Skip to main content

Advertisement

SpringerLink
Log in

RNF149 confers cisplatin resistance in esophageal squamous cell carcinoma via destabilization of PHLPP2 and activating PI3K/AKT signalling

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

A Letter to the Editor to this article was published on 20 October 2023

Abstract

Chemo-resistance has been identified as a crucial factor contributing to tumor recurrence and a leading cause of worse prognosis in patients with ESCC. Therefore, unravel the critical regulators and effective strategies to overcome drug resistance will have a significant clinical impact on the disease. In our study we found that RNF149 was upregulated in ESCC and high RNF149 expression was associated with poor prognosis with ESCC patients. Functionally, we have demonstrated that overexpression of RNF149 confers CDDP resistance to ESCC; however, inhibition of RNF149 reversed this phenomenon both in vitro and in vivo. Mechanistically, we demonstrated that RNF149 interacts with PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2) and induces E3 ligase-dependent protein degradation of PHLPP2, substantially activating the PI3K/AKT signalling pathway in ESCC. Additionally, we found that inhibition of PI3K/AKT signalling pathway by AKT siRNA or small molecule inhibitor significantly suppressed RNF149-induced CDDP resistance. Importantly, RNF149 locus was also found to be amplified not only in ESCC but also in various human cancer types. Our data suggest that RNF149 might function as an oncogenic gene. Targeting the RNF149/PHLPP2/PI3K/Akt axis may be a promising prognostic factor and valuable therapeutic target for malignant tumours.

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

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Article  PubMed  Google Scholar 

  2. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349(23):2241–52.

    Article  CAS  PubMed  Google Scholar 

  3. Kadian LK, Arora M, Prasad CP, Pramanik R, Chauhan SS. Signaling pathways and their potential therapeutic utility in esophageal squamous cell carcinoma. Clin Transl Oncol. 2022;24:1014–32.

    Article  CAS  PubMed  Google Scholar 

  4. Li B, Xu WW, Lam AKY, Wang Y, Hu HF, Guan XY, Qin YR, Saremi N, Tsao SW, He QY, et al. Significance of PI3K/AKT signaling pathway in metastasis of esophageal squamous cell carcinoma and its potential as a target for anti-metastasis therapy. Oncotarget. 2017;8(24):38755–66.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Deng L, Wu X, Zhu X, Yu Z, Liu Z, Wang J, Zheng Y. Combination effect of curcumin with docetaxel on the PI3K/AKT/mTOR pathway to induce autophagy and apoptosis in esophageal squamous cell carcinoma. Am J Transl Res. 2021;13(1):57–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang L, Zhang Z, Yu X, Li Q, Wang Q, Chang A, Huang X, Han X, Song Y, Hu J, et al. SOX9/miR-203a axis drives PI3K/AKT signaling to promote esophageal cancer progression. Cancer Lett. 2020;468:14–26.

    Article  PubMed  Google Scholar 

  7. Wang H, Yang X, Guo Y, Shui L, Li S, Bai Y, Liu Y, Zeng M, Xia J. HERG1 promotes esophageal squamous cell carcinoma growth and metastasis through TXNDC5 by activating the PI3K/AKT pathway. J Exp Clin Cancer Res. 2019;38(1):324.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Yu J, Wang W, Yao W, Yang Z, Gao P, Liu M, Wang H, Chen S, Wang D, Wang W, et al. Gambogic acid affects ESCC progression through regulation of PI3K/AKT/mTOR signal pathway. J Cancer. 2020;11(19):5568–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang Y, Lyu Z, Qin Y, Wang X, Sun L, Zhang Y, Gong L, Wu S, Han S, Tang Y, et al. FOXO1 promotes tumor progression by increased M2 macrophage infiltration in esophageal squamous cell carcinoma. Theranostics. 2020;10(25):11535–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hillier LW, Graves TA, Fulton RS, Fulton LA, Pepin KH, Minx P, Wagner-McPherson C, Layman D, Wylie K, Sekhon M, et al. Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature. 2005;434(7034):724–31.

    Article  CAS  PubMed  Google Scholar 

  11. Won S, Jung J, Park E, Kim H. Identification of genes related to intramuscular fat content of pigs using genome-wide association study. Asian Austral J Anim Sci. 2018;31(2):157–62.

    Article  CAS  Google Scholar 

  12. Loomis SJ, Klein AP, Lee KE, Chen F, Bomotti S, Truitt B, Iyengar SK, Klein R, Klein BEK, Duggal P. Exome array analysis of nuclear lens opacity. Ophthalmic Epidemiol. 2018;25(3):215–9.

    Article  PubMed  Google Scholar 

  13. Beckner ME, Pollack IF, Nordberg ML, Hamilton RL. Glioblastomas with copy number gains in EGFR and RNF139 show increased expressions of carbonic anhydrase genes transformed by ENO1. BBA Clin. 2016;5:1–15.

    Article  PubMed  Google Scholar 

  14. Hong SW, Jin DH, Shin JS, Moon JH, Na YS, Jung KA, Kim SM, Kim JC, Kim KP, Hong YS, et al. Ring finger protein 149 is an E3 ubiquitin ligase active on wild-type v-Raf murine sarcoma viral oncogene homolog B1 (BRAF). J Biol Chem. 2012;287(28):24017–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nair VS, Gevaert O, Davidzon G, Napel S, Graves EE, Hoang CD, Shrager JB, Quon A, Rubin DL, Plevritis SK. Prognostic PET 18F-FDG uptake imaging features are associated with major oncogenomic alterations in patients with resected non-small cell lung cancer. Can Res. 2012;72(15):3725–34.

