|
The Aurora-A/NPAT/Wnt-β-catenin pathway enhances the metastasis and stemness of lung cancer cells
|
Y. Zhao   , Y. Zhao , P. Li , X. Fu , J. Duan , Y. Tang , Y. Ma , Q. Zhou |
| Department of Medical Oncology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong 518052, China , zhaoyan_nsyy@163.com |
|
|
Abstract: (580 Views) |
Background: Aurora-A kinase (Aurora-A) serves as an oncogene in many cancers, but whether its expression is linked to the stemness of lung cancer (LC) cells remains obscure. Hence, this study probed the impact as well as mechanism of Aurora-A in affecting the stemness of LC cells. Materials and Methods: Functional assays were implemented to assess the malignant behaviors along with stemness of LC cells. Western blot analysis detected the stemness markers together with the Wnt-β-catenin pathway-linked genes protein levels. TOP/FOP-Flash reporter assay assessed the activity of the Wnt/β-catenin pathway. Hematoxylin and eosin staining as well as immunohistochemistry analysis of tumor tissues were implemented. Results: Our findings indicated that Aurora-A was up-regulated in LC cells, and silenced Aurora-A hindered LC cell proliferation, migration, invasion along with stemness. Nuclear protein, coactivator of histone transcription (NPAT) was also high-expressed in LC cells, and was positively modulated by Aurora-A. Silenced NPAT inhibited LC cell malignant behaviors along with stemness. Aurora-A activated the Wnt/β-catenin pathway and promoted LC cell malignant behaviors along with stemness via regulating NPAT. In an established xenograft model, Aurora-A inhibition reduced tumor growth, metastasis along with stemness in vivo. Conclusion: In summary, Aurora-A/NPAT/Wnt-β-catenin signaling pathway accelerates LC cell malignant behaviors along with stemness. The modulation of Aurora-A might be an underlying therapeutic approach in LC patients. |
|
| Keywords: lung cancer, malignant, Aurora-A, NPAT, Wnt-β-catenin. |
|
|
Full-Text [PDF 1344 kb]
(100 Downloads)
|
|
Type of Study: Original Research |
Subject:
Radiation Biology
|
|
|
|
|
|
|
| References |
1. 1. Bade BC and Dela Cruz CS (2020) Lung cancer; epidemiology, etiology, and prevention. Clin Chest Med, 41(1): 1-24. [ DOI:10.1016/j.ccm.2019.10.001] 2. Nasim F, Sabath BF, Eapen GA (2019) Lung cancer. Med Clin North Am, 103(3): 463-473. [ DOI:10.1016/j.mcna.2018.12.006] 3. Jones GS and Baldwin DR (2018) Recent advances in the management of lung cancer. Clin Med (Lond), 18(Suppl 2): s41-s46. [ DOI:10.7861/clinmedicine.18-2-s41] 4. Wu F, Wang L, Zhou C (2021) Lung cancer in China: current and prospect. Curr Opin Oncol, 33(1): 40-46. [ DOI:10.1097/CCO.0000000000000703] 5. Brody H (2020) Lung cancer. Nature, 587(7834): S7. [ DOI:10.1038/d41586-020-03152-0] 6. He Y, Luo W, Liu Y, et al. (2022) IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer. J Clin Invest, 132(20): e157917. [ DOI:10.1172/JCI157917] 7. Maiuthed A, Chantarawong W, Chanvorachote P (2108) Lung cancer stem cells and cancer stem cell-targeting natural compounds. Anticancer Res, 38(7): 3797-3809. [ DOI:10.21873/anticanres.12663] 8. Prasetyanti PR and Medema JP (2017) Intra-tumor heterogeneity from a cancer stem cell perspective. Mol Cancer, 16(1): 41. [ DOI:10.1186/s12943-017-0600-4] 