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High serum LDL promotes EMT and stemness through LDLR/FOXQ1/NF-κB1 pathway in epithelial ovarian cancer

Oncogene volume 44, pages 4587–4600 (2025)Cite this article

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Abstract

Epithelial ovarian cancer (EOC), the deadliest gynecological malignancy, is increasingly linked to dysregulated lipid metabolism. Nevertheless, the involvement of circulating low-density lipoprotein (LDL) in ovarian cancer progression remains controversial. Analyses of single-cell RNA sequencing and clinical data demonstrated a positive correlation between elevated LDL levels and EOC progression. Mechanistically, LDL internalized via LDL receptor (LDLR) enhanced epithelial-mesenchymal transition (EMT) and stemness in ovarian cancer cells, driven by the upregulation of the key transcription factor FOXQ1. Intriguingly, our investigations unveiled a novel transcriptional complex comprising FOXQ1/β-Catenin/ADNP. Both β-Catenin and ADNP interacted with FOXQ1 at the Forkhead domain, where FOXQ1 bound to the NF-κB1 gene promoter to enhance transcriptional activation. Notably, β-Catenin and ADNP were identified for the first time as competitive repressors within this regulatory axis. These findings were further corroborated in vivo using an ovarian cancer xenograft metastasis model, as well as in human pathological specimens, highlighting LDL-driven metastasis via FOXQ1 upregulation. Collectively, LDL promotes ovarian cancer metastasis through LDLR/FOXQ1/NF-κB1 axis. Furthermore, we discover a novel transcriptional complex, where FOXQ1 acts as the central regulator while β-Catenin/ADNP serve as co-repressors. These insights suggest that modulating serum LDL levels or targeting FOXQ1 may offer promising strategies to curb ovarian cancer progression.

LDL promotes ovarian cancer metastasis through LDLR/FOXQ1/NF-κB1 axis. High serum LDL uptake mediated by LDLR enhances EMT and stemness of ovarian cancer cells via upregulating FOXQ1 expression. Both β-Catenin and ADNP interact with FOXQ1 in the Forkhead domain (FH), also where FOXQ1 binds to NF-κB1 gene promoter to active its transcription, suggesting that β-Catenin and ADNP may act as competitive repressors in this novel transcriptional regulatory complex. Thus, controlling serum LDL levels and targeting FOXQ1 may be effective interventions for preventing metastasis in women with ovarian cancer.

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Fig. 1: Serum LDL levels were associated with progression and poor prognosis of ovarian cancer.
Fig. 2: LDL promoted metastasis of ovarian cancer in vitro.
Fig. 3: LDLR mediated LDL uptake enhanced metastasis and simvastatin inhibited the process.
Fig. 4: LDL promoted ovarian cancer metastasis by upregulating FOXQ1.
Fig. 5: FOXQ1 interacted with β-Catenin and ADNP and served as a transcription factor to activate NF-κB1 transcription.
Fig. 6: High-fat diet promoted the metastasis of ovarian cancer via regulating FOXQ1 in vivo.

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Data availability

The RNA sequencing data have been uploaded to the GEO database (GSE301160). All the raw data and code generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    PubMed  Google Scholar 

  2. Buza N. Immunohistochemistry in gynecologic carcinomas: practical update with diagnostic and clinical considerations based on the 2020 WHO classification of tumors. Semin Diagn Pathol. 2022;39:58–77.

    Article  PubMed  Google Scholar 

  3. Sambasivan S. Epithelial ovarian cancer: review article. Cancer Treat Res Commun. 2022;33:100629.

    PubMed  Google Scholar 

  4. Webb PM, Jordan SJ. Epidemiology of epithelial ovarian cancer. Best Pr Res Clin Obstet Gynaecol. 2017;41:3–14.

    Article  Google Scholar 

  5. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4:579–91.

    Article  CAS  PubMed  Google Scholar 

  6. Vekic J, Zeljkovic A, Stefanovic A, Jelic-Ivanovic Z, Spasojevic-Kalimanovska V. Obesity and dyslipidemia. Metabolism. 2019;92:71–81.

