Skip to main content

Advertisement

SpringerLink
Log in

MicroRNA-10a-5p-mediated downregulation of GATA6 inhibits tumor progression in ovarian cancer

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

Abstract

Ovarian cancer is the common cause of cancer-related death in women and is considered the most deadly gynecological cancer. It has been established that GATA-binding protein 6 (GATA6) is abnormally expressed in several types of malignant tumors and acts as an oncogenic protein or a tumor suppressor. However, the underlying mechanism of GATA6 in ovarian cancer progression has not been elucidated. Data in the present study revealed that GATA6 expression was negatively correlated to microRNA-10a-5p (miR-10a-5p) in ovarian cancer tissue and cells and that GATA6 is directly targeted by miR-10a-5p. Notably, upregulated miR-10a-5p dramatically inhibited ovarian cancer cell proliferation, tumorigenic ability, migration, and invasion by targeting GATA6. In vitro and in vivo experiments confirmed that miR-10a-5p-mediated downregulation of GATA6 suppressed Akt pathway activation. Overall, our findings suggest that miR-10a-5p could be a novel therapeutic target for ovarian cancer, and targeting the miR-10a-5p/GATA6/Akt axis could improve outcomes in this patient population.

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
Fig. 8

Similar content being viewed by others

Data availability

The data are available at the TCGA and the GTEx. GATA 6 mRNA in ovarian cell lines are available from the CCLE dataset. The data utilized in this study were acquired from publicly available reports, thereby obviating the necessity for supplementary statements of permission or consent pertaining to these databases.

References

  1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2023). http://www.nccn.org/professionals. Accessed 2 June 2023

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30. https://doi.org/10.3322/caac.21590.

    Article  PubMed  Google Scholar 

  3. Network CGAR. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15. https://doi.org/10.1038/nature10166.

    Article  CAS  Google Scholar 

  4. Patch AM, Christie EL, Etemadmoghadam D, et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015;521(7553):489–94. https://doi.org/10.1038/nature14410.

    Article  PubMed  CAS  Google Scholar 

  5. Matulonis UA, Sood AK, Fallowfield L, Howitt BE, Sehouli J, Karlan BY. Ovarian cancer. Nat Rev Dis Primers. 2016;2:16061. https://doi.org/10.1038/nrdp.2016.61.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Morrisey EE, Ip HS, Lu MM, Parmacek MS. GATA-6: a zinc finger transcription factor that is expressed in multiple cell lineages derived from lateral mesoderm. Dev Biol. 1996;177(1):309–22. https://doi.org/10.1006/dbio.1996.0165.

    Article  PubMed  CAS  Google Scholar 

  7. Liang G, Meng W, Huang X, et al. miR-196b-5p-mediated downregulation of TSPAN12 and GATA6 promotes tumor progression in non-small cell lung cancer. Proc Natl Acad Sci U S A. 2020;117(8):4347–57. https://doi.org/10.1073/pnas.1917531117.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Kamnasaran D, Qian B, Hawkins C, Stanford WL, Guha A. GATA6 is an astrocytoma tumor suppressor gene identified by gene trapping of mouse glioma model. Proc Natl Acad Sci U S A. 2007;104(19):8053–8. https://doi.org/10.1073/pnas.0611669104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Tan HW, Leung CO, Chan KK, et al. Deregulated GATA6 modulates stem cell-like properties and metabolic phenotype in hepatocellular carcinoma. Int J Cancer. 2019;145(7):1860–73. https://doi.org/10.1002/ijc.32248.

    Article  PubMed  CAS  Google Scholar 

  10. Guoping M, Ran L, Yanru Q. miR-143 inhibits cell proliferation of gastric cancer cells through targeting GATA6. Oncol Res. 2018;26(7):1023–9. https://doi.org/10.3727/096504018X15151515028670.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Belaguli NS, Aftab M, Rigi M, Zhang M, Albo D, Berger DH. GATA6 promotes colon cancer cell invasion by regulating urokinase plasminogen activator gene expression. Neoplasia. 2010;12(11):856–65. https://doi.org/10.1593/neo.10224.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Deng L, Liu H. MicroRNA-506 suppresses growth and metastasis of oral squamous cell carcinoma via targeting GATA6. Int J Clin Exp Med. 2015;8(2):1862–70.

