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LncRNA MAGI2-AS3 inhibits tumor progression and angiogenesis by regulating ACY1 via interacting with transcription factor HEY1 in clear cell renal cell carcinoma

Cancer Gene Therapy volume 29, pages 585–596 (2022)Cite this article

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Abstract

Clear cell renal cell carcinoma (ccRCC) represents the most common type of RCC in adults, characterized by hyper-vascularization and metastatic relapse. Surgical resection is the main treatment due to poor response of ccRCC to radio-and chemotherapy. However, the high complexity of tumor vasculature in ccRCC has thwarted effects to develop new therapeutic strategies for ccRCC. In this study, we identify the anti-angiogenic activity of MAGI2-AS3 in ccRCC. 86 paired samples of tumor tissues and adjacent no-tumor tissues were collected from ccRCC patients. Dual-luciferase reporter assay, RIP, and ChIP assays were employed to confirm interactions between MAGI2-AS3, transcription factor HEY1, and the ACY1 gene. In other studies, we assayed human ccRCC cells RLC-310 for their viability, migration and invasion using CCK-8 detection and transwell chamber systems. Angiogenesis was evaluated in the Matrigel-based human umbilical vein endothelial cell (HUVEC)-RLC-310 coculture model and immunohistochemical staining for vascular endothelial growth factor (VEGF) and CD31 in tumor tissues collected from a xenograft ccRCC mouse model. MAGI2-AS3 and ACY1 expression was downregulated in ccRCC tissues, and low expression of MAGI2-AS3 was associated with poor patient survival. Overexpression of MAGI2-AS3 could reduce ccRCC cell viability and migration, inhibit vessel-like tube formation of HUVECs in vitro, and repress tumor growth and angiogenesis in vivo. MAGI2-AS3 bound with HEY1 and reduced the HEY1 enrichment at the ACY1 promoter region, thus increasing ACY1 gene transcription. HEY1 knockdown or ACY1 overexpression that resisted MAGI2-AS3 knockdown was found in the in vivo and in vitro settings. The present study demonstrates that MAGI2-AS3 exerts tumor-suppressive, anti-angiogenic activities in ccRCC by modulating the HEY1/ACY1 pathway, thus lending support for conducting further investigations of anti-angiogenesis therapy for ccRCC.

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Fig. 1: Expression pattern of MAGI2-AS3 in ccRCC tissues and cells.
Fig. 2: MAGI2-AS3 retarded ccRCC cell viability, migration and invasion.
Fig. 3: MAGI2-AS3 inhibited tumor angiogenesis in ccRCC.
Fig. 4: MAGI2-AS3 bound with HEY1 and reduced the HEY1 enrichment at the ACY1 promoter region.
Fig. 5: The MAGI2-AS3/HEY1/ACY1 signaling pathway affected ccRCC cell viability, migration and invasion.
Fig. 6: The MAGI2-AS3/HEY1/ACY1 signaling pathway regulated tumor angiogenesis in ccRCC.
Fig. 7: A systematic diagram showing the involvement of the MAGI2-AS3/HEY1/ACY1 signaling pathway in ccRCC.

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The datasets generated/analyzed during the current study are available.

References

  1. Capitanio U, Bensalah K, Bex A, Boorjian SA, Bray F, Coleman J, et al. Epidemiology of renal cell carcinoma. Eur Urol 2019;75:74–84.

    Article  Google Scholar 

  2. Xue D, Wang H, Chen Y, Shen D, Lu J, Wang M, et al. Circ-AKT3 inhibits clear cell renal cell carcinoma metastasis via altering miR-296-3p/E-cadherin signals. Mol Cancer 2019;18:151.

    Article  Google Scholar 

  3. Lalani AA, McGregor BA, Albiges L, Choueiri TK, Motzer R, Powles T, et al. Systemic treatment of metastatic clear cell renal cell carcinoma in 2018: current paradigms, use of immunotherapy, and future directions. Eur Urol 2019;75:100–10.

    Article  Google Scholar 

  4. Frew IJ, Moch H. A clearer view of the molecular complexity of clear cell renal cell carcinoma. Annu Rev Pathol 2015;10:263–89.

    Article  CAS  Google Scholar 

  5. Qu L, Wang ZL, Chen Q, Li YM, He HW, Hsieh JJ, et al. Prognostic value of a long non-coding RNA signature in localized clear cell renal cell carcinoma. Eur Urol 2018;74:756–63.

    Article  CAS  Google Scholar 

  6. Vuong L, Kotecha RR, Voss MH, Hakimi AA. Tumor microenvironment dynamics in clear-cell renal cell carcinoma. Cancer Discov 2019;9:1349–57.

    Article  CAS  Google Scholar 

  7. Qu L, Ding J, Chen C, Wu ZJ, Liu B, Gao Y, et al. Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer Cell 2016;29:653–68.

    Article  CAS  Google Scholar 

  8. Flippot R, Mouawad R, Spano JP, Roupret M, Comperat E, Bitker MO, et al. Expression of long non-coding RNA MFI2-AS1 is a strong predictor of recurrence in sporadic localized clear-cell renal cell carcinoma. Sci Rep. 2017;7:8540.

