Skip to main content

Advertisement

SpringerLink
Log in

High RAD18 Expression is Associated with Disease Progression and Poor Prognosis in Patients with Gastric Cancer

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

RAD18 plays an important role in DNA damage repair by inducing monoubiquitinated PCNA (mUB-PCNA) in both cancer and normal tissues. Previous studies have not determined the significance of RAD18 expression in clinical gastric cancer (GC) samples. Thus, this study aimed to clarify the expression and functional significance of RAD18 in GC.

Methods

Overall, 96 resected GC samples were subjected to an immunohistochemical analysis of RAD18. GC cell lines were also subjected to functional RNA interference analyses of RAD18.

Results

RAD18 expression was predominantly nuclear and was observed at higher levels in GC tissues than in normal tissues. In GC tissues, strong RAD18 expression was associated with progression of lymph node metastasis (p = 0.0001), lymphatic invasion (p = 0.0255), venous invasion (p < 0.0001), recurrence (p = 0.028), and disease stage (p = 0.0253). Moreover, GC patients with high tumor RAD18 expression had shorter overall survival (p = 0.0061) and recurrence-free survival durations (p = 0.035) than those with low tumor RAD18 expression. RAD18 knockdown inhibited GC proliferation and invasiveness and increased chemosensitivity by suppressing mUB-PCNA.

Conclusions

RAD18 expression may be a useful marker of progression and poor prognosis of GC. Moreover, therapeutic strategies that target RAD18 might be a novel chemosensitizer to eradicate the refractory GC.

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

Similar content being viewed by others

References

  1. Carlomagno N, Incollingo P, Tammaro V, et al. Diagnostic, predictive, prognostic, and therapeutic molecular biomarkers in third millennium: a breakthrough in gastric cancer. Biomed Res Int. 2017;2017:7869802.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Cao J, Qi F, Liu T. Adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis. Scand J Gastroenterol. 2014;49(6):690–704.

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. Varanasi L, Do PM, Goluszko E, Martinez LA. Rad18 is a transcriptional target of E2F3. Cell Cycle. 2012;11(6):1131–41.

    Article  CAS  PubMed  Google Scholar 

  5. Hibbert RG, Huang A, Boelens R, Sixma TK. E3 ligase Rad18 promotes monoubiquitination rather than ubiquitin chain formation by E2 enzyme Rad6. Proc Natl Acad Sci USA. 2011;108(14):5590–5.

    Article  CAS  PubMed  Google Scholar 

  6. Zou S, Yang J, Guo J, et al. RAD18 promotes the migration and invasion of esophageal squamous cell cancer via the JNK-MMPs pathway. Cancer Lett. 2018;417:65–74.

    Article  CAS  PubMed  Google Scholar 

  7. Suzuki M, Yokobori T, Gombodorj N, et al. High stromal transforming growth factor beta-induced expression is a novel marker of progression and poor prognosis in gastric cancer. J Surg Oncol. 2018;118(6):966–74.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang W, Qin Z, Zhang X, Xiao W. Roles of sequential ubiquitination of PCNA in DNA-damage tolerance. FEBS Lett. 2011;585(18):2786–94.

    Article  CAS  PubMed  Google Scholar 

  9. Hedglin M, Aitha M, Pedley A, Benkovic SJ. Replication protein A dynamically regulates monoubiquitination of proliferating cell nuclear antigen. J Biol Chem. 2019;294(13):5157–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Garg P, Burgers PM. Ubiquitinated proliferating cell nuclear antigen activates translesion DNA polymerases eta and REV1. Proc Natl Acad Sci USA. 2005;102(51):18361–6.

    Article  CAS  PubMed  Google Scholar 

  11. Nakamura T, Ishikawa S, Koga Y, et al. Mutation analysis of Rad18 in human cancer cell lines and non small cell lung cancer tissues. J Exp Clin Cancer Res. 2009;28:106.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Durando M, Tateishi S, Vaziri C. A non-catalytic role of DNA polymerase eta in recruiting Rad18 and promoting PCNA monoubiquitination at stalled replication forks. Nucleic Acids Res. 2013;41(5):3079–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shiomi N, Mori M, Tsuji H, et al. Human RAD18 is involved in S phase-specific single-strand break repair without PCNA monoubiquitination. Nucleic Acids Res. 2007;35(2):e9.

