Skip to main content

AGR2-induced glucose metabolism facilitated the progression of endometrial carcinoma via enhancing the MUC1/HIF-1α pathway

Human Cell volume 33, pages 790–800 (2020)Cite this article

Abstract

Anterior gradient 2 (AGR2) was proved to modulate cancer progression. However, the role of AGR2 on endometrial cancer was not established. Here, we investigated the effects of AGR2 expression on endometrial cancer and explored the regulation mechanism. In the study, we found that AGR2 was overexpressed in tumor tissues of 30 endometrial cancer patients. A high level of AGR2 promoted endometrial cancer cells proliferation, migration and invasion. AGR2 induced the expression of lactate dehydrogenase A (LDHA), phosphoglycerate kinase 1 (PGK1), kallikrein 2 (HK2), and enolase 1-α (ENO1), glucose uptake and lactate production. AGR2 could bind to MUC1 and induce MUC1 and hypoxia-inducible factor 1α (HIF-1α). The inhibition effects of AGR2 knockdown on cells proliferation, migration and invasion ability were abolished by the overexpression of MUC1. Besides, the overexpression of MUC1 also reversed the inhibition effects of AGR2 knockdown on the expression of LDHA, HK2, PGK1 and ENO1, glucose uptake and lactate production. AGR2 knockdown inhibited tumor growth, the levels of Ki-67, MUC1, HIF-1α and glycolysis. In conclusion, AGR2 was overexpressed in endometrial cancer and AGR2-induced glucose metabolism facilitated the progression of endometrial carcinoma via the MUC1/HIF-1α pathway. AGR2 may be an effective therapeutic target for endometrial carcinoma.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. Lancet (Lond Engl). 2016;387(10023):1094–108. https://doi.org/10.1016/s0140-6736(15)00130-0.

    Article  Google Scholar 

  2. Al-Maghrabi J, Abdelrahman A, Al-Maghrabi B, Buhmeida A, Abuzenadah A, Al-Qahtani M, et al. Loss of p27 expression in endometrial carcinoma patients with recurrent tumor is significantly associated with poor survival. Eur J Gynaecol Oncol. 2018;39(1):119–23.

    Google Scholar 

  3. Abdulfatah E, Ahmed Q, Alosh B, Bandyopadhyay S, Bluth MH, Ali-Fehmi R. Gynecologic cancers: molecular updates 2018. Clin Lab Med. 2018;38(2):421–38. https://doi.org/10.1016/j.cll.2018.02.007.

    Article  PubMed  Google Scholar 

  4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. https://doi.org/10.3322/caac.21387.

    Article  PubMed  Google Scholar 

  5. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11–30. https://doi.org/10.3322/caac.21166.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Vale CL, Tierney J, Bull SJ, Symonds PR. Chemotherapy for advanced, recurrent or metastatic endometrial carcinoma. Cochrane Database Syst Rev. 2012;8:CD003915. https://doi.org/10.1002/14651858.CD003915.pub4.

    Article  Google Scholar 

  7. Persson S, Rosenquist M, Knoblach B, Khosravi-Far R, Sommarin M, Michalak M. Diversity of the protein disulfide isomerase family: identification of breast tumor induced Hag2 and Hag3 as novel members of the protein family. Mol Phylogenet Evol. 2005;36(3):734–40. https://doi.org/10.1016/j.ympev.2005.04.002.

    CAS  Article  PubMed  Google Scholar 

  8. Alavi M, Mah V, Maresh EL, Bagryanova L, Horvath S, Chia D, et al. High expression of AGR2 in lung cancer is predictive of poor survival. BMC Cancer. 2015;15:655. https://doi.org/10.1186/s12885-015-1658-2.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Zhang J, Jin Y, Xu S, Zheng J, Zhang QI, Wang Y, et al. AGR2 is associated with gastric cancer progression and poor survival. Oncol Lett. 2016;11(3):2075–83. https://doi.org/10.3892/ol.2016.4160.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Kyoungsook P, Jin CY, Hyekyung S, Kwangsoo K, Junsoo P, Mijoung O, et al. AGR2, a mucinous ovarian cancer marker, promotes cell proliferation and migration. Exp Mol Med. 2011;43(2):91–100.

    Article  Google Scholar 

  11. Jung SY, Yun J, Kim SJ, Kang S, Kim DY, Kim YJ, et al. Basic helix-loop-helix transcription factor Twist1 is a novel regulator of anterior gradient protein 2 homolog (AGR2) in breast cancer. Biochem Biophys Res Commun. 2019;516(1):149–56. https://doi.org/10.1016/j.bbrc.2019.05.191.

    CAS  Article  PubMed  Google Scholar 

  12. Kamal A, Valentijn A, Barraclough R, Rudland P, Rahmatalla N, Martin-Hirsch P, et al. High AGR2 protein is a feature of low grade endometrial cancer cells. Oncotarget. 2018;9(59):31459–72. https://doi.org/10.18632/oncotarget.25838.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol. 2008;70(1):431–57.

    CAS  Article  Google Scholar 

  14. Ren J, Raina D, Chen W, Li G, Huang L, Kufe D. MUC1 oncoprotein functions in activation of fibroblast growth factor receptor signaling. Mol Cancer Res Mcr. 2006;4(11):873.

    CAS  Article  Google Scholar 

  15. Singh PK, Yunfei W, Swanson BJ, Kandavel S, Andrius K, Cerny RL, et al. Platelet-derived growth factor receptor beta-mediated phosphorylation of MUC1 enhances invasiveness in pancreatic adenocarcinoma cells. Cancer Res. 2007;67(11):5201–10.