    Article  CAS  Google Scholar 

  16. Shimada Y, Imamura M, Wagata T, Yamaguchi N, Tobe T. Characterization of 21 newly established esophageal cancer cell lines. Cancer. 1992;69(2):277–84.

    Article  CAS  PubMed  Google Scholar 

  17. He S, Niu G, Shang J, Deng Y, Wan Z, Zhang C, You Z, Shen H. The oncogenic Golgi phosphoprotein 3 like overexpression is associated with cisplatin resistance in ovarian carcinoma and activating the NF-kappaB signaling pathway. J Exp Clin Cancer Res. 2017;36(1):137.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zhu J, Wu Y, Lao S, Shen J, Yu Y, Fang C, Zhang N, Li Y, Zhang R. Targeting TRIM54/Axin1/beta-catenin axis prohibits proliferation and metastasis in hepatocellular carcinoma. Front Oncol. 2021;11: 759842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lin C, Liu A, Zhu J, Zhang X, Wu G, Ren P, Wu J, Li M, Li J, Song L. miR-508 sustains phosphoinositide signalling and promotes aggressive phenotype of oesophageal squamous cell carcinoma. Nat Commun. 2014;5:4620.

    Article  CAS  PubMed  Google Scholar 

  20. Cha JH, Jeong Y, Oh AR, Lee SB, Hong SS, Kim K. Emerging roles of PHLPP phosphatases in metabolism. BMB Rep. 2021;54(9):451–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hribal ML, Mancuso E, Spiga R, Mannino GC, Fiorentino TV, Andreozzi F, Sesti G. PHLPP phosphatases as a therapeutic target in insulin resistance-related diseases. Expert Opin Ther Targets. 2016;20(6):663–75.

    Article  CAS  PubMed  Google Scholar 

  22. Newton AC, Trotman LC. Turning off AKT: PHLPP as a drug target. Annu Rev Pharmacol Toxicol. 2014;54:537–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Grzechnik AT, Newton AC. PHLPPing through history: a decade in the life of PHLPP phosphatases. Biochem Soc Trans. 2016;44(6):1675–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Baffi TR, Cohen-Katsenelson K, Newton AC. PHLPPing the script: emerging roles of PHLPP phosphatases in cell signaling. Annu Rev Pharmacol Toxicol. 2021;61:723–43.

    Article  CAS  PubMed  Google Scholar 

  25. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170(4):605–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30(2):193–204.

    Article  PubMed  Google Scholar 

  27. Xie Y, Shi X, Sheng K, Han G, Li W, Zhao Q, Jiang B, Feng J, Li J, Gu Y. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (review). Mol Med Rep. 2019;19(2):783–91.

    CAS  PubMed  Google Scholar 

  28. Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015;15(1):7–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Revathidevi S, Munirajan AK. Akt in cancer: mediator and more. Semin Cancer Biol. 2019;59:80–91.

    Article  CAS  PubMed  Google Scholar 

  30. Yang Q, Jiang W, Hou P. Emerging role of PI3K/AKT in tumor-related epigenetic regulation. Semin Cancer Biol. 2019;59:112–24.

    Article  CAS  PubMed  Google Scholar 

  31. Shi N, Yu H, Chen T. Inhibition of esophageal cancer growth through the suppression of PI3K/AKT/mTOR signaling pathway. Onco Targets Ther. 2019;12:7637–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhou S, Guo Z, Zhou C, Zhang Y, Wang S. Circ_NRIP1 is oncogenic in malignant development of esophageal squamous cell carcinoma (ESCC) via miR-595/SEMA4D axis and PI3K/AKT pathway. Cancer Cell Int. 2021;21(1):250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xu JC, Chen TY, Liao LT, Chen T, Li QL, Xu JX, Hu JW, Zhou PH, Zhang YQ. NETO2 promotes esophageal cancer progression by inducing proliferation and metastasis via PI3K/AKT and ERK pathway. Int J Biol Sci. 2021;17(1):259–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu S, Jiang H, Min L, Ning T, Xu J, Wang T, Wang X, Zhang Q, Cao R, Zhang S, et al. Lysophosphatidic acid mediated PI3K/Akt activation contributed to esophageal squamous cell cancer progression. Carcinogenesis. 2021;42(4):611–20.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by National Natural Science Foundation of China (No. 82103637).

Author information

Author notes

  1. Jinrong Zhu, Jiuren Tang and Yongqi Wu have contributed equally to this work.

Authors and Affiliations

  1. School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China

    Jinrong Zhu, Jiuren Tang, Yongqi Wu, Xiangyu Qiu, Xin Jin & Rongxin Zhang

Authors
  1. Jinrong Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiuren Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yongqi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiangyu Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xin Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rongxin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JZ and RZ designed all experiments, supervised the project, and wrote the manuscript. YW and XQ conducted the molecular cloning and performed all the in vitro experiments. JT and XJ performed the in vivo experiments.

Corresponding authors

Correspondence to Jinrong Zhu or Rongxin Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest to disclose.

Ethics approval and consent to participate

Not applicable.

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 (DOC 50 KB)

Supplementary file2 (TIF 73 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

Zhu, J., Tang, J., Wu, Y. et al. RNF149 confers cisplatin resistance in esophageal squamous cell carcinoma via destabilization of PHLPP2 and activating PI3K/AKT signalling. Med Oncol 40, 290 (2023). https://doi.org/10.1007/s12032-023-02137-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-023-02137-z

Keywords

Search

Navigation