    PubMed  PubMed Central  Google Scholar 

  13. Zhao X, Zhang W, Ji W. miR-181a targets GATA6 to inhibit the progression of human laryngeal squamous cell carcinoma. Future Oncol. 2018;14(17):1741–53. https://doi.org/10.2217/fon-2018-0064.

    Article  PubMed  CAS  Google Scholar 

  14. Deng X, Jiang P, Chen J, et al. GATA6 promotes epithelial-mesenchymal transition and metastasis through MUC1/beta-catenin pathway in cholangiocarcinoma. Cell Death Dis. 2020;11(10):860. https://doi.org/10.1038/s41419-020-03070-z.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Liu H, Du F, Sun L, et al. GATA6 suppresses migration and metastasis by regulating the miR-520b/CREB1 axis in gastric cancer. Cell Death Dis. 2019;10(2):35. https://doi.org/10.1038/s41419-018-1270-x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Li H, Feng C, Shi S. miR-196b promotes lung cancer cell migration and invasion through the targeting of GATA6. Oncol Lett. 2018;16(1):247–52. https://doi.org/10.3892/ol.2018.8671.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Tian F, Chen J, Zheng S, et al. miR-124 targets GATA6 to suppress cholangiocarcinoma cell invasion and metastasis. BMC Cancer. 2017;17(1):175. https://doi.org/10.1186/s12885-017-3166-z.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Tang J, Gao W, Liu G, et al. miR-944 suppresses EGF-induced EMT in colorectal cancer cells by directly targeting GATA6. Onco Targets Ther. 2021;14:2311–25. https://doi.org/10.2147/OTT.S290567.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bennett-Toomey J, Stocco C. Chapter eight—GATA regulation and function during the ovarian life cycle. In: Litwack G, editor. Vitamins and Hormones. Academic Press; 2018. p. 193–225.

    Google Scholar 

  20. Shen W, Niu N, Lawson B, et al. GATA6: a new predictor for prognosis in ovarian cancer. Hum Pathol. 2019;86:163–9. https://doi.org/10.1016/j.humpath.2019.01.001.

    Article  PubMed  CAS  Google Scholar 

  21. Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol. 2009;4:199–227. https://doi.org/10.1146/annurev.pathol.4.110807.092222.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Peng Y, Croce CM. The role of MicroRNAs in human cancer. Signal Transduct Target Ther. 2016;1:15004. https://doi.org/10.1038/sigtrans.2015.4.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Dioguardi M, Spirito F, Sovereto D, et al. MicroRNA-21 expression as a prognostic biomarker in oral cancer: systematic review and meta-analysis. Int J Environ Res Public Health. 2022. https://doi.org/10.3390/ijerph19063396.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Shao C, Yang F, Qin Z, Jing X, Shu Y, Shen H. The value of miR-155 as a biomarker for the diagnosis and prognosis of lung cancer: a systematic review with meta-analysis. BMC Cancer. 2019;19(1):1103. https://doi.org/10.1186/s12885-019-6297-6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Mazumder S, Datta S, Ray JG, Chaudhuri K, Chatterjee R. Liquid biopsy: miRNA as a potential biomarker in oral cancer. Cancer Epidemiol. 2019;58:137–45. https://doi.org/10.1016/j.canep.2018.12.008.

