Skip to main content

Advertisement

SpringerLink
Log in

The endonuclease FEN1 mediates activation of STAT3 and facilitates proliferation and metastasis in breast cancer

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

The metastasis accounts for most deaths from breast cancer (BRCA). Understanding the molecular mechanisms of BRCA metastasis is urgently demanded. Flap Endonuclease 1 (FEN1), a pivotal factor in DNA metabolic pathways, contributes to tumor growth and drug resistance, however, little is known about the role of FEN1 in BRCA metastasis.

Methods and results

In this study, FEN1 expression and its clinical correlation in BRCA were investigated using bioinformatics, showing being upregulated in BRCA samples and significant relationships with tumor stage, node metastasis, and prognosis. Immunohistochemistry (IHC) staining of local BRCA cohort indicated that the ratio of high FEN1 expression in metastatic BRCA tissues rose over that in non-metastatic tissues. The assays of loss-of-function and gain-of-function showed that FEN1 enhanced BRCA cell proliferation, migration, invasion, xenograft growth as well as lung metastasis. It was further found that FEN1 promoted the aggressive behaviors of BRCA cells via Signal Transducer and Activator of Transcription 3 (STAT3) activation. Specifically, the STAT3 inhibitor Stattic thwarted the FEN1-induced enhancement of migration and invasion, while the activator IL-6 rescued the decreased migration and invasion caused by FEN1 knockdown. Additionally, overexpression of FEN1 rescued the inhibitory effect of nuclear factor-κB (NF-κB) inhibitor BAY117082 on phosphorylated STAT3. Simultaneously, the knockdown of FEN1 attenuated the phosphorylation of STAT3 promoted by the NF-κB activator tumor necrosis factor α (TNF-α).

Conclusions

These results indicate a novel mechanism that NF-κB-driven FEN1 contributes to promoting BRCA growth and metastasis by STAT3 activation.

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
Fig. 7

Similar content being viewed by others

Data availability

The datasets generated and analysed during the current study are available in the NCBI repository (accession number PRJNA1020382).The other data that support the findings of this study are available in the figures and the supplementary material of this article.

Abbreviations

BRCA:

breast cancer

CRC:

colorectal cancer

DNMT3a:

DNA methyltransferases 3a

DPF3:

double phd fingers 3

DFS:

disease-free survival

DEGs:

differentially expressed genes

ERα:

estrogen receptorα

ERK:

extracellular signal-regulated kinase

Elk-1:

ets-like protein-1

EMT:

epithelial mesenchymal transition

FEN1:

Flap Endonuclease 1

GEPIA2:

Gene Expression Profiling Interactive Analysis, version 2

HCC:

hepatocellular carcinoma

HE:

Hematoxylin and Eosin

HRP:

horseradish peroxidase

IL-6:

interleukin 6

IL-17:

interleukin 17

IHC:

Immunohistochemistry

IRS:

Immunoreactivity score

KEGG:

Kyoto Encyclopedia of Genes and Genomes

MMP2:

matrix metallopeptidase 2

MMP9:

matrix metallopeptidase 9

NF-κB:

nuclear factor-κB

NSCLC:

non-small-cell lung cancer

OS:

overall survival

PCNA:

proliferating cell nuclear antigen

RFS:

relapse-free survival

STAT3:

Signal Transducer and Activator of Transcription 3

TNF-α:

tumor necrosis factorα

TNBC:

triple-negative breast cancer

TGF-β1:

transforming growth factor-beta1

TRIM47:

tripartite motif 47

TCGA-BRCA:

The Cancer Genome Atlas Breast Cancer

UALCAN:

University of ALabama at Birmingham CANcer

References

  1. Siegel RL, Miller KD, Wagle NS, Jemal A (2023) Cancer statistics, 2023. CA Cancer J Clin 73(1):17–48

    Article  PubMed  Google Scholar 

  2. Kim MY (2021) Breast Cancer Metastasis. Adv Exp Med Biol 1187:183–204

    Article  CAS  PubMed  Google Scholar 

  3. Park M, Kim D, Ko S, Kim A, Mo K, Yoon H (2022) Breast Cancer Metastasis: Mechanisms and Therapeutic Implications. Int J Mol Sci 23(12)

  4. Li B, Xia A, Xie S, Lin L, Ji Z, Suo T, Zhang X, Huang H (2021) Signal-Amplified detection of the Tumor Biomarker FEN1 based on cleavage-Induced Ligation of a Dumbbell DNA Probe and Rolling Circle amplification. Anal Chem 93(6):3287–3294