    Article  PubMed  Google Scholar 

  14. Watanabe K, Tateishi S, Kawasuji M, Tsurimoto T, Inoue H, Yamaizumi M. Rad18 guides poleta to replication stalling sites through physical interaction and PCNA monoubiquitination. EMBO J. 2004;23(19):3886–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu T, Chen H, Kim H, Huen MS, Chen J, Huang J. RAD18-BRCTx interaction is required for efficient repair of UV-induced DNA damage. DNA Repair (Amst). 2012;11(2):131–8.

    Article  CAS  Google Scholar 

  16. Yan X, Chen J, Meng Y, et al. RAD18 may function as a predictor of response to preoperative concurrent chemoradiotherapy in patients with locally advanced rectal cancer through caspase-9-caspase-3-dependent apoptotic pathway. Cancer Med. 2019;8(6):3094–104.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Lou P, Zou S, Shang Z, et al. RAD18 contributes to the migration and invasion of human cervical cancer cells via the interleukin1beta pathway. Mol Med Rep. 2019;20(4):3415–23.

    CAS  PubMed  Google Scholar 

  18. Wong RP, Aguissa-Toure AH, Wani AA, et al. Elevated expression of Rad18 regulates melanoma cell proliferation. Pigment Cell Melanoma Res. 2012;25(2):213–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

The authors express deep gratitude to the Rotary Club Foundation for financial assistance during the course of the study. This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS; Grant Numbers 17K19893, 18K07665, and 18H02877). This work was also supported in part by the Research Grant of the Princess Takamatsu Cancer Research Fund, Suzuken Memorial Foundation, and Pancreas Research Foundation of Japan.

Author information

Authors and Affiliations

  1. Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan

    Seded Baatar MD, Tuya Bai PhD, Takehiko Yokobori MD, PhD, Nobuhiro Nakazawa MD, Yasunari Ubukata MD, Akiharu Kimura MD, PhD, Norimichi Kogure MD, PhD, Akihiko Sano MD, PhD, Makoto Sohda MD, PhD, Makoto Sakai MD, PhD, Kyoichi Ogata MD, PhD, Hiroyuki Kuwano MD, PhD, Ken Shirabe MD, PhD & Hiroshi Saeki MD, PhD

  2. Research Program for Omics-Based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Japan

    Takehiko Yokobori MD, PhD & Navchaa Gombodorj MD, PhD

  3. Department of Radiation Oncology, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia

    Navchaa Gombodorj MD, PhD

  4. Department of Bioimaging and Information Analysis, Graduate School of Medicine, Gunma University, Maebashi, Japan

    Amartuvshin Tumenjargal MD

Authors
  1. Seded Baatar MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tuya Bai PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takehiko Yokobori MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Navchaa Gombodorj MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nobuhiro Nakazawa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasunari Ubukata MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akiharu Kimura MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Norimichi Kogure MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Akihiko Sano MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Makoto Sohda MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Makoto Sakai MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Amartuvshin Tumenjargal MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kyoichi Ogata MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hiroyuki Kuwano MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ken Shirabe MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hiroshi Saeki MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takehiko Yokobori MD, PhD.

Ethics declarations

Ethics Approval and Consent to Participate

This study conformed to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board for Clinical Research at Gunma University Hospital (Maebashi, Gunma, Japan; approval number HS2019-043). Patient consent was obtained using the opt-out method.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Figure 1

Overall survival curve of 631 GC samples from the online microarray database (www.kmplot.com) according to RAD18 mRNA expression. GC patients with high levels of RAD18 mRNA expression (n = 369) exhibited worse survival outcomes compared with GC patients with low levels of RAD18 mRNA expression (n = 262) (p = 0.0098). (TIFF 28950 kb)

Supplementary Figure 2

(a) Kaplan–Meier analysis of overall survival in our cohort of GC patients (n = 34). The analyses were based on RAD18 expression (p = 0.845). (B) Kaplan–Meier analyses of recurrence-free survival (n = 34) according to RAD18 expression (p = 0.884). The overall survival and recurrence-free survival rates were evaluated insignificant value in GC patients. (TIFF 28950 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baatar, S., Bai, T., Yokobori, T. et al. High RAD18 Expression is Associated with Disease Progression and Poor Prognosis in Patients with Gastric Cancer. Ann Surg Oncol 27, 4360–4368 (2020). https://doi.org/10.1245/s10434-020-08518-2

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-020-08518-2

Search

Navigation