Skip to main content

Advertisement

SpringerLink
Log in

LncRNA ITGB2-AS1 promotes the progression of clear cell renal cell carcinoma by modulating miR-328-5p/HMGA1 axis

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of renal cell carcinoma and long non-coding RNAs (lncRNAs) play important roles in the progression of ccRCC. In this study, we aim to explore the potential function of ITGB2-AS1 in ccRCC progression and its underlying molecular mechanism. We first explored the association between ITGB2-AS1 expression level and ccRCC prognosis. We found that the expression level of ITGB2-AS1 was significantly higher in ccRCC tumor and cell lines, and highly expressed ITGB2-AS1 was also associated with a poorer prognosis. Consistently, silencing ITGB2-AS1 inhibited proliferation, promoted apoptosis in ccRCC cell lines, and curbed the tumorigenesis in the Xenograft model, reduced tumorigenesis in a xenograft tumor growth model. We further identified and confirmed the miRNA miR-328-5p as a target of ITGB2-AS1, and miR-328-5p negatively regulated the expression of HMGA1 protein. The anti-tumor effect of silencing ITGB2-AS1 could be partially rescued by inhibiting miR-328-5p activity or overexpressing HMGA1, indicating that ITGB2-AS1 promotes the survival and progression of ccRCC by modulating miR-328-5p/HMGA1 axis. Collectively, our data demonstrated that ITGB2-AS1 expression level is positively correlated with the survival and tumorigenesis of ccRCC. As a target of ITGB2-AS1, miR-328-5p seems to function as a tumor-suppressor, and the oncogenic effect of ITGB2-AS1 is partially mediated via the miR-328-5p/HMGA1 axis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Figure5

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. https://doi.org/10.3322/caac.21492.

    Article  Google Scholar 

  2. Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev. 2008;34:193–205. https://doi.org/10.1016/j.ctrv.2007.12.001.

    Article  PubMed  Google Scholar 

  3. Kim SH, Park B, Hwang EC, Hong SH, Jeong CW, Kwak C, et al. Retrospective multicenter long-term follow-up analysis of prognostic risk factors for recurrence-free, metastasis-free, cancer-specific, and overall survival after curative nephrectomy in non-metastatic renal cell carcinoma. Front Oncol. 2019;9:859. https://doi.org/10.3389/fonc.2019.00859.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Jonasch E, Gao J, Rathmell WK. Renal cell carcinoma. BMJ. 2014;349:g4797. https://doi.org/10.1136/bmj.g4797.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yu G, Yao W, Wang J, Ma X, Xiao W, Li H, et al. LncRNAs expression signatures of renal clear cell carcinoma revealed by microarray. PLoS ONE. 2012;7:e42377. https://doi.org/10.1371/journal.pone.0042377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schmitt AM, Chang HY. Long noncoding RNAs in cancer pathways. Cancer Cell. 2016;29:452–63. https://doi.org/10.1016/j.ccell.2016.03.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhan Y, Chen Z, Li Y, He A, He S, Gong Y, et al. Long non-coding RNA DANCR promotes malignant phenotypes of bladder cancer cells by modulating the miR-149/MSI2 axis as a ceRNA. J Exp Clin Cancer Res. 2018;37:273. https://doi.org/10.1186/s13046-018-0921-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen DL, Lu YX, Zhang JX, Wei XL, Wang F, Zeng ZL, et al. Long non-coding RNA UICLM promotes colorectal cancer liver metastasis by acting as a ceRNA for microRNA-215 to regulate ZEB2 expression. Theranostics. 2017;7:4836–49. https://doi.org/10.7150/thno.20942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang M, Qin Q, Zhu J, Guo Y, Yin T, Wu H, et al. Long noncoding RNA ITGB2-AS1 promotes growth and metastasis through miR-4319/RAF1 axis in pancreatic ductal adenocarcinoma. J Cell Physiol. 2020.https://doi.org/10.1002/jcp.29471

  10. Dai J, Xu LJ, Han GD, Jiang HT, Sun HL, Zhu GT, et al. (2018) Down-regulation of long non-coding RNA ITGB2-AS1 inhibits osteosarcoma proliferation and metastasis by repressing Wnt/β-catenin signalling and predicts favourable prognosis. Artif Cells Nanomed Biotechnol 46: S783–S90.https://doi.org/10.1080/21691401.2018.1511576

  11. Liu M, Gou L, Xia J, Wan Q, Jiang Y, Sun S, et al. LncRNA ITGB2-AS1 Could Promote the Migration and Invasion of Breast Cancer Cells through Up-Regulating ITGB2. Int J Mol Sci 2018;19.https://doi.org/10.3390/ijms19071866

  12. Zhou C, Liu HS, Wang FW, Hu T, Liang ZX, Lan N, et al. circCAMSAP1 promotes tumor growth in colorectal cancer via the miR-328–5p/E2F1 Axis. Mol Ther. 2020;28:914–28. https://doi.org/10.1016/j.ymthe.2019.12.008.