    Article  CAS  PubMed  Google Scholar 

  5. Balakrishnan L, Bambara RA (2013) Flap endonuclease 1. Annu Rev Biochem 82:119–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zheng L, Jia J, Finger LD, Guo Z, Zer C, Shen B (2011) Functional regulation of FEN1 nuclease and its link to cancer. Nucleic Acids Res 39(3):781–794

    Article  CAS  PubMed  Google Scholar 

  7. Zhang H, Ba S, Mahajan D, Lee JY, Ye R, Shao F, Lu L, Li T (2018) Versatile types of DNA-Based nanobiosensors for specific detection of Cancer Biomarker FEN1 in living cells and cell-free systems. Nano Lett 18(11):7383–7388

    Article  CAS  PubMed  Google Scholar 

  8. Zhang K, Keymeulen S, Nelson R, Tong TR, Yuan YC, Yun X, Liu Z, Lopez J, Raz DJ, Kim JY (2018) Overexpression of Flap Endonuclease 1 correlates with enhanced proliferation and poor prognosis of Non-small-cell Lung Cancer. Am J Pathol 188(1):242–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Abdel-Fatah TM, Russell R, Albarakati N, Maloney DJ, Dorjsuren D, Rueda OM, Moseley P, Mohan V, Sun H, Abbotts R et al (2014) Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer. Mol Oncol 8(7):1326–1338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wu H, Yan Y, Yuan J, Luo M, Wang Y (2022) miR-4324 inhibits ovarian cancer progression by targeting FEN1. J Ovarian Res 15(1):32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang Y, Liu X, Liu L, Chen J, Hu Q, Shen S, Zhou Y, Chen S, Xue C, Cui G et al (2020) Upregulation of FEN1 Is Associated with the Tumor Progression and Prognosis of Hepatocellular Carcinoma. Dis Markers 2020:2514090

  12. He L, Luo L, Zhu H, Yang H, Zhang Y, Wu H, Sun H, Jiang F, Kathera CS, Liu L et al (2017) FEN1 promotes tumor progression and confers cisplatin resistance in non-small-cell lung cancer. Mol Oncol 11(6):640–654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zeng X, Qu X, Zhao C, Xu L, Hou K, Liu Y, Zhang N, Feng J, Shi S, Zhang L et al (2019) FEN1 mediates miR-200a methylation and promotes breast cancer cell growth via MET and EGFR signaling. Faseb j 33(10):10717–10730

    Article  CAS  PubMed  Google Scholar 

  14. Wang Y, Li S, Zhu L, Zou J, Jiang X, Chen M, Chen B (2019) Letrozole improves the sensitivity of breast cancer cells overexpressing aromatase to cisplatin via down-regulation of FEN1. Clin Transl Oncol 21(8):1026–1033

    Article  PubMed  Google Scholar 

  15. Yang F, Hu Z, Guo Z (2022) Small-molecule inhibitors targeting FEN1 for Cancer Therapy. Biomolecules 12(7)

  16. Bian S, Ni W, Zhu M, Zhang X, Qiang Y, Zhang J, Ni Z, Shen Y, Qiu S, Song Q et al (2022) Flap endonuclease 1 facilitated Hepatocellular Carcinoma Progression by enhancing USP7/MDM2-mediated P53 inactivation. Int J Biol Sci 18(3):1022–1038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yuwei X, Bingzi D, Zhaowei S, Yujie F, Wei Z, Kun L, Kui L, Jingyu C, Chengzhan Z (2023) FEN1 promotes cancer progression of cholangiocarcinoma by regulating the Wnt/β-catenin signaling pathway. Dig Liver Dis

  18. Xu L, Qu JL, Song N, Zhang LY, Zeng X, Che XF, Hou KZ, Shi S, Feng ZY, Qu XJ et al (2020) Biological and clinical significance of flap endonuclease–1 in triple–negative breast cancer: support of metastasis and a poor prognosis. Oncol Rep 44(6):2443–2454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Johnson DE, O’Keefe RA, Grandis JR (2018) Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 15(4):234–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Siersbæk R, Scabia V, Nagarajan S, Chernukhin I, Papachristou EK, Broome R, Johnston SJ, Joosten SEP, Green AR, Kumar S et al (2020) IL6/STAT3 signaling hijacks estrogen receptor α enhancers to drive breast Cancer metastasis. Cancer Cell 38(3):412–423e419