9. Najafi M, Mortezaee K, Majidpoor J (2019) Cancer stem cell (CSC) resistance drivers. Life Sci, 234: 116781. [ DOI:10.1016/j.lfs.2019.116781] 10. Wang X, Chen Y, Wang X, et al. (2021) Stem cell factor SOX2 confers ferroptosis resistance in lung cancer via upregulation of SLC7A11. Cancer Res, 81(20): 5217-5229. [ DOI:10.1158/0008-5472.CAN-21-0567] 11. Rowbotham SP, Goruganthu MUL, Arasada RR, et al. (2022) Lung cancer stem cells and their clinical implications. Cold Spring Harb Perspect Med, 12(4): a041270. [ DOI:10.1101/cshperspect.a041270] 12. Mou PK, Yang EJ, Shi C, et al. (2021) Aurora kinase A, a synthetic lethal target for precision cancer medicine. Exp Mol Med, 53(5): 835-847. [ DOI:10.1038/s12276-021-00635-6] 13. Sun H, Wang H, Wang X, et al. (2020) Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Theranostics, 10(15): 6928-6945. [ DOI:10.7150/thno.43811] 14. Li M, Gao K, Chu L, et al. (2018) The role of Aurora-A in cancer stem cells. Int J Biochem Cell Biol, 98: 89-92. [ DOI:10.1016/j.biocel.2018.03.007] 15. Lin X, Xiang X, Hao L, et al. (2020) The role of Aurora-A in human cancers and future therapeutics. Am J Cancer Res, 10(9): 2705-2729. 16. Pirngruber J and Johnsen SA (2010) Induced G1 cell-cycle arrest controls replication-dependent histone mRNA 3' end processing through p21, NPAT and CDK9. Oncogene, 29(19): 2853-63. [ DOI:10.1038/onc.2010.42] 17. Ghule PN, Becker KA, Harper JW, et al. (2007) Cell cycle dependent phosphorylation and subnuclear organization of the histone gene regulator p220(NPAT) in human embryonic stem cells. J Cell Physiol, 213(1): 9-17. [ DOI:10.1002/jcp.21119] 18. Kalla C, Scheuermann MO, Kube I, et al. (2007) Analysis of 11q22-q23 deletion target genes in B-cell chronic lymphocytic leukaemia: evidence for a pathogenic role of NPAT, CUL5, and PPP2R1B. Eur J Cancer, 43(8): 1328-35. [ DOI:10.1016/j.ejca.2007.02.005] 19. Susanti S, Iwasaki H, Inafuku M, et al. (2013) Mechanism of arctigenin-mediated specific cytotoxicity against human lung adenocarcinoma cell lines. Phytomedicine, 21(1): 39-46. [ DOI:10.1016/j.phymed.2013.08.003] 20. Nardone V, Barbarino M, Angrisani A, et al. (2021) CDK4, CDK6/cyclin-D1 Complex inhibition and radiotherapy for cancer control: a role for autophagy. Int J Mol Sci, 22(16): 8391. [ DOI:10.3390/ijms22168391] 21. Tang J, Li J, Lian J, et al. (2023) CDK2-activated TRIM32 phosphorylation and nuclear translocation promotes radioresistance in triple-negative breast cancer. J Adv Res, 61: 239-251. [ DOI:10.1016/j.jare.2023.09.011] 22. Yu J, Liu D, Sun X, et al. (2019) CDX2 inhibits the proliferation and tumor formation of colon cancer cells by suppressing Wnt/β-catenin signaling via transactivation of GSK-3β and Axin2 expression. Cell Death Dis, 10(1): 26. [ DOI:10.1038/s41419-018-1263-9] 23. Becker KA, Ghule PN, Lian JB, et al. (2010) Cyclin D2 and the CDK substrate p220(NPAT) are required for self-renewal of human embryonic stem cells. J Cell Physiol, 222(2): 456-64. [ DOI:10.1002/jcp.21967] 24. Wang R, Song Y, Liu X, et al. (2017) UBE2C induces EMT through Wnt/β‑catenin and PI3K/Akt signaling pathways by regulating phosphorylation levels of Aurora-A. Int J Oncol, 2 50(4):1116-1126. [ DOI:10.3892/ijo.2017.3880] 25. Lung Cancer. Am Fam Physician, 2022. 