    Article  CAS  PubMed  Google Scholar 

  13. Liu Z, Yu Y, Huang Z, Kong Y, Hu X, Xiao W, et al. CircRNA-5692 inhibits the progression of hepatocellular carcinoma by sponging miR-328–5p to enhance DAB2IP expression. Cell Death Dis. 2019;10:900. https://doi.org/10.1038/s41419-019-2089-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang S, Li P, Zhao L, Xu L. LINC00210 as a miR-328-5p sponge promotes nasopharyngeal carcinoma tumorigenesis by activating NOTCH3 pathway. Biosci Rep 2018; 38. 10.1042/bsr20181168

  15. Luo T, Yan Y, He Q, Ma X, Wang W. miR-328–5p inhibits MDA-MB-231 breast cancer cell proliferation by targeting RAGE. Oncol Rep. 2018;39:2906–14. https://doi.org/10.3892/or.2018.6353.

    Article  CAS  PubMed  Google Scholar 

  16. Dong H, Sun S, Yan T, Liang C, Zhu J, Miao C, et al. MicroRNA-195 inhibits proliferation and metastasis in renal cell carcinoma via regulating HMGA1. Am J Transl Res. 2020;12:2781–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Martens-Uzunova ES, Böttcher R, Croce CM, Jenster G, Visakorpi T, Calin GA. Long noncoding RNA in prostate, bladder, and kidney cancer. Eur Urol. 2014;65:1140–51. https://doi.org/10.1016/j.eururo.2013.12.003.

    Article  CAS  PubMed  Google Scholar 

  18. 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. https://doi.org/10.1016/j.eururo.2018.07.032.

    Article  CAS  PubMed  Google Scholar 

  19. Seles M, Hutterer GC, Foßelteder J, Svoboda M, Resel M, Barth DA, et al. Long Non-Coding RNA PANTR1 is Associated with Poor Prognosis and Influences Angiogenesis and Apoptosis in Clear-Cell Renal Cell Cancer. Cancers (Basel) 2020;12.https://doi.org/10.3390/cancers12051200

  20. Duan J, Ma X, Shi J, Xuan Y, Wang H, Li P, et al. Long noncoding RNA LINC-PINT promotes proliferation through EZH2 and predicts poor prognosis in clear cell renal cell carcinoma. Onco Targets Ther. 2019;12:4729–40. https://doi.org/10.2147/ott.S202938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zheng XL, Zhang YY, Lv WG (2019) Long noncoding RNA ITGB1 promotes migration and invasion of clear cell renal cell carcinoma by downregulating Mcl-1. Eur Rev Med Pharmacol Sci 23: 1996–2002.https://doi.org/10.26355/eurrev_201903_17238

  22. Abak A, Amini S, Sakhinia E, Abhari A. MicroRNA-221: biogenesis, function and signatures in human cancers. Eur Rev Med Pharmacol Sci. 2018;22:3094–117. https://doi.org/10.26355/eurrev_201805_15069.

    Article  CAS  PubMed  Google Scholar 

  23. Sun CC, Li SJ, Yuan ZP, Li DJ. MicroRNA-346 facilitates cell growth and metastasis, and suppresses cell apoptosis in human non-small cell lung cancer by regulation of XPC/ERK/Snail/E-cadherin pathway. Aging (Albany NY). 2016;8:2509–24. https://doi.org/10.18632/aging.101080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sun CC, Li SJ, Zhang F, Zhang YD, Zuo ZY, Xi YY, et al. The novel miR-9600 suppresses tumor progression and promotes paclitaxel sensitivity in non-small-cell lung cancer through altering STAT3 expression. Mol Ther Nucleic Acids. 2016;5:e387. https://doi.org/10.1038/mtna.2016.96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Huang R, Huang D, Dai W, Yang F. Overexpression of HMGA1 correlates with the malignant status and prognosis of breast cancer. Mol Cell Biochem. 2015;404:251–7. https://doi.org/10.1007/s11010-015-2384-4.

    Article  CAS  PubMed  Google Scholar 

  26. Kettunen E, Anttila S, Seppänen JK, Karjalainen A, Edgren H, Lindström I, et al. Differentially expressed genes in nonsmall cell lung cancer: expression profiling of cancer-related genes in squamous cell lung cancer. Cancer Genet Cytogenet. 2004;149:98–106. https://doi.org/10.1016/s0165-4608(03)00300-5.