    Article  PubMed  PubMed Central  Google Scholar 

  21. Liu M, Li H, Zhang H, Zhou H, Jiao T, Feng M, Na F, Sun M, Zhao M, Xue L et al (2022) RBMS1 promotes gastric cancer metastasis through autocrine IL-6/JAK2/STAT3 signaling. Cell Death Dis 13(3):287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. El-Tanani M, Al Khatib AO, Aladwan SM, Abuelhana A, McCarron PA, Tambuwala MM (2022) Importance of STAT3 signalling in cancer, metastasis and therapeutic interventions. Cell Signal 92:110275

    Article  CAS  PubMed  Google Scholar 

  23. Zhu H, Wu C, Wu T, Xia W, Ci S, He W, Zhang Y, Li L, Zhou S, Zhang J et al (2019) Inhibition of AKT sensitizes Cancer cells to antineoplastic drugs by Downregulating Flap Endonuclease 1. Mol Cancer Ther 18(12):2407–2420

    Article  CAS  PubMed  Google Scholar 

  24. Zhao E, Zhou C, Chen S (2021) Flap endonuclease 1 (FEN1) as a novel diagnostic and prognostic biomarker for gastric cancer. Clin Res Hepatol Gastroenterol 45(1):101455

    Article  CAS  PubMed  Google Scholar 

  25. Flach KD, Periyasamy M, Jadhav A, Dorjsuren D, Siefert JC, Hickey TE, Opdam M, Patel H, Canisius S, Wilson DM 3rd et al (2020) Endonuclease FEN1 coregulates ERα activity and provides a novel drug interface in tamoxifen-resistant breast Cancer. Cancer Res 80(10):1914–1926

    Article  CAS  PubMed  Google Scholar 

  26. Xu L, Shen JM, Qu JL, Song N, Che XF, Hou KZ, Shi J, Zhao L, Shi S, Liu YP et al (2021) FEN1 is a prognostic biomarker for ER + breast cancer and associated with tamoxifen resistance through the ERα/cyclin D1/Rb axis. Ann Transl Med 9(3):258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zeng X, Che X, Liu YP, Qu XJ, Xu L, Zhao CY, Zheng CL, Hou KZ, Teng Y (2017) FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells. Exp Ther Med 14(4):3265–3272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Guo Y, Du Z, Zhou Y, Sun H, Liang R, Sun MX, Tang Z, Liu SB (2022) FEN1 status and its correlation with clinicopathologic characteristic in Colorectal Cancer. Comb Chem High Throughput Screen 25(6):1040–1046

    Article  CAS  PubMed  Google Scholar 

  29. Kim C, Gao R, Sei E, Brandt R, Hartman J, Hatschek T, Crosetto N, Foukakis T, Navin NE (2018) Chemoresistance Evolution in Triple-negative breast Cancer delineated by single-cell sequencing. Cell 173(4):879–893e813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ebright RY, Lee S, Wittner BS, Niederhoffer KL, Nicholson BT, Bardia A, Truesdell S, Wiley DF, Wesley B, Li S et al (2020) Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis. Science 367(6485):1468–1473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Derakhshan F, Reis-Filho JS (2022) Pathogenesis of Triple-negative breast Cancer. Annu Rev Pathol 17:181–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jin LY, Gu YL, Zhu Q, Li XH, Jiang GQ (2021) The role of ferroptosis-related genes for overall survival prediction in breast cancer. J Clin Lab Anal 35(12):e24094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen Y, Meng Z, Zhang L, Liu F (2021) CD2 is a Novel Immune-related prognostic biomarker of invasive breast carcinoma that modulates the Tumor Microenvironment. Front Immunol 12:664845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang X, Fu Y, Xing Y (2022) TRIM47 promotes ovarian cancer cell proliferation, migration, and invasion by activating STAT3 signaling. Clin (Sao Paulo) 77:100122

    Article  Google Scholar 

  35. Ma JH, Qin L, Li X (2020) Role of STAT3 signaling pathway in breast cancer. Cell Commun Signal 18(1):33

    Article  PubMed  PubMed Central  Google Scholar 

  36. Xiang Y, Li JP, Guo W, Wang DQ, Yao A, Zhang HM, Huang F, Li HH, Dai ZT, Zhang ZJ et al (2019) Novel interactions between ERα-36 and STAT3 mediate breast cancer cell migration. Cell Commun Signal 17(1):93

