Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Cellular and Molecular Biology

TSLP enhances progestin response in endometrial cancer via androgen receptor signal pathway

British Journal of Cancer volume 130, pages 585–596 (2024)Cite this article

Subjects

Abstract

Background

The enriched proteins within in vitro fertilisation (IVF)-generated human embryonic microenvironment could reverse progestin resistance in endometrial cancer (EC).

Methods

The expression of thymic stromal lymphopoietin (TSLP) in EC was evaluated by immunoblot and IHC analysis. Transcriptome sequencing screened out the downstream pathway regulated by TSLP. The role of TSLP, androgen receptor (AR) and KANK1 in regulating the sensitivity of EC to progestin was verified through a series of in vitro and in vivo experiments.

Results

TSLP facilitates the formation of a BMP4/BMP7 heterodimer, resulting in activation of Smad5, augmenting AR signalling. AR in turn sensitises EC cells to progestin via KANK1. Downregulation of TSLP, loss of AR and KANK1 in EC patients are associated with tumour malignant progress. Moreover, exogenous TSLP could rescue the anti-tumour effect of progestin on mouse in vivo xenograft tumour.

Conclusions

Our findings suggest that TSLP enhances the sensitivity of EC to progestin through the BMP4/Smad5/AR/KANK1 axis, and provide a link between embryo development and cancer progress, paving the way for the establishment of novel strategy overcoming progestin resistance using embryo original factors.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: TSLP facilitates the sensitivity of EC cells to progestin.
Fig. 2: Augmented AR signalling attributes to intensive progestin response.
Fig. 3: TSLP upregulates AR through the BMP4/Smad5 pathway.
Fig. 4: KANK1 is required for TSLP-enhancing progestin response.
Fig. 5: Expression profiles of TSLP, AR and KANK1 in endometrial cancer and the clinical outcome.
Fig. 6: TSLP sensitised endometrial cancer to progestin treatment in vivo.

Similar content being viewed by others

Data availability

The datasets used and/or analysed during this study are available from the corresponding author on reasonable request.

References

  1. Yang S, Thiel KW, Leslie KK. Progesterone: the ultimate endometrial tumor suppressor. Trends Endocrinol Metab TEM. 2011;22:145–52.

    Article  CAS  PubMed  Google Scholar 

  2. Zhang Z, Dong L, Sui L, Yang Y, Liu X, Yu Y, et al. Metformin reverses progestin resistance in endometrial cancer cells by downregulating GloI expression. Int J Gynecol Cancer. 2011;21:213–21.

    Article  PubMed  Google Scholar 

  3. Kim MK, Seong SJ, Kang SB, Bae DS, Kim JW, Nam JH, et al. Six months response rate of combined oral medroxyprogesterone/levonorgestrel-intrauterine system for early-stage endometrial cancer in young women: a Korean Gynecologic-Oncology Group Study. J Gynecol Oncol. 2019;30:e47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mintz B, Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA. 1975;72:3585–9.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pierce GB, Pantazis CG, Caldwell JE, Wells RS. Specificity of the control of tumor formation by the blastocyst. Cancer Res. 1982;42:1082–7.

    CAS  PubMed  Google Scholar 

  6. Gerschenson M, Graves K, Carson SD, Wells RS, Pierce GB. Regulation of melanoma by the embryonic skin. Proc Natl Acad Sci USA. 1986;83:7307–10.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sun D, Qin Z, Xu Y, Xiao Q, Xu Y, Bai M, et al. The IVF-generated human embryonic microenvironment reverses progestin resistance in endometrial cancer cells by inducing cancer stem cell differentiation. Cancer Lett. 2022;526:311–21.

    Article  CAS  PubMed  Google Scholar 

  8. De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med. 2011;208:469–78.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Xie F, Meng YH, Liu LB, Chang KK, Li H, Li MQ, et al. Cervical carcinoma cells stimulate the angiogenesis through TSLP promoting growth and activation of vascular endothelial cells. Am J Reprod Immunol. 2013;70:69–79.

    Article  CAS  PubMed  Google Scholar 

  10. Li H, Zhao H, Yu J, Su Y, Cao S, An X, et al. Increased prevalence of regulatory T cells in the lung cancer microenvironment: a role of thymic stromal lymphopoietin. Cancer Immunol Immunother CII. 2011;60:1587–96.