    Article  Google Scholar 

  9. Hamilton MJ, Young M, Jang K, Sauer S, Neang VE, King AT, et al. HOTAIRM1 lncRNA is downregulated in clear cell renal cell carcinoma and inhibits the hypoxia pathway. Cancer Lett 2019;472:50–8.

    Article  Google Scholar 

  10. Ren H, Li Z, Tang Z, Li J, Lang X Long noncoding MAGI2-AS3 promotes colorectal cancer progression through regulating miR-3163/TMEM106B axis. J Cell Physiol. 2019;https://doi.org/10.1002/jcp.29360

  11. Yang Y, Yang H, Xu M, Zhang H, Sun M, Mu P, et al. Long non-coding RNA (lncRNA) MAGI2-AS3 inhibits breast cancer cell growth by targeting the Fas/FasL signalling pathway. Hum Cell 2018;31:232–41.

    Article  Google Scholar 

  12. Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 2004;18:901–11.

    Article  CAS  Google Scholar 

  13. Lopez-Mateo I, Arruabarrena-Aristorena A, Artaza-Irigaray C, Lopez JA, Calvo E, Belandia B HEY1 functions are regulated by its phosphorylation at Ser-68. Biosci Rep. 2016;36:

  14. Long PM, Stradecki HM, Minturn JE, Wesley UV, Jaworski DM. Differential aminoacylase expression in neuroblastoma. Int J Cancer 2011;129:1322–30.

    Article  CAS  Google Scholar 

  15. Zhong Y, Onuki J, Yamasaki T, Ogawa O, Akatsuka S, Toyokuni S. Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma. Carcinogenesis 2009;30:158–64.

    Article  CAS  Google Scholar 

  16. Chen Z, Zhang Z, Zhao D, Feng W, Meng F, Han S, et al. Long noncoding RNA (lncRNA) FOXD2-AS1 promotes cell proliferation and metastasis in hepatocellular carcinoma by regulating MiR-185/AKT Axis. Med Sci Monit 2019;25:9618–29.

    Article  CAS  Google Scholar 

  17. Wu P, Liu JL, Pei SM, Wu CP, Yang K, Wang SP, et al. Integrated genomic analysis identifies clinically relevant subtypes of renal clear cell carcinoma. BMC Cancer 2018;18:287.

    Article  CAS  Google Scholar 

  18. Oliveira RC, Ivanovic RF, Leite KRM, Viana NI, Pimenta RCA, Junior JP, et al. Expression of micro-RNAs and genes related to angiogenesis in ccRCC and associations with tumor characteristics. BMC Urol 2017;17:113.

    Article  Google Scholar 

  19. Yang H, Li W, Lv Y, Fan Q, Mao X, Long T, et al. Exploring the mechanism of clear cell renal cell carcinoma metastasis and key genes based on multi-tool joint analysis. Gene 2019;720:144103.

    Article  CAS  Google Scholar 

  20. Yao J, Chen Y, Wang Y, Liu S, Yuan X, Pan F, et al. Decreased expression of a novel lncRNA CADM1-AS1 is associated with poor prognosis in patients with clear cell renal cell carcinomas. Int J Clin Exp Pathol 2014;7:2758–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang F, Zu Y, Zhu S, Yang Y, Huang W, Xie H, et al. Long noncoding RNA MAGI2-AS3 regulates CCDC19 expression by sponging miR-15b-5p and suppresses bladder cancer progression. Biochem Biophys Res Commun 2018;507:231–5.

    Article  CAS  Google Scholar 

  22. Shi H, Hayes MT, Kirana C, Miller RJ, Keating JP, Stubbs RS. Overexpression of aminoacylase 1 is associated with colorectal cancer progression. Hum Pathol 2013;44:1089–97.

    Article  CAS  Google Scholar 

  23. Qin C, Chen J, Li J, Ju X, Zhang S, Cao Q, et al. Variants in angiogenesis-related genes and the risk of clear cell renal cell carcinoma. Mutagenesis 2014;29:419–25.

    Article  CAS  Google Scholar 

  24. Li HC, Li JP, Wang ZM, Fu DL, Li ZL, Zhang D, et al. Identification of angiogenesis-related miRNAs in a population of patients with renal clear cell carcinoma. Oncol Rep. 2014;32:2061–9.

    Article  CAS  Google Scholar 

  25. Su H, Wang H, Shi G, Zhang H, Sun F, Ye D. Downregulation of long non-coding RNA ENSG00000241684 is associated with poor prognosis in advanced clear cell renal cell carcinoma. Eur J Surg Oncol 2018;44:840–6.

    Article  Google Scholar 

  26. Ko FC, Martins JS, Reddy P, Bragdon B, Hussein AI, Gerstenfeld LC, et al. Acute phosphate restriction impairs bone formation and increases marrow adipose tissue in growing mice. J Bone Min Res 2016;31:2204–14.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to acknowledge the helpful comments on this paper received from the reviewers.

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  1. Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, People’s Republic of China

    Guanbo Wang, Hai Li & Yi Hou

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Wang, G., Li, H. & Hou, Y. LncRNA MAGI2-AS3 inhibits tumor progression and angiogenesis by regulating ACY1 via interacting with transcription factor HEY1 in clear cell renal cell carcinoma. Cancer Gene Ther 29, 585–596 (2022). https://doi.org/10.1038/s41417-021-00339-z

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