Skip to main content

Advertisement

SpringerLink
Log in

LncRNA FOXD3-AS1 promotes breast cancer progression by mediating ARF6

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

Breast cancer is one of the most common malignant tumor in women. The high metastatic characteristics cause a high mortality rate of breast cancer. Increasing number of studies have indicated that long non-coding RNAs (lncRNAs) play key roles in the progression of human cancers including breast cancer. In this study, we studied the expression and molecular mechanisms of lncRNA FOXD3-AS1 in breast cancer.

Methods

The expression of lncRNA FOXD3-AS1 was analyzed by TCGA database and RT-qPCR assay. CCK8 assay was used to measure cell proliferation ability. Cell migration and invasion capacities were detected by transwell assay. Potential targets of lncRNA and miRNA were predicted by bioinformatic tools. The targeting relationship between genes was verified by dual-luciferase reporter assay. The nude mice tumor model was performed to study the effect of FOXD3-AS1 on breast cancer in vivo. Protein expression was detected by western blot.

Results

In the present study, we found that the FOXD3-AS1 expression was significantly increased in breast cancer tissues compared with normal tissues and involved in the poor prognosis of patients. Functionally, knockdown of FOXD3-AS1 suppressed cell proliferation and metastasis abilities in vitro, and tumor growth in vivo. Mechanistically, FOXD3-AS1 functioned as a competing endogenous RNA (ceRNA) to upregulate ARF6 expression by targeting miR-127-3p. In addition, the roles of FOXD3-AS1 on cell proliferation and metastasis were achieved through miR-127-3p/ARF6 axis.

Conclusion

In summary, our results reported the regulatory mechanism of FOXD3-AS1 in breast cancer progression by targeting miR-127-3p/ARF6 axis to affect cell proliferation, migration, invasion and tumor growth.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Li Y, Moran MS, Huo Q, Yang Q, Haffty BG. Post-mastectomy radiotherapy for breast cancer patients with t1–t2 and 1–3 positive lymph nodes: a meta-analysis. PLoS One. 2013;8(12): e81765.

    Article  Google Scholar 

  2. Saad ED, Katz A, Buyse M. Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials. J Clin Oncol. 2010;28(11):1958–62.

    Article  Google Scholar 

  3. Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA, et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011;472(7341):120–4.

    Article  CAS  Google Scholar 

  4. Peng WX, Koirala P, Mo YY. LncRNA-mediated regulation of cell signaling in cancer. Oncogene. 2017;36(41):5661–7.

    Article  CAS  Google Scholar 

  5. Li Z, Qin X, Bian W, Li Y, Shan B, Yao Z, Li S. Exosomal lncRNA ZFAS1 regulates esophageal squamous cell carcinoma cell proliferation, invasion, migration and apoptosis via microRNA-124/STAT3 axis. J Exp Clin Cancer Res. 2019;38(1):477.

    Article  CAS  Google Scholar 

  6. Fan CN, Ma L, Liu N. Systematic analysis of lncRNA-miRNA-mRNA competing endogenous RNA network identifies four-lncRNA signature as a prognostic biomarker for breast cancer. J Transl Med. 2018;16(1):264.

    Article  CAS  Google Scholar 

  7. Liang ZX, Liu HS, Wang FW, Xiong L, Zhou C, Hu T, He XW, Wu XJ, Xie D, Wu XR, et al. LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization. Cell Death Dis. 2019;10(11):829.

    Article  Google Scholar 

  8. Wang Y, Yang L, Chen T, Liu X, Guo Y, Zhu Q, Tong X, Yang W, Xu Q, Huang D, et al. A novel lncRNA MCM3AP-AS1 promotes the growth of hepatocellular carcinoma by targeting miR-194-5p/FOXA1 axis. Mol Cancer. 2019;18(1):28.

    Article  Google Scholar 

  9. Dong H, Hu J, Zou K, Ye M, Chen Y, Wu C, Chen X, Han M. Activation of LncRNA TINCR by H3K27 acetylation promotes Trastuzumab resistance and epithelial-mesenchymal transition by targeting MicroRNA-125b in breast Cancer. Mol Cancer. 2019;18(1):3.