105(5): https://www.aafp.phosphorylation levels of Aurora-A.Int J Oncol, 2 50(4):1116-1126. org/pubs/afp/issues/2022/0500/p487-s1.html. 26. The L (2019) Lung cancer: some progress, but still a lot more to do. Lancet, 394(10212): 1880. [ DOI:10.1016/S0140-6736(19)32795-3] 27. Liu M, Wu H, Xu C (2023) Targeting cancer stem cell pathways for lung cancer therapy. Curr Opin Oncol, 35(1): 78-85. [ DOI:10.1097/CCO.0000000000000912] 28. Adhikari B, Bozilovic J, Diebold M, et al. (2020) PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase. Nat Chem Biol, 16(11): 1179-1188. [ DOI:10.1038/s41589-020-00652-y] 29. Zhang S, Li J, Zhou G, et al. (2017) Aurora-A regulates autophagy through the Akt pathway in human prostate cancer. Cancer Biomarker, 19(1): 27-34. [ DOI:10.3233/CBM-160238] 30. Lo Iacono M, Monica V, Saviozzi S, et al. (2011) Aurora Kinase A expression is associated with lung cancer histological-subtypes and with tumor de-differentiation. J Transl Med, 9: 100. [ DOI:10.1186/1479-5876-9-100] 31. Smith SL, Bowers NL, Betticher DC, et al. (2005) Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability. Br J Cancer, 93(6): 719-29. [ DOI:10.1038/sj.bjc.6602779] 32. Long S and Zhang XF (2023) AURKA is a prognostic potential therapeutic target in skin cutaneous melanoma modulating the tumor microenvironment, apoptosis, and hypoxia. J Cancer Res Clin Oncol, 149(7): 3089-3107. [ DOI:10.1007/s00432-022-04164-1] 33. Xia Z, Wei P, Zhang H, et al. (2013) AURKA governs self-renewal capacity in glioma-initiating cells via stabilization/activation of β-catenin/Wnt signaling. Mol Cancer Res, 11(9): 1101-11. [ DOI:10.1158/1541-7786.MCR-13-0044] 34. Becker KA, Ghule PN, Therrien JA, et al. (2006) Self-renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase. J Cell Physiol, 209(3): 883-93. [ DOI:10.1002/jcp.20776] 35. Nishimura Y, Yamakawa D, Shiromizu T, et al., (2021) Aurora A and AKT Kinase Signaling Associated with Primary Cilia. Cells, 10(12): 3602. [ DOI:10.3390/cells10123602] 36. Meng J, Liu HL, Ma D, et al. (2020) Upregulation of aurora kinase A promotes vascular smooth muscle cell proliferation and migration by activating the GSK-3β/β-catenin pathway in aortic-dissecting aneurysms. Life Sci, 262: 118491. [ DOI:10.1016/j.lfs.2020.118491] 37. Saiprasad G, Chitra P, Manikandan R, et al., Hesperidin induces apoptosis and triggers autophagic markers through inhibition of Aurora-A mediated phosphoinositide-3-kinase/Akt/mammalian target of rapamycin and glycogen synthase kinase-3 beta signalling cascades in experimental colon carcinogenesis. Eur J Cancer, 50(14): 2489-507. [ DOI:10.1016/j.ejca.2014.06.013] 38. Subramaniyan B, Jagadeesan K, Ramakrishnan S, et al. (2016) Targeting the interaction of Aurora kinases and SIRT1 mediated by Wnt signaling pathway in colorectal cancer: A critical review. Biomed Pharmacother, 82: 413-24. [ DOI:10.1016/j.biopha.2016.05.027] |
|
| Send email to the article author |
|
|
|
| Add your comments about this article |
|
|
|
|
Zhao Y, Zhao Y, Li P, Fu X, Duan J, Tang Y, et al . The Aurora-A/NPAT/Wnt-β-catenin pathway enhances the metastasis and stemness of lung cancer cells. Int J Radiat Res 2025; 23 (1) :147-154 URL: http://ijrr.com/article-1-5998-en.html
|