    Article  CAS  PubMed  Google Scholar 

  7. Ji Z, Shen Y, Feng X, Kong Y, Shao Y, Meng J, et al. Deregulation of Lipid Metabolism: The Critical Factors in Ovarian Cancer. Front Oncol. 2020;10:593017.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Yarmolinsky J, Bull CJ, Vincent EE, Robinson J, Walther A, Smith GD, et al. Association between genetically proxied inhibition of HMG-CoA reductase and epithelial ovarian cancer. Jama. 2020;323:646–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Trabert B, Hathaway CA, Rice MS, Rimm EB, Sluss PM, Terry KL, et al. Ovarian cancer risk in relation to blood cholesterol and triglycerides. Cancer Epidemiol Biomark Prev. 2021;30:2044–51.

    Article  CAS  Google Scholar 

  10. Zhang D, Xi Y, Feng Y. Ovarian cancer risk in relation to blood lipid levels and hyperlipidemia: a systematic review and meta-analysis of observational epidemiologic studies. Eur J Cancer Prev. 2021;30:161–70.

    Article  CAS  PubMed  Google Scholar 

  11. Lin Q, Liu W, Xu S, Sun L. Associations of preoperative serum high-density lipoprotein cholesterol and low-density lipoprotein cholesterol levels with the prognosis of ovarian cancer. Arch Gynecol Obstet. 2022;305:683–91.

    Article  CAS  PubMed  Google Scholar 

  12. Li AJ, Elmore RG, Chen IY, Karlan BY. Serum low-density lipoprotein levels correlate with survival in advanced stage epithelial ovarian cancers. Gynecol Oncol. 2010;116:78–81.

    Article  CAS  PubMed  Google Scholar 

  13. Tang S, Zheng F, Chen K, Niu Y, Fu Z, Wu Y, et al. Novel scoring system incorporating lipoproteins to predict outcomes of epithelial ovarian cancer patients. Int J Gynecol Cancer. 2024.

  14. Chang WC, Wang HC, Cheng WC, Yang JC, Chung WM, Ho YP, et al. LDLR-mediated lipidome-transcriptome reprogramming in cisplatin insensitivity. Endocr Relat Cancer. 2020;27:81–95.

    Article  CAS  PubMed  Google Scholar 

  15. Scoles DR, Xu X, Wang H, Tran H, Taylor-Harding B, Li A, et al. Liver X receptor agonist inhibits proliferation of ovarian carcinoma cells stimulated by oxidized low density lipoprotein. Gynecol Oncol. 2010;116:109–16.

    Article  CAS  PubMed  Google Scholar 

  16. Babaei G, Aziz SG, Jaghi NZZ. EMT, cancer stem cells and autophagy; the three main axes of metastasis. Biomed Pharmacother. 2021;133:110909.

    Article  CAS  PubMed  Google Scholar 

  17. Najafi M, Mortezaee K, Majidpoor J. Cancer stem cell (CSC) resistance drivers. Life Sci. 2019;234:116781.

    Article  CAS  PubMed  Google Scholar 

  18. Song Y, Chen Y, Li Y, Lyu X, Cui J, Cheng Y, et al. Resveratrol suppresses epithelial-mesenchymal transition in GBM by regulating smad-dependent signaling. Biomed Res Int. 2019;2019:1321973.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bieller A, Pasche B, Frank S, Gläser B, Kunz J, Witt K, et al. Isolation and characterization of the human forkhead gene FOXQ1. DNA Cell Biol. 2001;20:555–61.

    Article  CAS  PubMed  Google Scholar 

  20. Li Y, Zhang Y, Yao Z, Li S, Yin Z, Xu M. Forkhead box Q1: a key player in the pathogenesis of tumors (Review). Int J Oncol. 2016;49:51–58.

    Article  CAS  PubMed  Google Scholar 

  21. Wu J, Wu Y, Chen S, Guo Q, Shao Y, Liu C, et al. PARP1-stabilised FOXQ1 promotes ovarian cancer progression by activating the LAMB3/WNT/β-catenin signalling pathway. Oncogene. 2024;43:866–83.

    Article  CAS  PubMed  Google Scholar 

  22. Bassan M, Zamostiano R, Davidson A, Pinhasov A, Giladi E, Perl O, et al. Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem. 1999;72:1283–93.