    Article  CAS  PubMed  Google Scholar 

  11. Demehri S, Cunningham TJ, Manivasagam S, Ngo KH, Moradi Tuchayi S, Reddy R, et al. Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis. J Clin Investig. 2016;126:1458–70.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Yue W, Lin Y, Yang X, Li B, Liu J, He R. Thymic stromal lymphopoietin (TSLP) inhibits human colon tumor growth by promoting apoptosis of tumor cells. Oncotarget. 2016;7:16840–54.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Demehri S, Turkoz A, Manivasagam S, Yockey LJ, Turkoz M, Kopan R. Elevated epidermal thymic stromal lymphopoietin levels establish an antitumor environment in the skin. Cancer Cell. 2012;22:494–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hackenberg R, Beck S, Filmer A, Hushmand Nia A, Kunzmann R, Koch M, et al. Androgen responsiveness of the new human endometrial cancer cell line MFE-296. Int J Cancer. 1994;57:117–22.

    Article  CAS  PubMed  Google Scholar 

  15. Lovely LP, Appa Rao KB, Gui Y, Lessey BA. Characterization of androgen receptors in a well-differentiated endometrial adenocarcinoma cell line (Ishikawa). J Steroid Biochem Mol Biol. 2000;74:235–41.

    Article  CAS  PubMed  Google Scholar 

  16. Gibson DA, Simitsidellis I, Saunders PT. Regulation of androgen action during establishment of pregnancy. J Mol Endocrinol. 2016;57:R35–47.

    Article  CAS  PubMed  Google Scholar 

  17. Hackenberg R, Schulz KD. Androgen receptor mediated growth control of breast cancer and endometrial cancer modulated by antiandrogen- and androgen-like steroids. J Steroid Biochem Mol Biol. 1996;56:113–7.

    Article  CAS  PubMed  Google Scholar 

  18. Niwa K, Hashimoto M, Morishita S, Yokoyama Y, Lian Z, Tagami K, et al. Preventive effects of danazol on endometrial carcinogenesis in mice. Cancer Lett. 2000;158:133–9.

    Article  CAS  PubMed  Google Scholar 

  19. Gibson DA, Simitsidellis I, Cousins FL, Critchley HO, Saunders PT. Intracrine androgens enhance decidualization and modulate expression of human endometrial receptivity genes. Sci Rep. 2016;6:19970.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  20. Marshall E, Lowrey J, MacPherson S, Maybin JA, Collins F, Critchley HO, et al. In silico analysis identifies a novel role for androgens in the regulation of human endometrial apoptosis. J Clin Endocrinol Metab. 2011;96:E1746–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rahman MS, Akhtar N, Jamil HM, Banik RS, Asaduzzaman SM. TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res. 2015;3:15005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wan M, Cao X. BMP signaling in skeletal development. Biochem Biophys Res Commun. 2005;328:651–7.

    Article  CAS  PubMed  Google Scholar 

  23. Catic A, Kurtovic-Kozaric A, Johnson SH, Vasmatzis G, Pins MR, Kogan J. A novel cytogenetic and molecular characterization of renal metanephric adenoma: Identification of partner genes involved in translocation t(9;15)(p24;q24). Cancer Genet. 2017;214-215:9–15.

    Article  CAS  PubMed  Google Scholar 

  24. Luo FY, Xiao S, Liu ZH, Zhang PF, Xiao ZQ, Tang CE. Kank1 reexpression induced by 5-Aza-2’-deoxycytidine suppresses nasopharyngeal carcinoma cell proliferation and promotes apoptosis. Int J Clin Exp Pathol. 2015;8:1658–65.

    PubMed  PubMed Central  Google Scholar 

  25. Chen T, Wang K, Tong X. In vivo and in vitro inhibition of human gastric cancer progress by upregulating Kank1 gene. Oncol Rep. 2017;38:1663–9.

    Article  CAS  PubMed  Google Scholar 

  26. Kakinuma N, Roy BC, Zhu Y, Wang Y, Kiyama R. Kank regulates RhoA-dependent formation of actin stress fibers and cell migration via 14-3-3 in PI3K-Akt signaling. J Cell Biol. 2008;181:537–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gu C, Zhang Z, Yu Y, Liu Y, Zhao F, Yin L, et al. Inhibiting the PI3K/Akt pathway reversed progestin resistance in endometrial cancer. Cancer Sci. 2011;102:557–64.

    Article  CAS  PubMed  Google Scholar 

  28. Jiang T, Chen N, Zhao F, Wang XJ, Kong B, Zheng W, et al. High levels of Nrf2 determine chemoresistance in type II endometrial cancer. Cancer Res. 2010;70:5486–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Catalano S, Giordano C, Rizza P, Gu G, Barone I, Bonofiglio D, et al. Evidence that leptin through STAT and CREB signaling enhances cyclin D1 expression and promotes human endometrial cancer proliferation. J Cell Physiol. 2009;218:490–500.