    Article  CAS  PubMed  Google Scholar 

  27. Balcerczak M, Pasz-Walczak G, Balcerczak E, Wojtylak M, Kordek R, Mirowski M. HMGI(Y) gene expression in colorectal cancer: comparison with some histological typing, grading, and clinical staging. Pathol Res Pract. 2003;199:641–6. https://doi.org/10.1078/0344-0338-00475.

    Article  CAS  PubMed  Google Scholar 

  28. Hillion J, Roy S, Heydarian M, Cope L, Xian L, Koo M, et al. The High Mobility Group A1 (HMGA1) gene is highly overexpressed in human uterine serous carcinomas and carcinosarcomas and drives Matrix Metalloproteinase-2 (MMP-2) in a subset of tumors. Gynecol Oncol. 2016;141:580–7. https://doi.org/10.1016/j.ygyno.2016.03.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang X, Zamolyi RQ, Zhang H, Pannain VL, Medeiros F, Erickson-Johnson M, et al. Fusion of HMGA1 to the LPP/TPRG1 intergenic region in a lipoma identified by mapping paraffin-embedded tissues. Cancer Genet Cytogenet. 2010;196:64–7. https://doi.org/10.1016/j.cancergencyto.2009.09.003.

    Article  CAS  PubMed  Google Scholar 

  30. Colamaio M, Tosti N, Puca F, Mari A, Gattordo R, Kuzay Y, et al. HMGA1 silencing reduces stemness and temozolomide resistance in glioblastoma stem cells. Expert Opin Ther Targets. 2016;20:1169–79. https://doi.org/10.1080/14728222.2016.1220543.

    Article  CAS  PubMed  Google Scholar 

  31. Li N, McNiff J, Hui P, Manfioletti G, Tallini G. Differential expression of HMGA1 and HMGA2 in dermatofibroma and dermatofibrosarcoma protuberans: potential diagnostic applications, and comparison with histologic findings, CD34, and factor XIIIa immunoreactivity. Am J Dermatopathol. 2004;26:267–72. https://doi.org/10.1097/00000372-200408000-00001.

    Article  CAS  PubMed  Google Scholar 

  32. Nezhad MH, Drieschner N, Helms S, Meyer A, Tadayyon M, Klemke M, et al. 6p21 rearrangements in uterine leiomyomas targeting HMGA1. Cancer Genet Cytogenet. 2010;203:247–52. https://doi.org/10.1016/j.cancergencyto.2010.08.005.

    Article  CAS  PubMed  Google Scholar 

  33. Takaha N, Sowa Y, Takeuchi I, Hongo F, Kawauchi A, Miki T. Expression and Role of HMGA1 in Renal Cell Carcinoma. J Urol. 2021;187(6):2215–22. https://doi.org/10.1016/j.juro.2012.01.069.

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by Jiangxi Provincial Science Foundation. Project number: 20192564, Project Title: Investigating the role of negative costimulatory molecules in the expression and immunotherapy of bladder tumors. Principal investigator: Wenshen Zhang.

Author information

Authors and Affiliations

  1. Department of Urology, The First People’s Hospital of Jiujiang in Jiangxi Province, Affiliated Medical College of Jiujiang Hospital, Nanchang University, No. 48, Taling South Road, Xunyang District, Jiujiang City, 332000, Jiangxi Province, China

    Wensheng Zhang, Yigang Lu, Xungang Li, Zhuo Zhang, Xinxi Deng, Yang Yang & Bin Wan

  2. Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Huibo Shi

  3. Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Wuhan, China

    Huibo Shi

  4. Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China

    Huibo Shi

Authors
  1. Wensheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yigang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huibo Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xungang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhuo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xinxi Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bin Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bin Wan.

Ethics declarations

Ethical standards

All the experiments involving animals and human samples were approved by Ethics Committee of the First People's Hospital of Jiujiang, Jiangxi Province, China (Approval number of human subject study No.191223002); and animal care and use ethical committee of Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia province, China. The authors declare that there are no competing interests associated with the manuscript.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (JPG 1349 kb)

Supplementary file2 (DOCX 11 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, W., Lu, Y., Shi, H. et al. LncRNA ITGB2-AS1 promotes the progression of clear cell renal cell carcinoma by modulating miR-328-5p/HMGA1 axis. Human Cell 34, 1545–1557 (2021). https://doi.org/10.1007/s13577-021-00563-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-021-00563-7

Keywords

Search

Navigation