    Article  Google Scholar 

  10. Chen X, Gao J, Yu Y, Zhao Z, Pan Y. LncRNA FOXD3-AS1 promotes proliferation, invasion and migration of cutaneous malignant melanoma via regulating miR-325/MAP3K2. Biomed Pharmacother. 2019;120:109438.

    Article  CAS  Google Scholar 

  11. Zeng Z, Zhao G, Zhu H, Nie L, He L, Liu J, Li R, Xiao S, Hua G. LncRNA FOXD3-AS1 promoted chemo-resistance of NSCLC cells via directly acting on miR-127-3p/MDM2 axis. Cancer Cell Int. 2020;20:350.

    Article  CAS  Google Scholar 

  12. Wu Q, Shi M, Meng W, Wang Y, Hui P, Ma J. Long noncoding RNA FOXD3-AS1 promotes colon adenocarcinoma progression and functions as a competing endogenous RNA to regulate SIRT1 by sponging miR-135a-5p. J Cell Physiol. 2019;234(12):21889–902.

    Article  CAS  Google Scholar 

  13. Guan Y, Bhandari A, Xia E, Yang F, Xiang J, Wang O. lncRNA FOXD3-AS1 is associated with clinical progression and regulates cell migration and invasion in breast cancer. Cell Biochem Funct. 2019;37(4):239–44.

    Article  CAS  Google Scholar 

  14. Shi Y, Zhao Y, Zhang Y, AiErken N, Shao N, Ye R, Lin Y, Wang S. TNNT1 facilitates proliferation of breast cancer cells by promoting G1/S phase transition. Life Sci. 2018;208:161–6.

    Article  CAS  Google Scholar 

  15. Fang K, Hu C, Zhang X, Hou Y, Gao D, Guo Z, Li L. LncRNA ST8SIA6-AS1 promotes proliferation, migration and invasion in breast cancer through the p38 MAPK signalling pathway. Carcinogenesis. 2020;41(9):1273–81.

    Article  CAS  Google Scholar 

  16. Ma WG, Shi SM, Chen L, Lou G, Feng XL. SP1-induced lncRNA FOXD3-AS1 contributes to tumorigenesis of cervical cancer by modulating the miR-296-5p/HMGA1 pathway. J Cell Biochem. 2021;122(2):235–48.

    Article  CAS  Google Scholar 

  17. Hu J, Pan J, Luo Z, Duan Q, Wang D. Long non-coding RNA FOXD3-AS1 silencing exerts tumor suppressive effects in nasopharyngeal carcinoma by downregulating FOXD3 expression via microRNA-185-3p upregulation. Cancer Gene Ther. 2021;28(6):602–18.

    Article  CAS  Google Scholar 

  18. Zhao X, Li D, Huang D, Song H, Mei H, Fang E, Wang X, Yang F, Zheng L, Huang K, et al. Risk-associated long noncoding RNA FOXD3-AS1 inhibits neuroblastoma progression by repressing PARP1-mediated activation of CTCF. Mol Ther. 2018;26(3):755–73.

    Article  CAS  Google Scholar 

  19. Chan JJ, Tay Y. Noncoding RNA:RNA regulatory networks in cancer. Int J Mol Sci. 2018;19(5):1310.

    Article  Google Scholar 

  20. Liu S, Zhang Y, Huang C, Lin S. miR-215-5p is an anticancer gene in multiple myeloma by targeting RUNX1 and deactivating the PI3K/AKT/mTOR pathway. J Cell Biochem. 2020;121(2):1475–90.

    Article  CAS  Google Scholar 

  21. Li X, Zhang Y, Zhang H, Liu X, Gong T, Li M, Sun L, Ji G, Shi Y, Han Z, et al. miRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor EPB41L3. Mol Cancer Res. 2011;9(7):824–33.