    CAS  Article  Google Scholar 

  16. McGuckin MA, Walsh MD, Hohn BG, Ward BG, Wright RG. Prognostic significance of MUC1 epithelial mucin expression in breast cancer. Hum Pathol. 1995;26(4):432–9. https://doi.org/10.1016/0046-8177(95)90146-9.

    CAS  Article  PubMed  Google Scholar 

  17. Hebbar V, Damera G, Sachdev GP. Differential expression of MUC genes in endometrial and cervical tissues and tumors. BMC Cancer. 2005;5(1):124.

    Article  Google Scholar 

  18. Engel BJ, Bowser JL, Broaddus RR, Carson DD. MUC1 stimulates EGFR expression and function in endometrial cancer. Oncotarget. 2016;7(22):32796–809.

    Article  Google Scholar 

  19. Shukla SK, Purohit V, Mehla K, Gunda V, Chaika NV, Vernucci E, et al. MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer. Cancer Cell. 2017;32(1):71–87.e7.

    CAS  Article  Google Scholar 

  20. Huang J, Liu L, Feng M, An S, Zhou M, Li Z, et al. Effect of CoCl2 on fracture repair in a rat model of bone fracture. Mol Med Rep. 2015;12(4):5951–6. https://doi.org/10.3892/mmr.2015.4122.

    CAS  Article  PubMed  Google Scholar 

  21. Chaika NV, Gebregiworgis T, Lewallen ME, Purohit V, Radhakrishnan P, Liu X, et al. MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer. Proc Natl Acad Sci USA. 2012;109(34):13787–92. https://doi.org/10.1073/pnas.1203339109.

    Article  PubMed  Google Scholar 

  22. Prat J. Pathology of cancers of the female genital tract. Int J Gynaecol Obst. 2015;131(Suppl 2):S132–S145145. https://doi.org/10.1016/j.ijgo.2015.06.010.

    Article  Google Scholar 

  23. Ma SR, Mao L, Deng WW, Li YC, Bu LL, Yu GT, et al. AGR2 promotes the proliferation, migration and regulates epithelial-mesenchymal transition in salivary adenoid cystic carcinoma. Am J Transl Res. 2017;9(2):507–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Li Y, Wang W, Liu Z, Jiang Y, Lu J, Xie H, et al. AGR2 diagnostic value in nasopharyngeal carcinoma prognosis. Clin Chim Acta Int J Clin Chem. 2018;484:323–7. https://doi.org/10.1016/j.cca.2017.12.023.

    CAS  Article  Google Scholar 

  25. Fritzsche FR, Dahl E, Dankof A, Burkhardt M, Pahl S, Petersen I et al (2007) Expression of AGR2 in non small cell lung cancer. Histol Histopathol

  26. Milewski D, Balli D, Ustiyan V, Le T, Dienemann H, Warth A, et al. FOXM1 activates AGR2 and causes progression of lung adenomas into invasive mucinous adenocarcinomas. PLoS Genet. 2017;13(12):e1007097.

    Article  Google Scholar 

  27. Wang Z, Hao Y, Lowe AW. The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation. Cancer Res. 2008;68(2):492–7.

    CAS  Article  Google Scholar 

  28. Annibaldi A, Widmann C. Glucose metabolism in cancer cells. Curr Opin Clin Nutr Metab Care. 2010;13(4):466–70.

    CAS  Article  Google Scholar 

  29. Kufe DW. Functional targeting of the MUC1 oncogene in human cancers. Cancer Biol Ther. 2009;8(13):1197–203.

    CAS  Article  Google Scholar 

  30. Li Y, Liu D, Chen D, Kharbanda S, Kufe D. Human DF3/MUC1 carcinoma-associated protein functions as an oncogene. Oncogene. 2003;22(38):6107.

    CAS  Article  Google Scholar 

  31. Norris AM, Gore A, Balboni A, Young A, Longnecker DS, Korc M. AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia. Oncogene. 2013;32(33):3867–76. https://doi.org/10.1038/onc.2012.394.

    CAS  Article  PubMed  Google Scholar 

  32. Mehla K, Singh PK. MUC1: a novel metabolic master regulator. Biochim Biophys Acta (BBA) Rev Cancer 2014;1845(2):126–135

  33. Kosugi M, Ahmad R, Alam M, Uchida Y, Kufe D. MUC1-C oncoprotein regulates glycolysis and pyruvate kinase M2 activity in cancer cells. PLoS One. 2011;6(11):e28234.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Affiliations

  1. Department of Gynaecology, The Fourth Affiliated Hospital of Xinjiang Medical University, No. 116 Huanghe Road, Tianshan District, Urumqi City, 830000, Xinjiang Uygur Autonomous Region, China

    Wei Gong, Belize Ekmu, Xinmei Wang, Yanli Lu & Li Wan

Authors
  1. Wei Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Belize Ekmu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xinmei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanli Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WG conceived and designed the experiments, BE and XW analyzed and interpreted the results of the experiments, and YL and LW performed the experiments.

Corresponding author

Correspondence to Wei Gong.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests, and all authors would confirm its accuracy.

Ethics approval and consent to participate

The protocol of the study was approved by the Ethics Committee of The Fourth Affiliated Hospital of Xinjiang Medical University (No. 2017065), and all the patients signed written informed consent.

All animal experiments were approved by the Ethics Committee of The Fourth Affiliated Hospital of Xinjiang Medical University (No. 2017065).

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Patient consent for publication

Not Applicable.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gong, W., Ekmu, B., Wang, X. et al. AGR2-induced glucose metabolism facilitated the progression of endometrial carcinoma via enhancing the MUC1/HIF-1α pathway. Human Cell 33, 790–800 (2020). https://doi.org/10.1007/s13577-020-00356-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-020-00356-4

Keywords

  • Endometrial carcinoma
  • AGR2
  • Glucose metabolism
  • MUC1
  • HIF-1α