LIN28A-stabilized FBXL19-AS1 promotes breast cancer migration, invasion and EMT by regulating WDR66

  • Yayuan Zhang
  • Xiaojun Xiao
  • Wenbing Zhou
  • Jintao Hu
  • Dongxian ZhouEmail author


Breast cancer ranks as the top reason for the oncologic mortality for female around the world. The occurrence rate of breast cancer is rapidly rising, especially in China. Although the therapeutic regimes for breast cancer are diverse, the treatment outcome in patients remains dismal. Long non-coding RNAs have been greatly reported as important participators in cancer progression during the past decades. FBXL19 antisense RNA 1 (FBXL19-AS1) has been identified as a novel oncogene in colorectal cancer recently, but its role in breast cancer remains unknown. Present study attempted to explore the functional role and mechanism of FBXL19-AS1 in breast cancer progression. Expression of FBXL19-AS1, lin-28 homolog A (LIN28A), and WD repeat domain 66 (WDR66) were detected by qPCR and Western blotting. Transwell assay was used to detect cell migration and invasion. RIP assay was used to examine interaction between LIN28A and FBXL19-AS1. First, FBXL19-AS1 was highly expressed in breast cancer cell lines. Loss-of-function assays indicated that FBXL19-AS1 promoted cell migration, invasion, and EMT in breast cancer. Mechanistically, FBXL19-AS1 interacted with and was stabilized by LIN28A, an RNA-binding protein which has been reported to be able to stabilize lncRNAs. Moreover, WDR66 expression was promoted by FBXL19-AS1 at mRNA and protein level. Finally, rescue assays suggested that FBXL19-AS1 promoted migration, invasion, and EMT through regulating WDR66 in breast cancer. Current study proved that LIN28A-stabilized FBXL19-AS1 promoted breast cancer metastasis by regulating WDR66, identifying FBXL19-AS1 as a new biological marker in breast cancer.


LIN28A FBXL19-AS1 WDR66 Breast cancer Tumor progression 



The authors sincerely appreciate all members contributed to this work.

Compliance with ethical standards

Conflict of interest


Supplementary material

11626_2019_361_Fig6_ESM.png (677 kb)
Supplementary Figure 1

A Results of qPCR confirmed the overexpression of FBXL19-AS1 by pcDNA3.1/FBXL19-AS1 in BT474 and MDA-MB-231 cells. BC Transwell assay showed that cell migration and invasion were enhanced by FBXL19-AS1 overexpression. D Western blot assay showed that E-cadherin level was decreased, whereas N-cadherin and Vimentin levels were increased by FBXL19-AS1 overexpression. E The 13 RNA-binding proteins predicted to interact with FBXL19-AS1 in Starbase. *P < 0.05, **P < 0.01, ***P < 0.001. (PNG 676 kb)

11626_2019_361_MOESM1_ESM.tif (1 mb)
High resolution image (TIF 1068 kb)