    Article  PubMed  Google Scholar 

  26. Chen X, Wang L, Zhao Y, et al. ST6Gal-I modulates docetaxel sensitivity in human hepatocarcinoma cells via the p38 MAPK/caspase pathway. Oncotarget. 2016;7(32):51955–64. https://doi.org/10.18632/oncotarget.10192.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ghandi M, Huang FW, Jane-Valbuena J, et al. Next-generation characterization of the cancer cell line encyclopedia. Nature. 2019;569(7757):503–8. https://doi.org/10.1038/s41586-019-1186-3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Lin S, Gregory RI. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer. 2015;15(6):321–33. https://doi.org/10.1038/nrc3932.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17(1):9–26. https://doi.org/10.1016/j.devcel.2009.06.016.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Chung SY, Chao TC, Su Y. The stemness-high human colorectal cancer cells promote angiogenesis by producing higher amounts of angiogenic cytokines via activation of the Egfr/Akt/Nf-kappaB pathway. Int J Mol Sci. 2021. https://doi.org/10.3390/ijms22031355.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zhong Y, Wang Z, Fu B, et al. GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1. PLoS ONE. 2011;6(7): e22129. https://doi.org/10.1371/journal.pone.0022129.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Ediriweera MK, Tennekoon KH, Samarakoon SR. Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: biological and therapeutic significance. Semin Cancer Biol. 2019;59:147–60. https://doi.org/10.1016/j.semcancer.2019.05.012.

    Article  PubMed  CAS  Google Scholar 

  33. Silwal-Pandit L, Langerod A, Borresen-Dale AL. TP53 mutations in breast and ovarian cancer. Cold Spring Harb Perspect Med. 2017;7(1):a026252. https://doi.org/10.1101/cshperspect.a026252.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bullwinkel J, Baron-Lühr B, Lüdemann A, Wohlenberg C, Gerdes J, Scholzen T. Ki-67 protein is associated with ribosomal RNA transcription in quiescent and proliferating cells. J Cell Physiol. 2006;206(3):624–35. https://doi.org/10.1002/jcp.20494.

    Article  PubMed  CAS  Google Scholar 

  35. Capo-chichi CD, Roland IH, Vanderveer L, et al. Anomalous expression of epithelial differentiation-determining GATA factors in ovarian tumorigenesis. Cancer Res. 2003;63(16):4967–77.

    PubMed  CAS  Google Scholar 

  36. Tang JT, Zhao J, Sheng W, Zhou JP, Dong Q, Dong M. Ectopic expression of miR-944 impairs colorectal cancer cell proliferation and invasion by targeting GATA binding protein 6. J Cell Mol Med. 2019;23(5):3483–94. https://doi.org/10.1111/jcmm.14245.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Chen W, Chen Z, Zhang M, et al. GATA6 Exerts Potent Lung Cancer Suppressive Function by Inducing Cell Senescence. Front Oncol. 2020;10:824. https://doi.org/10.3389/fonc.2020.00824.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Wang CJ, Liu QH, Huang M, et al. Loss of GATA6 expression promotes lymphatic metastasis in bladder cancer. FASEB J. 2020;34(4):5754–66. https://doi.org/10.1096/fj.201903176R.

    Article  PubMed  CAS  Google Scholar 

  39. Guo L, Li Y, Zhao C, et al. RECQL4, negatively regulated by miR-10a-5p, facilitates cell proliferation and invasion via MAFB in ovarian cancer. Front Oncol. 2020;10:524128. https://doi.org/10.3389/fonc.2020.524128.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Liu LJ, Sun XY, Yang CX, Zou XY. MiR-10a-5p restrains the aggressive phenotypes of ovarian cancer cells by inhibiting HOXA1. Kaohsiung J Med Sci. 2021;37(4):276–85. https://doi.org/10.1002/kjm2.12335.

    Article  PubMed  CAS  Google Scholar 

  41. Ye J, Wei X, Shang Y, et al. Core 3 mucin-type O-glycan restoration in colorectal cancer cells promotes MUC1/p53/miR-200c-dependent epithelial identity. Oncogene. 2017;36(46):6391–407. https://doi.org/10.1038/onc.2017.241.