    Article  PubMed  PubMed Central  Google Scholar 

  37. Zhang J, Li S, Zhao Y, Ma P, Cao Y, Liu C, Zhang X, Wang W, Chen L, Li Y (2020) Cancer-associated fibroblasts promote the migration and invasion of gastric cancer cells via activating IL-17a/JAK2/STAT3 signaling. Ann Transl Med 8(14):877

    Article  PubMed  PubMed Central  Google Scholar 

  38. Wang J, Zhou L, Li Z, Zhang T, Liu W, Liu Z, Yuan YC, Su F, Xu L, Wang Y et al (2015) YY1 suppresses FEN1 over-expression and drug resistance in breast cancer. BMC Cancer 15:50

    Article  PubMed  PubMed Central  Google Scholar 

  39. He L, Hu Z, Sun Y, Zhang M, Zhu H, Jiang L, Zhang Q, Mu D, Zhang J, Gu L et al (2020) PRMT1 is critical to FEN1 expression and drug resistance in lung cancer cells. DNA Repair (Amst) 95:102953

    Article  CAS  PubMed  Google Scholar 

  40. Lu X, Liu R, Wang M, Kumar AK, Pan F, He L, Hu Z, Guo Z (2020) MicroRNA-140 impedes DNA repair by targeting FEN1 and enhances chemotherapeutic response in breast cancer. Oncogene 39(1):234–247

    Article  PubMed  Google Scholar 

  41. Zhou Q, Tian W, Jiang Z, Huang T, Ge C, Liu T, Zhao F, Chen T, Cui Y, Li H et al (2021) A positive Feedback Loop of AKR1C3-Mediated activation of NF-κB and STAT3 facilitates proliferation and metastasis in Hepatocellular Carcinoma. Cancer Res 81(5):1361–1374

    Article  CAS  PubMed  Google Scholar 

  42. Liu C, Yao Z, Wang J, Zhang W, Yang Y, Zhang Y, Qu X, Zhu Y, Zou J, Peng S et al (2020) Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway. Cell Death Differ 27(6):1765–1781

    Article  CAS  PubMed  Google Scholar 

  43. Shen Y, Zhang Y, Du J, Jiang B, Shan T, Li H, Bao H, Si Y (2021) CXCR5 down-regulation alleviates cognitive dysfunction in a mouse model of sepsis-associated encephalopathy: potential role of microglial autophagy and the p38MAPK/NF-κB/STAT3 signaling pathway. J Neuroinflammation 18(1):246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (grant no. 81902114, 32201078), the Science and Technology Innovation Project of Xuzhou (grant no. KC22118).

Author information

Authors and Affiliations

  1. Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China

    Min Wu, Xiaoshan Huang, Benmeng Wu, Yaqin Zhu, Lin Yu & Jingjing Liu

  2. Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, China

    Min Wu, Xiaoshan Huang, Benmeng Wu, Yaqin Zhu, Lin Yu & Jingjing Liu

  3. Department of Pathology, Jiangsu Cancer Hospital, Nanjing, China

    Miaolin Zhu

  4. School of Medical Technology, Xuzhou Medical University, Xuzhou, 221004, China

    Ting Lan

Authors
  1. Min Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoshan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Benmeng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miaolin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yaqin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lin Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ting Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jingjing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MW and TL designed the study. BMW performed the bioinformatic analysis. MW, XSH and YQZ conducted the in vitro experiments. MLZ collected the tumor tissue. XSH and BMW performed data analysis and interpretation. XSH and LY performed the animal experiment. MW and JJL wrote the draft of the manuscript. All authors have been involved in the writing of the manuscript and have read and approved the final version.

Corresponding authors

Correspondence to Min Wu, Ting Lan or Jingjing Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical Statement

All the patients, diagnosed and treated at Jiangsu Cancer Hospital, provided written informed consents. The whole study conformed to the Helsinki Declaration. The study protocol was approved by the Ethical Committee of Jiangsu Cancer Hospital with approval number JSCH-2020-156. All methods involving animals in this study were performed in accordance with the ARRIVE guidelines and were approved by the Ethics Committee of the Medical College of Yangzhou University (YXYLL-2019-73).

Additional information

Publisher’s Note

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

Electronic supplementary material

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, M., Huang, X., Wu, B. et al. The endonuclease FEN1 mediates activation of STAT3 and facilitates proliferation and metastasis in breast cancer. Mol Biol Rep 51, 553 (2024). https://doi.org/10.1007/s11033-024-09524-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11033-024-09524-3

Keywords

Search

Navigation