  1. Bai Y, Zhou X, Huang L, Wan Y, Li X, Wang Y (2018) Long noncoding RNA EZR-AS1 promotes tumor growth and metastasis by modulating Wnt/β-catenin pathway in breast cancer. Exp Ther Med 16:2235–2242Google Scholar
  2. Becker S (2015) A historic and scientific review of breast cancer: the next global healthcare challenge. Int J Gynecol Obstet 131:S36–S39CrossRefGoogle Scholar
  3. Chen C, Zhou L, Wang H, Chen J, Li W, Liu W, Shen M, Liu H, Fu X (2018a) Long noncoding RNA CNALPTC1 promotes cell proliferation and migration of papillary thyroid cancer via sponging miR-30 family. Am J Cancer Res 8:192–206Google Scholar
  4. Chen Y, Huang W, Sun W, Zheng B, Wang C, Luo Z, Wang J, Yan W (2018b) LncRNA MALAT1 promotes Cancer metastasis in osteosarcoma via activation of the PI3K-Akt signaling pathway. Cell Physiol Biochem 51:1313–1326CrossRefGoogle Scholar
  5. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigó R (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22:1775–1789CrossRefGoogle Scholar
  6. Fong HK, Hurley JB, Hopkins RS, Miake-Lye R, Johnson MS, Doolittle RF, Simon MI (1986) Repetitive segmental structure of the transducin beta subunit: homology with the CDC4 gene and identification of related mRNAs. Proc Natl Acad Sci 83:2162–2166CrossRefGoogle Scholar
  7. Gunsalus KTW, Wagoner MP, Meyer K, Potter WB, Schoenike B, Kim S, Alexander CM, Friedl A, Roopra A (2012) Induction of the RNA regulator LIN28A is required for the growth and pathogenesis of RESTless breast tumors. Cancer Res 72:3207–3216CrossRefGoogle Scholar
  8. Han D, Gao X, Wang M, Qiao Y, Xu Y, Yang J, Dong N, He J, Sun Q, Lv G, Xu C, Tao J, Ma N (2016) Long noncoding RNA H19 indicates a poor prognosis of colorectal cancer and promotes tumor growth by recruiting and binding to eIF4A3. Oncotarget 7:22159–22173Google Scholar
  9. Hong W, Dong E (2014) The past, present and future of breast cancer research in China. Cancer Lett 351:1–5CrossRefGoogle Scholar
  10. Lei W, Wang ZL, Feng HJ, Lin XD, Li CZ, Fan D (2018) Long non-coding RNA SNHG12promotes the proliferation and migration of glioma cells by binding to HuR. Int J Oncol. Scholar
  11. Li Y, Jiang B, Wu X, Huang Q, Chen W, Zhu H, Qu X, Xie L, Ma X, Huang G (2018) Long non-coding RNA MIAT is estrogen-responsive and promotes estrogen-induced proliferation in ER-positive breast cancer cells. Biochem Biophys Res Commun 503:45–50CrossRefGoogle Scholar
  12. Lian Y, Yan C, Ding J, Xia R, Ma Z, Hui B, Ji H, Zhou J, Wang K (2017) A novel lncRNA, LL22NC03-N64E9.1, represses KLF2 transcription through binding with EZH2 in colorectal cancer. Oncotarget 8:59435–59445Google Scholar
  13. Liu X, Zheng J, Xue Y, Qu C, Chen J, Wang Z, Li Z, Zhang L, Liu Y (2018) Inhibition of TDP43-mediated SNHG12-miR-195-SOX5 feedback loop impeded malignant biological behaviors of glioma cells. Mol Ther Nucleic Acids 10:142–158CrossRefGoogle Scholar
  14. Lu G, Li Y, Ma Y, Lu J, Chen Y, Jiang Q, Qin Q, Zhao L, Huang Q, Luo Z, Huang S, Wei Z (2018) Long noncoding RNA LINC00511 contributes to breast cancer tumourigenesis and stemness by inducing the miR-185-3p/E2F1/Nanog axis. J Exp Clin Cancer Res 37:289–289CrossRefGoogle Scholar
  15. Luo Y, Ouyang J, Zhou D, Zhong S, Wen M, Ou W, Yu H, Jia L, Huang Y (2018) Long noncoding RNA GAPLINC promotes cells migration and invasion in colorectal Cancer cell by regulating miR-34a/c-MET signal pathway. Dig Dis Sci 63:890–899CrossRefGoogle Scholar
  16. Piipponen M, Heino J, Kähäri V-M, Nissinen L (2018) Long non-coding RNA PICSAR decreases adhesion and promotes migration of squamous carcinoma cells by downregulating α2β1 and α5β1 integrin expression. Biology Open 7:bio037044CrossRefGoogle Scholar
  17. Qi D, Li J, Que B, Su J, Li M, Zhang C, Yang M, Zhou G, Ji W (2016) Long non-coding RNA DBCCR1-003 regulate the expression of DBCCR1 via DNMT1 in bladder cancer. Cancer Cell Int 16:81CrossRefGoogle Scholar
  18. Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, Cannady RS, Pratt-Chapman ML, Edge SB, Jacobs LA, Hurria A, Marks LB, LaMonte SJ, Warner E, Lyman GH, Ganz PA (2016) American Cancer Society/American Society of Clinical Oncology breast Cancer survivorship care guideline. J Clin Oncol 34:611–635CrossRefGoogle Scholar