    Article  PubMed  CAS  Google Scholar 

  42. Yasumizu Y, Rajabi H, Jin C, et al. MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer. Nat Commun. 2020;11(1):338. https://doi.org/10.1038/s41467-019-14219-6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Cai KQ, Caslini C, Capo-chichi CD, et al. Loss of GATA4 and GATA6 expression specifies ovarian cancer histological subtypes and precedes neoplastic transformation of ovarian surface epithelia. PLoS ONE. 2009;4(7): e6454. https://doi.org/10.1371/journal.pone.0006454.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Zhou Q, Yang HJ, Zuo MZ, Tao YL. Distinct expression and prognostic values of GATA transcription factor family in human ovarian cancer. J Ovarian Res. 2022;15(1):49. https://doi.org/10.1186/s13048-022-00974-6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Wang R, Wang J, Wang Y, Yang L. lncRNA TUSC7 sponges miR-10a-5p and inhibits BDNF/ERK pathway to suppress glioma cell proliferation and migration. Aging (Albany NY). 2023;15(8):3021–34. https://doi.org/10.18632/aging.204655.

    Article  PubMed  CAS  Google Scholar 

  46. Gu Y, Feng X, Jin Y, et al. Upregulation of miRNA-10a-5p promotes tumor progression in cervical cancer by suppressing UBE2I signaling. J Obstet Gynaecol. 2023;43(1):2171283. https://doi.org/10.1080/01443615.2023.2171283.

    Article  PubMed  CAS  Google Scholar 

  47. Yang L, Sun HF, Guo LQ, Cao HB. MiR-10a-5p: a promising biomarker for early diagnosis and prognosis evaluation of bladder cancer. Cancer Manag Res. 2021;13:7841–50. https://doi.org/10.2147/cmar.S326732.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Shen D, Zhao HY, Gu AD, et al. miRNA-10a-5p inhibits cell metastasis in hepatocellular carcinoma via targeting SKA1. Kaohsiung J Med Sci. 2021;37(9):784–94. https://doi.org/10.1002/kjm2.12392.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge TCGA and GTEx databases for providing their platforms. We thank Ph.D. Yaxing Zhao for providing lentivirus plasmids and for his guidance throughout this research. We also appreciate Ph.D. Wei Li for valuable advice throughout the study and Ph.D. Cong Wu and Dr. Zhihao Wang for their technical assistance.

Funding

This study was supported by the National Natural Science Foundation of China (No.82072088), Jiangsu Provincial Science and Technology Project of Chinese Medicine (YB201972), and the Postgraduate Research and Innovation Program of Yangzhou University (KYCX21_3291).

Author information

Author notes

  1. Feiying Gao, Qiang Wu have contributed equally.

Authors and Affiliations

  1. Medical College of Yangzhou University, Yangzhou, 225009, China

    Feiying Gao & Dan Lu

  2. Key Laboratory of Integrative Medicine in Geriatrics Control of Jiangsu Province, Yangzhou, 225009, China

    Feiying Gao & Qiang Wu

  3. Yangzhou Jiangdu Binjiang City People’s Hospital, Yangzhou, 225211, China

    Feiying Gao

  4. Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China

    Qiang Wu

  5. Northern Jiangsu People’s Hospital, Yangzhou, 225001, China

    Qiang Wu

Authors
  1. Feiying Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dan Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The experimental procedures, data analysis, and manuscript composition and refinement were carried out by FG and QW, with the guidance and funding support of DL, who served as the lead investigator and the research supervisor. All authors have thoroughly reviewed and consented to the publication of the final manuscript.

Corresponding author

Correspondence to Dan Lu.

Ethics declarations

Conflicts of interest

TCGA and GTEx are publicly accessible databases comprising patients who have received ethical approval. Researchers are able to freely download pertinent data for their investigations and subsequently publish relevant articles. Our study is founded upon open-source data, thereby eliminating any ethical concerns or potential conflicts of interest. The authors have no other relevant financial or non-financial interests to disclose.

Institutional review board statement

The Ethics Committee of the College of Medicine, Yangzhou University granted ethical approval for all animal studies and clinical data (No. YXYLL-2021–143).

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 (DOCX 2944 KB)

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

Gao, F., Wu, Q. & Lu, D. MicroRNA-10a-5p-mediated downregulation of GATA6 inhibits tumor progression in ovarian cancer. Human Cell 37, 271–284 (2024). https://doi.org/10.1007/s13577-023-00987-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-023-00987-3

Keywords

Search

Navigation