article : Google Scholar : PubMed/NCBI
9	Liang ML, Hsieh TH, Ng KH, Tsai YN, Tsai CF, Chao ME, Liu DJ, Chu SS, Chen W, Liu YR, et al: Downregulation of miR-137 and miR-6500-3p promotes cell proliferation in pediatric high-grade gliomas. Oncotarget. 7:19723–19737. 2016. View Article : Google Scholar : PubMed/NCBI
10	Catanzaro G, Besharat ZM, Miele E, Chiacchiarini M, Po A, Carai A, Marras CE, Antonelli M, Badiali M, Raso A, et al: The miR-139-5p regulates proliferation of supratentorial paediatric low-grade gliomas by targeting the PI3K/AKT/mTORC1 signalling. Neuropathol Appl Neurobiol. 44:687–706. 2018. View Article : Google Scholar : PubMed/NCBI
11	Wang G, Kang C and Pu P: Increased expression of Akt2 and activity of PI3K and cell proliferation with the ascending of tumor grade of human gliomas. Clin Neurol Neurosurg. 112:324–327. 2010. View Article : Google Scholar : PubMed/NCBI
12	Leslie K, Lang C, Devgan G, Azare J, Berishaj M, Gerald W, Kim YB, Paz K, Darnell JE, Albanese C, et al: Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res. 66:2544–2552. 2006. View Article : Google Scholar : PubMed/NCBI
13	Zhang X, Zhao M, Huang AY, Fei Z, Zhang W and Wang XL: The effect of cyclin D expression on cell proliferation in human gliomas. J Clin Neurosci. 12:166–168. 2005. View Article : Google Scholar : PubMed/NCBI
14	Wu S, Fu J, Dong Y, Yi Q, Lu D, Wang W, Qi Y, Yu R and Zhou X: GOLPH3 promotes glioma progression via facilitating JAK2-STAT3 pathway activation. J Neurooncol. 139:269–279. 2018. View Article : Google Scholar : PubMed/NCBI
15	Ren Z, Zou W, Cui J, Liu L, Qing Y and Li Y: Geraniin suppresses tumor cell growth and triggers apoptosis in human glioma via inhibition of STAT3 signaling. Cytotechnology. 69:765–773. 2017. View Article : Google Scholar : PubMed/NCBI
16	Zhang K, Pang B, Xin T, Hou X, Jia J, Feng B, Meng L, Xu S and Pang Q: Increased signal transducer and activator of transcription 3 (STAT3) and decreased cyclin D1 in recurrent astrocytic tumours compared with paired primary astrocytic tumours. J Int Med Res. 39:2103–2109. 2011. View Article : Google Scholar : PubMed/NCBI
17	Zhang F, Wang Z, Yuan J, Wei X, Tian R and Niu R: RNAi-mediated silencing of Anxa2 inhibits breast cancer cell proliferation by downregulating cyclin D1 in STAT3-dependent pathway. Breast Cancer Res Treat. 153:263–275. 2015. View Article : Google Scholar : PubMed/NCBI
18	Wang T, Yuan J, Zhang J, Tian R, Ji W, Zhou Y, Yang Y, Song W, Zhang F and Niu R: Anxa2 binds to STAT3 and promotes epithelial to mesenchymal transition in breast cancer cells. Oncotarget. 6:30975–30992. 2015.PubMed/NCBI
19	Lokman NA, Ween MP, Oehler MK and Ricciardelli C: The role of Annexin A2 in tumorigenesis and cancer progression. Cancer Microenviron. 4:199–208. 2011. View Article : Google Scholar : PubMed/NCBI
20	Sharma MR, Koltowski L, Ownbey RT, Tuszynski GP and Sharma MC: Angiogenesis-associated protein Annexin II in breast cancer: Selective expression in invasive breast cancer and contribution to tumor invasion and progression. Exp Mol Pathol. 81:146–156. 2006. View Article : Google Scholar : PubMed/NCBI
21	Inokuchi J, Narula N, Yee DS, Skarecky DW, Lau A, Ornstein DK and Tyson DR: Annexin A2 positively contributes to the malignant phenotype and secretion of IL-6 in DU145 prostate cancer cells. Int J Cancer. 124:68–74. 2009. View Article : Google Scholar : PubMed/NCBI
22	Shiozawa Y, Havens AM, Jung Y, Ziegler AM, Pedersen EA, Wang J, Wang J, Lu G, Roodman GD, Loberg RD, et al: Annexin II/Annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer. J Cell Biochem. 105:370–380. 2008. View Article : Google Scholar : PubMed/NCBI