  19. Shen B, Yuan Y, Zhang Y, Yu S, Peng W, Xe H, Feng J (2017) Long non-coding RNA FBXL19-AS1 plays oncogenic role in colorectal cancer by sponging miR-203. Biochem Biophys Res Commun 488:67–73CrossRefGoogle Scholar
  20. Shen H, Zhao L, Feng X, Xu C, Li C, Niu Y (2016) Lin28A activates androgen receptor via regulation of c-myc and promotes malignancy of ER-/Her2+ breast cancer. Oncotarget 7:60407–60418Google Scholar
  21. Shi D, Zhang Y, Lu R, Zhang Y (2018) The long non-coding RNA MALAT1 interacted with miR-218 modulates choriocarcinoma growth by targeting Fbxw8. Biomed Pharmacother 97:543–550CrossRefGoogle Scholar
  22. Shi Y, Li J, Liu Y, Ding J, Fan Y, Tian Y, Wang L, Lian Y, Wang K, Shu Y (2015) The long noncoding RNA SPRY4-IT1 increases the proliferation of human breast cancer cells by upregulating ZNF703 expression. Mol Cancer 14:51–51CrossRefGoogle Scholar
  23. Sun Y, Jin JG, Mi WY, Wu H, Zhang SR, Meng Q, Zhang ST (2017) Long non-coding RNA UCA1 targets miR-122 to promote proliferation, migration, and invasion of glioma cells. Oncol Res 26Google Scholar
  24. Sun Y, Zeng C, Gan S, Li H, Cheng Y, Chen D, Li R, Zhu W (2018) LncRNA HOTTIP-mediated HOXA11 expression promotes cell growth, migration and inhibits cell apoptosis in breast Cancer. Int J Mol Sci 19:472CrossRefGoogle Scholar
  25. Wang C, Gu Y, Zhang E, Zhang K, Qin N, Dai J, Zhu M, Liu J, Xie K, Jiang Y, Guo X, Liu M, Jin G, Ma H, Jiang T, Yin R, Xia Y, Liu L, Wang S, Shen B, Huo R, Xu L, Sha J, Qu B, Shen H, Hu Z (2018a) A cancer-testis non-coding RNA LIN28B-AS1 activates driver gene LIN28B by interacting with IGF2BP1 in lung adenocarcinoma. Oncogene 38:1611–1624. Scholar
  26. Wang Q, Ma C, Kemmner W (2013) Wdr66 is a novel marker for risk stratification and involved in epithelial-mesenchymal transition of esophageal squamous cell carcinoma. BMC Cancer 13:137CrossRefGoogle Scholar
  27. Wang Z, Pang J, Ji B, Zhang S, Cheng Y, Yu L, Pan W (2018b) RNA binding protein Lin28A promotes osteocarcinoma cells progression by associating with the long noncoding RNA MALAT1. Biotechnol Lett 40:493–500CrossRefGoogle Scholar
  28. Yang F, Wu Q, Zhang Y, Xiong H, Li X, Li B, Xie W, Zhang L, Xu M, Zhang K, He F (2018) LncRNA LOC653786 promotes growth of RCC cells via upregulating FOXM1. Oncotarget 9:12101–12111Google Scholar
  29. Yong W, Yu D, Jun Z, Yachen D, Weiwei W, Midie X, Xingzhu J, Xiaohua W (2018) Long noncoding RNA NEAT1, regulated by LIN28B, promotes cell proliferation and migration through sponging miR-506 in high-grade serous ovarian cancer. Cell Death Dis 9:861–861CrossRefGoogle Scholar
  30. Zhang Y, Chen W, Pan T, Wang H, Zhang Y, Li C (2019) LBX2-AS1 is activated by ZEB1 and promotes the development of esophageal squamous cell carcinoma by interacting with HNRNPC to enhance the stability of ZEB1 and ZEB2 mRNAs. Biochem Biophys Res Commun 511:566–572. Scholar
  31. Zhang Y, Yu S, Zhang Z, Gang Z, Jia X (2018a) Long non-coding RNA AK096174 promotes cell proliferation and invasion in gastric cancer by regulating WDR66 expression. Biosci Rep 38:BSR20180277CrossRefGoogle Scholar
  32. Zhang Z, Sun L, Zhang Y, Lu G, Li Y, Wei Z (2018b) Long non-coding RNA FEZF1-AS1 promotes breast cancer stemness and tumorigenesis via targeting miR-30a/Nanog axis. J Cell Physiol 233:8630–8638CrossRefGoogle Scholar
  33. Zhong W, Yang J, Li M, Li L, Li A (2018) Long noncoding RNA NEAT1 promotes the growth of human retinoblastoma cells via regulation of miR-204/CXCR4 axis. J Cell Physiol:0Google Scholar

Copyright information

© The Society for In Vitro Biology 2019

Authors and Affiliations

  1. 1.Department of Thyroid and Breast Surgery, Shenzhen People’s Hospital, 2nd Clinical Medical CollegeJinan UniversityShenzhenChina
  2. 2.Ultrasonography Department, Shenzhen People’s Hospital, 2nd Clinical Medical CollegeJinan UniversityShenzhenChina
  3. 3.Department of Pathology, Shenzhen People’s Hospital, 2nd Clinical Medical CollegeJinan UniversityShenzhenChina

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