    Article  CAS  PubMed  Google Scholar 

  30. Wang Y, Wang Y, Zhang Z, Park JY, Guo D, Liao H, et al. Mechanism of progestin resistance in endometrial precancer/cancer through Nrf2-AKR1C1 pathway. Oncotarget. 2016;7:10363–72.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chen J, Bai M, Ning C, Xie B, Zhang J, Liao H, et al. Gankyrin facilitates follicle-stimulating hormone-driven ovarian cancer cell proliferation through the PI3K/AKT/HIF-1α/cyclin D1 pathway. Oncogene. 2016;35:2506–17.

    Article  CAS  PubMed  Google Scholar 

  32. Chen X, Zhang Z, Feng Y, Fadare O, Wang J, Ai Z, et al. Aberrant survivin expression in endometrial hyperplasia: another mechanism of progestin resistance. Mod Pathol. 2009;22:699–708.

    Article  PubMed  Google Scholar 

  33. Bjerkan L, Schreurs O, Engen SA, Jahnsen FL, Baekkevold ES, Blix IJ, et al. The short form of TSLP is constitutively translated in human keratinocytes and has characteristics of an antimicrobial peptide. Mucosal Immunol. 2015;8:49–56.

    Article  CAS  PubMed  Google Scholar 

  34. Guo J, Wu G. The signaling and functions of heterodimeric bone morphogenetic proteins. Cytokine Growth Factor Rev. 2012;23:61–7.

    Article  CAS  PubMed  Google Scholar 

  35. Corren J, Ziegler SF. TSLP: from allergy to cancer. Nat Immunol. 2019;20:1603–9.

    Article  CAS  PubMed  Google Scholar 

  36. Pedroza-Gonzalez A, Xu K, Wu TC, Aspord C, Tindle S, Marches F, et al. Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation. J Exp Med. 2011;208:479–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cunningham TJ, Tabacchi M, Eliane JP, Tuchayi SM, Manivasagam S, Mirzaalian H, et al. Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Investig. 2017;127:106–16.

    Article  PubMed  Google Scholar 

  38. Zhang Y, Jin LP. Effects of TSLP on obstetrical and gynecological diseases. Am J Reprod Immunol. 2017;77:e12612.

  39. Bessa PC, Casal M, Reis RL. Bone morphogenetic proteins in tissue engineering: the road from the laboratory to the clinic, part I (basic concepts). J Tissue Eng Regener Med. 2008;2:1–13.

    Article  CAS  Google Scholar 

  40. Valera E, Isaacs MJ, Kawakami Y, Izpisúa Belmonte JC, Choe S. BMP-2/6 heterodimer is more effective than BMP-2 or BMP-6 homodimers as inductor of differentiation of human embryonic stem cells. PLoS ONE. 2010;5:e11167.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  41. Koh JT, Zhao Z, Wang Z, Lewis IS, Krebsbach PH, Franceschi RT. Combinatorial gene therapy with BMP2/7 enhances cranial bone regeneration. J Dent Res. 2008;87:845–9.

    Article  CAS  PubMed  Google Scholar 

  42. Hayes SA, Zarnegar M, Sharma M, Yang F, Peehl DM, ten Dijke P, et al. SMAD3 represses androgen receptor-mediated transcription. Cancer Res. 2001;61:2112–8.

    CAS  PubMed  Google Scholar 

  43. Kato J, Seto T. Correlation of androgen receptors with histological differentiation in human endometrial carcinomas. Acta Obstetricia et Gynecologica Scandinavica. 1985;64:209–12.

    Article  CAS  PubMed  Google Scholar 

  44. Sasagawa S, Shimizu Y, Kami H, Takeuchi T, Mita S, Imada K, et al. Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile. Steroids. 2008;73:222–31.

    Article  CAS  PubMed  Google Scholar 

  45. Brenner RM, Slayden OD. Progesterone receptor antagonists and the endometrial antiproliferative effect. Semin Reprod Med. 2005;23:74–81.

    Article  CAS  PubMed  Google Scholar 

  46. Gu Y, Zhang M. Upregulation of the Kank1 gene inhibits human lung cancer progression in vitro and in vivo. Oncol Rep. 2018;40:1243–50.