23	Villano JL, Seery TE and Bressler LR: Temozolomide in malignant gliomas: Current use and future targets. Cancer Chemother Pharmacol. 64:647–655. 2009. View Article : Google Scholar : PubMed/NCBI
24	Maule F, Bresolin S, Rampazzo E, Boso D, Della Puppa A, Esposito G, Porcù E, Mitola S, Lombardi G, Accordi B, et al: Annexin 2A sustains glioblastoma cell dissemination and proliferation. Oncotarget. 7:54632–54649. 2016. View Article : Google Scholar : PubMed/NCBI
25	Reeves SA, Chavez-Kappel C, Davis R, Rosenblum M and Israel MA: Developmental regulation of Annexin II (Lipocortin 2) in human brain and expression in high grade glioma. Cancer Res. 52:6871–6876. 1992.PubMed/NCBI
26	Aukrust I, Hollas H, Strand E, Evensen L, Travé G, Flatmark T and Vedeler A: The mRNA-binding site of Annexin A2 resides in helices C-D of its domain IV. J Mol Biol. 368:1367–1378. 2007. View Article : Google Scholar : PubMed/NCBI
27	Chiang Y, Rizzino A, Sibenaller ZA, Wold MS and Vishwanatha JK: Specific down-regulation of Annexin II expression in human cells interferes with cell proliferation. Mol Cell Biochem. 199:139–147. 1999. View Article : Google Scholar : PubMed/NCBI
28	Zhang HJ, Yao DF, Yao M, Huang H, Wang L, Yan MJ, Yan XD, Gu X, Wu W and Lu SL: Annexin A2 silencing inhibits invasion, migration, and tumorigenic potential of hepatoma cells. World J Gastroenterol. 19:3792–3801. 2013. View Article : Google Scholar : PubMed/NCBI
29	Zhang J, Guo B, Zhang Y, Cao J and Chen T: Silencing of the Annexin II gene down-regulates the levels of S100A10, c-Myc, and plasmin and inhibits breast cancer cell proliferation and invasion. Saudi Med J. 31:374–381. 2010.PubMed/NCBI
30	Kumble KD, Hirota M, Pour PM and Vishwanatha JK: Enhanced levels of annexins in pancreatic carcinoma cells of Syrian hamsters and their intrapancreatic allografts. Cancer Res. 52:163–167. 1992.PubMed/NCBI
31	Zhai H, Acharya S, Gravanis I, Mehmood S, Seidman RJ, Shroyer KR, Hajjar KA and Tsirka SE: Annexin A2 promotes glioma cell invasion and tumor progression. J Neurosci. 31:14346–14360. 2011. View Article : Google Scholar : PubMed/NCBI
32	Tatenhorst L, Rescher U, Gerke V and Paulus W: Knockdown of annexin 2 decreases migration of human glioma cells in vitro. Neuropathol Appl Neurobiol. 32:271–277. 2006. View Article : Google Scholar : PubMed/NCBI
33	Baldin V, Lukas J, Marcote MJ, Pagano M and Draetta G: Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 7:812–821. 1993. View Article : Google Scholar : PubMed/NCBI
34	Zhou C, Ma J, Su M, Shao D, Zhao J, Zhao T, Song Z, Meng Y and Jiao P: Down-regulation of STAT3 induces the apoptosis and G1 cell cycle arrest in esophageal carcinoma ECA109 cells. Cancer Cell Int. 18:532018. View Article : Google Scholar : PubMed/NCBI
35	Rahaman SO, Harbor PC, Chernova O, Barnett GH, Vogelbaum MA and Haque SJ: Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene. 21:8404–8413. 2002. View Article : Google Scholar : PubMed/NCBI
36	Yuan J, Yang Y, Gao Z, Wang Z, Ji W, Song W, Zhang F and Niu R: Tyr23 phosphorylation of Anxa2 enhances STAT3 activation and promotes proliferation and invasion of breast cancer cells. Breast Cancer Res Treat. 164:327–340. 2017. View Article : Google Scholar : PubMed/NCBI
37	Sansone P and Bromberg J: Targeting the interleukin-6/Jak/stat pathway in human malignancies. J Clin Oncol. 30:1005–1014. 2012. View Article : Google Scholar : PubMed/NCBI
38	Cui L, Song J, Wu L, Cheng L, Chen A, Wang Y, Huang Y and Huang L: Role of Annexin A2 in the EGF-induced epithelial-mesenchymal transition in human CaSki cells. Oncol Lett. 13:377–383. 2017. View Article : Google Scholar : PubMed/NCBI