    Article  CAS  PubMed  Google Scholar 

  23. Blaj C, Bringmann A, Schmidt EM, Urbischek M, Lamprecht S, Fröhlich T, et al. ADNP Is a Therapeutically Inducible Repressor of WNT Signaling in Colorectal Cancer. Clin Cancer Res. 2017;23:2769–80.

    Article  CAS  PubMed  Google Scholar 

  24. Karagoz K, Mehta GA, Khella CA, Khanna P, Gatza ML. Integrative proteogenomic analyses of human tumours identifies ADNP as a novel oncogenic mediator of cell cycle progression in high-grade serous ovarian cancer with poor prognosis. EBioMedicine. 2019;50:191–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ozawa M, Baribault H, Kemler R. The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. Embo j. 1989;8:1711–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7:3.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Tortelote GG, Reis RR, de Almeida Mendes F, Abreu JG. Complexity of the Wnt/β‑catenin pathway: Searching for an activation model. Cell Signal. 2017;40:30–43.

    Article  CAS  PubMed  Google Scholar 

  28. Go GW, Mani A. Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis. Yale J Biol Med. 2012;85:19–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med. 2001;5:378–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Katoh M, Katoh M. Human FOX gene family (Review). Int J Oncol. 2004;25:1495–1500.

    CAS  PubMed  Google Scholar 

  31. Goretsky T, Bradford EM, Ye Q, Lamping OF, Vanagunas T, Moyer MP, et al. Beta-catenin cleavage enhances transcriptional activation. Sci Rep. 2018;8:671.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet. 2019;393:1240–53.

    Article  PubMed  Google Scholar 

  33. Reid BM, Permuth JB, Sellers TA. Epidemiology of ovarian cancer: a review. Cancer Biol Med. 2017;14:9–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhu F, Xu X, Shi B, Zeng L, Wang L, Wu X, et al. The positive predictive value of low-density lipoprotein for recurrence-free survival in ovarian cancer. Int J Gynaecol Obstet. 2018;143:232–8.

    Article  CAS  PubMed  Google Scholar 

  35. Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Huang Y, Hong W, Wei X. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol. 2022;15:129.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Huang T, Song X, Xu D, Tiek D, Goenka A, Wu B, et al. Stem cell programs in cancer initiation, progression, and therapy resistance. Theranostics. 2020;10:8721–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, et al. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 2008;68:4311–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Najafi M, Farhood B, Mortezaee K. Cancer stem cells (CSCs) in cancer progression and therapy. J Cell Physiol. 2019;234:8381–95.

    Article  CAS  PubMed  Google Scholar 

  40. Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017;14:611–29.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Lambert AW, Weinberg RA. Linking EMT programmes to normal and neoplastic epithelial stem cells. Nat Rev Cancer. 2021;21:325–38.

    Article  CAS  PubMed  Google Scholar 

  42. Montecucco F, Quercioli A, Mach F. Ezetimibe/simvastatin. Expert Opin Drug Saf. 2009;8:715–25.

    Article  CAS  PubMed  Google Scholar 

  43. Wang J, Li W, Zhao Y, Kang D, Fu W, Zheng X, et al. Members of FOX family could be drug targets of cancers. Pharm Ther. 2018;181:183–96.

    Article  CAS  Google Scholar 

  44. Pei Y, Wang P, Liu H, He F, Ming L. FOXQ1 promotes esophageal cancer proliferation and metastasis by negatively modulating CDH1. Biomed Pharmacother. 2015;74:89–94.

    Article  CAS  PubMed  Google Scholar 

  45. Peng X, Luo Z, Kang Q, Deng D, Wang Q, Peng H, et al. FOXQ1 mediates the crosstalk between TGF-β and Wnt signaling pathways in the progression of colorectal cancer. Cancer Biol Ther. 2015;16:1099–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang J, Liu Y, Zhang J, Cui X, Li G, Wang J, et al. FOXQ1 promotes gastric cancer metastasis through upregulation of Snail. Oncol Rep. 2016;35:3607–13.

    Article  CAS  PubMed  Google Scholar 

  47. Sehrawat A, Kim SH, Vogt A, Singh SV. Suppression of FOXQ1 in benzyl isothiocyanate-mediated inhibition of epithelial-mesenchymal transition in human breast cancer cells. Carcinogenesis. 2013;34:864–73.

