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Rubicon can predict prognosis in patients with pancreatic ductal adenocarcinoma after neoadjuvant chemoradiotherapy

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Abstract

Background

Despite previous therapeutic studies on autophagy in cancer, its role in the treatment of pancreatic ductal adenocarcinoma remains controversial, especially regarding its effect on chemotherapy, radiotherapy, and both combined. We focused on RUN domain Beclin-1 interacting and cysteine-rich-containing protein (Rubicon) to reveal its contribution to pancreatic ductal adenocarcinoma after chemoradiotherapy.

Methods

To evaluate the clinical significance of Rubicon, immunohistochemistry was performed, and Rubicon expression was analyzed across 81 specimens resected from patients with pancreatic ductal adenocarcinoma after neoadjuvant chemoradiotherapy. A gemcitabine-resistant pancreatic ductal adenocarcinoma cell line was established followed by Rubicon expression and autophagy flux estimation. Finally, gemcitabine sensitivity, invasion ability, and cell viability were evaluated using Rubicon-targeting small interfering RNA.

Results

Rubicon expression in resected pancreatic ductal adenocarcinoma samples after chemoradiotherapy revealed significantly worse overall survival and recurrence-free survival in the Rubicon-high expression group than in the Rubicon-low expression group (overall survival: median [years] 2.02 vs. 3.21, p = 0.0359; recurrence-free survival: median [years] 0.90 vs. 1.90, p = 0.0146). In vitro, gemcitabine-resistant pancreatic ductal adenocarcinoma cell lines exhibited higher Rubicon expression and lower autophagy flux than the parental cell line (p < 0.01). Transduction with small interfering RNA downregulated the expression without affecting gemcitabine sensitivity, but it reduced invasion ability and cell viability (p < 0.01) in the gemcitabine-resistant pancreatic ductal adenocarcinoma cell line.

Conclusions

High Rubicon expression is a significant, unfavorable prognostic factor in pancreatic ductal adenocarcinoma after neoadjuvant chemoradiotherapy. Downregulation of Rubicon expression improves invasion ability and cell viability in gemcitabine-resistant pancreatic ductal adenocarcinoma.

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Data availability

The data that support the fndings of this study are available on request from the corresponding author, Shogo Kobayashi.

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Acknowledgements

The authors would like to thank Editage (www.editage.com) for English language editing.

Funding

The authors received no specific funding for this work.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Osaka, Suita, 565-0871, Japan

    Daiki Marukawa, Shogo Kobayashi, Kazuki Sasaki, Yoshifumi Iwagami, Daisaku Yamada, Yoshito Tomimaru, Takehiro Noda, Hidenori Takahashi, Yuichiro Doki & Hidetoshi Eguchi

  2. Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan

    Kunihito Gotoh

  3. Department of Gastroenterological Surgery, Osaka International Center Institute, Osaka, Japan

    Hirofumi Akita

  4. Department of Gastroenterological Surgery, Osaka Police Hospital, Osaka, Japan

    Tadafumi Asaoka

  5. Department of Gastroenterological Surgery, Rinku General Medical Center, Izumisano, Japan

    Masahiro Tanemura

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  1. Daiki Marukawa
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  14. Hidetoshi Eguchi
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Contributions

DM, KG, SK, and HE designed the study. DM, KG, SK, KS, YI, DY, YT, HA, TA, TN, HT, MT, YD, and HE drafted the manuscript.

Corresponding author

Correspondence to Shogo Kobayashi.

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Supplementary Information

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10147_2023_2306_MOESM1_ESM.tif

Supplementary file1 Growth inhibition assay of parent MIAPaCa-2 cells treated with gemcitabine with the IC70 value at 5 ng/mL (TIF 1378 KB)

10147_2023_2306_MOESM2_ESM.tif

Supplementary file2 Kaplan–Meier analysis of PDAC patients without neoadjuvant chemoradiotherapy, grouped according to Rubicon expression levels. There were no significant differences in OS or RFS between the two groups (TIF 1473 KB)

Supplementary file3 (DOCX 29 KB)

Supplementary file4 (DOCX 27 KB)

Supplementary file5 (DOCX 25 KB)

Supplementary file6 (DOCX 27 KB)

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Marukawa, D., Gotoh, K., Kobayashi, S. et al. Rubicon can predict prognosis in patients with pancreatic ductal adenocarcinoma after neoadjuvant chemoradiotherapy. Int J Clin Oncol 28, 576–586 (2023). https://doi.org/10.1007/s10147-023-02306-0

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  • DOI: https://doi.org/10.1007/s10147-023-02306-0

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