    Article  CAS  Google Scholar 

  22. Zheng A, Song X, Zhang L, Zhao L, Mao X, Wei M, Jin F. Long non-coding RNA LUCAT1/miR-5582-3p/TCF7L2 axis regulates breast cancer stemness via Wnt/beta-catenin pathway. J Exp Clin Cancer Res. 2019;38(1):305.

    Article  Google Scholar 

  23. Elango R, Alsaleh KA, Vishnubalaji R, Manikandan M, Ali AM, Abd El-Aziz N, Altheyab A, Al-Rikabi A, Alfayez M, Aldahmash A, et al. MicroRNA expression profiling on paired primary and lymph node metastatic breast cancer revealed distinct microRNA profile associated with LNM. Front Oncol. 2020;10:756.

    Article  Google Scholar 

  24. Bitaraf A, Babashah S, Garshasbi M. Aberrant expression of a five-microRNA signature in breast carcinoma as a promising biomarker for diagnosis. J Clin Lab Anal. 2020;34(2): e23063.

    Article  CAS  Google Scholar 

  25. Fellenberg J, Lehner B, Saehr H, Schenker A, Kunz P. Tumor suppressor function of miR-127-3p and miR-376a-3p in osteosarcoma cells. Cancers. 2019;11(12):2019.

    Article  CAS  Google Scholar 

  26. Herr I, Sahr H, Zhao Z, Yin L, Omlor G, Lehner B, Fellenberg J. MiR-127 and miR-376a act as tumor suppressors by in vivo targeting of COA1 and PDIA6 in giant cell tumor of bone. Cancer Lett. 2017;409:49–55.

    Article  CAS  Google Scholar 

  27. Eades G, Wolfson B, Zhang Y, Li Q, Yao Y, Zhou Q. lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6. Mol Cancer Res. 2015;13(2):330–8.

    Article  CAS  Google Scholar 

  28. Hashimoto A, Hashimoto S, Sugino H, Yoshikawa A, Onodera Y, Handa H, Oikawa T, Sabe H. ZEB1 induces EPB41L5 in the cancer mesenchymal program that drives ARF6-based invasion, metastasis and drug resistance. Oncogenesis. 2016;5(9): e259.

    Article  CAS  Google Scholar 

  29. Onodera Y, Nam JM, Hashimoto A, Norman JC, Shirato H, Hashimoto S, Sabe H. Rab5c promotes AMAP1-PRKD2 complex formation to enhance beta1 integrin recycling in EGF-induced cancer invasion. J Cell Biol. 2012;197(7):983–96.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by Xi’an Science and Technology Bureau Project, (No: 21YXYJ0130). This work was also funded by the fourth batch of school-level key disciplines of the Xi’an Medical University.

Author information

Authors and Affiliations

  1. Clinical Laboratory, the Second Affiliated Hospital of Xi’an Medical College, Xi’an, 710038, Shaanxi, China

    Xingxing Zhang, Xiaojun Zhao, Fang Liu & Chunjuan Li

  2. Division One of Obstetrics, the Second Affiliated Hospital of Xi’an Medical College, Xi’an, 710038, Shaanxi, China

    Lihua Chang

  3. Department of Cardiothoracic Surgery, the Second Affiliated Hospital of Xi’an Medical College, Peng Ge, No. 167, Fangdong Street, Textile City, Xi’an, 710038, Shaanxi, China

    Peng Ge

  4. Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi’an Medical University, Xi’an, 710038, Shaanxi, China

    Peng Ge

  5. Department of Gynecology, the Second Affiliated Hospital of Xi’an Medical University, Xi’an, 710038, Shaanxi, China

    Peng Ge

Authors
  1. Xingxing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaojun Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lihua Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chunjuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peng Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peng Ge.

Ethics declarations

Conflict of interest

The authors declared that they have no conflicts of interest.

Additional information

Publisher's Note

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

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Zhao, X., Chang, L. et al. LncRNA FOXD3-AS1 promotes breast cancer progression by mediating ARF6. Breast Cancer 29, 908–920 (2022). https://doi.org/10.1007/s12282-022-01373-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-022-01373-x

Keywords

Search

Navigation