    Article  CAS  PubMed  Google Scholar 

  48. Wang X, Zhu X. Tumor forkhead box Q1 is elevated, correlates with increased tumor size, international federation of gynecology and obstetrics stage but worse overall survival in epithelial ovarian cancer patients. Cancer Biother Radiopharm. 2022;37:837–42.

    CAS  PubMed  Google Scholar 

  49. Luo Y, Wang J, Wang F, Liu X, Lu J, Yu X, et al. Foxq1 promotes metastasis of nasopharyngeal carcinoma by inducing vasculogenic mimicry via the EGFR signaling pathway. Cell Death Dis. 2021;12:411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pizzolato G, Moparthi L, Söderholm S, Cantù C, Koch S. The oncogenic transcription factor FOXQ1 is a differential regulator of Wnt target genes. J Cell Sci 2022;135.

  51. Zhu X, Hua E, Tu Q, Liu M, Xu L, Feng J. Foxq1 promotes alveolar epithelial cell death through Tle1-mediated inhibition of the NF-κB signaling pathway. Am J Respir Cell Mol Biol. 2024;71:53–65.

    Article  CAS  PubMed  Google Scholar 

  52. Sun X, Peng X, Cao Y, Zhou Y, Sun Y. ADNP promotes neural differentiation by modulating Wnt/β-catenin signaling. Nat Commun. 2020;11:2984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jin B, Wang C, Li J, Du X, Ding K, Pan J. Anthelmintic niclosamide disrupts the interplay of p65 and FOXM1/β-catenin and eradicates leukemia stem cells in chronic myelogenous leukemia. Clin Cancer Res. 2017;23:789–803.

    Article  CAS  PubMed  Google Scholar 

  54. Katoh M, Katoh M. WNT signaling and cancer stemness. Essays Biochem. 2022;66:319–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bian J, Dannappel M, Wan C, Firestein R. Transcriptional regulation of Wnt/β-catenin pathway in colorectal cancer. Cells. 2020;9.

  56. Nguyen VHL, Hough R, Bernaudo S, Peng C. Wnt/β-catenin signalling in ovarian cancer: insights into its hyperactivation and function in tumorigenesis. J Ovarian Res. 2019;12:122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by Zhejiang Provincial Natural Science Foundation of China (Grant number LY24H260002), the National Natural Science Foundation of China (Grant numbers 82303377, 32370584), Zhejiang University School of Public Health Interdisciplinary Research Innovation Team Development Project. We thank for the technical support by the Core Facilities and Qiong Huang, Zhejiang University School of Medicine.

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  1. These authors contributed equally: Song Tang, Kelie Chen, Fang Zheng, Zhiqin Fu.

Authors and Affiliations

  1. Department of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Song Tang, Weiguo Lu, Dajing Xia & Yihua Wu

  2. Department of Toxicology of School of Public Health, Zhejiang University, Hangzhou, Zhejiang, China

    Song Tang, Xinxin Liu, Xiaoyu Yuan, Zhenyan Cui, Dajing Xia & Yihua Wu

  3. Department of Gynecological Radiotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China

    Song Tang

  4. Department of Gynecology and Obstetrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Kelie Chen, Fang Zheng & Zhiqin Fu

  5. Department of Pathology, University Hospital Bonn, Bonn, Germany

    Yuequn Niu

  6. Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Heng Ni

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Contributions

TS was responsible for methodology, formal analysis, data curation, writing the original draft and visualization. CKL was responsible for data curation and funding acquisition. ZF and FZQ contributed to investigation and formal analysis. NYQ and LXX were responsible for software. NH, YXY, and CZY contributed to validation. LWG, XDJ, and WYH contributed to conceptualization, supervision and funding acquisition.

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Correspondence to Weiguo Lu, Dajing Xia or Yihua Wu.

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Tang, S., Chen, K., Zheng, F. et al. High serum LDL promotes EMT and stemness through LDLR/FOXQ1/NF-κB1 pathway in epithelial ovarian cancer. Oncogene 44, 4587–4600 (2025). https://doi.org/10.1038/s41388-025-03609-4

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