    CAS  PubMed  Google Scholar 

  47. Cui Z, Shen Y, Chen KH, Mittal SK, Yang JY, Zhang G. KANK1 inhibits cell growth by inducing apoptosis through regulating CXXC5 in human malignant peripheral nerve sheath tumors. Sci Rep. 2017;7:40325.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang J, Jia J, Zhou L. Long non-coding RNA CASC2 enhances cisplatin sensitivity in oral squamous cell cancer cells by the miR-31-5p/KANK1 axis. Neoplasma. 2020;67:1279–92.

    Article  CAS  PubMed  Google Scholar 

  49. Pu J, Shen J, Zhong Z, Yanling M, Gao J. KANK1 regulates paclitaxel resistance in lung adenocarcinoma A549 cells. Artif Cells Nanomed Biotechnol. 2020;48:639–47.

    Article  CAS  PubMed  Google Scholar 

  50. Ren TJ, Liu C, Hou JF, Shan FX. CircDDX17 reduces 5-fluorouracil resistance and hinders tumorigenesis in colorectal cancer by regulating miR-31-5p/KANK1 axis. Eur Rev Med Pharmacol Sci. 2020;24:1743–54.

    PubMed  Google Scholar 

  51. Ai Z, Yin L, Zhou X, Zhu Y, Zhu D, Yu Y, et al. Inhibition of survivin reduces cell proliferation and induces apoptosis in human endometrial cancer. Cancer. 2006;107:746–56.

    Article  CAS  PubMed  Google Scholar 

  52. Murphy LC, Dotzlaw H, Wong MS, Miller T, Murphy LJ. Mechanisms involved in the evolution of progestin resistance in human breast cancer cells. Cancer Res. 1991;51:2051–7.

    CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by grants from National Natural Science Foundation of China (grants 82371642), Shanghai Municipal Science and Technology Committee of Multi-center Clinical Study Project (20Z21900400), Shanghai Collaborative Innovation Center of Translational Medicine (TM202015), the Shanghai Municipal Public Health Bureau (202040078) for JX, Clinical Treatment Technology Standards for Assisted Reproductive Treatment in Patients with Crohn’s Syndrome, Shanghai Science and Technology Commission (23DZ2202100), the start funding (RCQD2307) from Shanghai Tongji hospital for ZZ, Cross- and jointly project (2023-3-ZD-02) from Tongji University for ZZ, Health care project of Shanghai Pudong New Area Science and Technology Development Fund for Livelihood Research (PKJ2021-Y05) and Scientific research project of Shanghai Municipal Health Commission (202140279).

Author information

Author notes

  1. These authors contributed equally: Mu Lv, Yuan Xu.

Authors and Affiliations

  1. Reproductive Medicine Center, Department of Obstetrics and Gynecology, Tongji Hospital, School of Medicine, Tongji University, 200065, Shanghai, China

    Mu Lv, Zuoshu Qin, Jun Xiang, Yanqiu Wang & Zhenbo Zhang

  2. Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China

    Yuan Xu, Jingjie Li, Baozhu Huang & Youji Feng

  3. Department of Obstetrics and Gynecology, The International Peace Maternity & Child Health Hospital of China Welfare Institute, Shanghai Jiao Tong University School of Medicine, 200030, Shanghai, China

    Peiqin Chen

  4. Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, Shanghai, China

    Yong Liu

  5. Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, 200090, Shanghai, China

    Xiang Tao

  6. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Wenxin Zheng

  7. Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Wenxin Zheng

  8. Department of Obstetrics and Gynecology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, 358 Datong Road, 200137, Shanghai, China

    Linxia Li

  9. Department of Clinical Laboratory Medicine, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, 200040, Shanghai, China

    Hong Liao

Authors
  1. Mu Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peiqin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jingjie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zuoshu Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Baozhu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiang Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jun Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yanqiu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Youji Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wenxin Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Zhenbo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Linxia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hong Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZZ, LL and HL performed the study concept and designed the study. ML performed most of the experiments, analysed and interpreted the data, and wrote the manuscript. YX performed part of the experiments. PC, JL, ZQ and BH provided technical and material support. YL, XT, JX and YW conducted the data collection and analysis. YF and WZ revised the manuscript with comments from all authors. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zhenbo Zhang, Linxia Li or Hong Liao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The animal experiments in this study were authorised by Shanghai General Hospital’s Animal Ethics Committee, with a project license number of 2020AW121.

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.

Supplementary information

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

Lv, M., Xu, Y., Chen, P. et al. TSLP enhances progestin response in endometrial cancer via androgen receptor signal pathway. Br J Cancer 130, 585–596 (2024). https://doi.org/10.1038/s41416-023-02545-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-023-02545-y

Search

Advanced search

Quick links