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High RRN3 expression is associated with malignant characteristics and poor prognosis in pancreatic cancer

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Abstract

Background

Pancreatic cancer has an extremely poor prognosis and is one of the most chemoresistant cancers. Targeting cancer cell transcriptional complexes may enhance chemotherapy effectiveness. RNA-polymerase I (Pol-I)-mediated transcription is an essential initial step for ribosome biogenesis and is related to cancer cell proliferation. RRN3 is a Pol-I-specific transcription initiation factor. In this study, we aimed to elucidate the function and clinical significance of RRN3 in pancreatic cancer.

Methods

We performed immunohistochemical staining to detect RRN3 protein expression in 96 pancreatic cancer tissues and analyzed the relationship between RRN3 protein expression, clinicopathological factors, and cancer patient prognosis. Moreover, we evaluated RRN3 function in vitro and in vivo using proliferation, invasion, and chemosensitivity assays in PANC-1 and SW1990 cell lines, with/without depleting RRN3 expression.

Results

RRN3 was mainly expressed in cancer cell nuclei. High levels of RRN3 expression were associated with Ki-67 expression and shorter overall survival. Additionally, proliferation and invasion ability were decreased when RRN3 was silenced with siRNA, compared to non-targeting siRNA-transfected cells. Chemosensitivity analysis showed that inhibition of RRN3 enhanced the sensitivity of pancreatic cancer cell lines to gemcitabine and paclitaxel. RRN3 siRNA-transfected PANC-1 tumors showed significantly reduced tumor volumes and high gemcitabine sensitivity compared to the control in a mouse xenograft model.

Conclusion

High levels of RRN3 expression are associated with poor prognosis and cancer malignancy, such as proliferation, invasion ability, and chemosensitivity in pancreatic cancer. RRN3 targeting with anticancer drugs may be a promising therapeutic strategy to overcome refractory pancreatic cancer.

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Availability of data and materials

The whole data presented in this study are available on request to the corresponding author.

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Acknowledgements

We would like to thank Ms. Yukiko Suto for her excellent assistance and Editage (www.editage.com) for English language editing.

Funding

None.

Author information

Authors and Affiliations

  1. Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi, Gunma, 371-8511, Japan

    Chingunjav Batbayar, Norihiro Ishii, Norifumi Harimoto, Dolgormaa Gantumur, Ryo Muranushi, Kouki Hoshino, Takahiro Yamanaka, Kei Hagiwara, Mariko Tsukagoshi, Akira Watanabe, Kenichiro Araki & Ken Shirabe

  2. Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Japan

    Takehiko Yokobori, Navchaa Gombodorj & Bilguun Erkhem-Ochir

  3. Division of Gastroenterological Surgery, Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan

    Hideyuki Saito

  4. Department of Surgery and Laparoscopic Surgery, Gunma Prefecture Saiseikai Maebashi Hospital, Maebashi, Japan

    Yasuo Hosouchi

Authors
  1. Chingunjav Batbayar
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  2. Norihiro Ishii
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  3. Norifumi Harimoto
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  4. Takehiko Yokobori
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  6. Dolgormaa Gantumur
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Contributions

NI, TY, and CB: processed the experimental data, performed the analysis, drafted the manuscript, and designed the figures. NI, TY, NH, and KS: planned and supervised the work. NI, TY, and KS: contributed to interpreting the results and revising the draft manuscript. NI, TY, and CB: performed all experiments and data analysis in the revision process. All authors discussed the results and commented on the manuscript. All authors have read and agreed to the published version of manuscript.

Corresponding author

Correspondence to Norihiro Ishii.

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Conflict of interest

The authors declare that there are no competing interests.

Ethics approval and consent to participate

All clinical samples and patient data were analyzed following our institutional guidelines and the Declaration of Helsinki (approved number: HS2020-124). The patients’ approval for this retrospective observational research was obtained using an opt-out approach.

Patient consent for publication

The patients’ approval for this retrospective observational research and publication was obtained using an opt-out approach.

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Supplementary Information

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Supplementary file1 (DOCX 15 KB)

10147_2023_2342_MOESM2_ESM.tif

Supplementary file2 Supplementary Figure 1. Overall survival curve according to RRN3 expression in 178 pancreatic cancer samples from the transcriptomic data in the TCGA dataset. Pancreatic cancer patients with high levels of RRN3 expression (n = 89) showed lower survival rate than those with low levels of RRN3 (n = 89) (log-rank test, P = 0.023). (TIF 791 KB)

10147_2023_2342_MOESM3_ESM.tif

Supplementary file3 Supplementary Figure 2. Post-recurrence survival curve in the patients who recieved chemotherapy after recurrence. Patients with high RRN3 expression (n = 32) showed lower post-recurrence survival rate than those with low RRN3 expression (n = 23) (log-rank test, P = 0.025). (TIF 645 KB)

10147_2023_2342_MOESM4_ESM.tif

Supplementary file4 Supplementary Figure 3. RRN3 expression profiles in 55 tissue types and 69 cell lines from different tissue types. These figures were generated by combining the HPA and GTEx transcriptomics datasets using the internal normalization pipeline from The Human Protein Atlas website (https://www.proteinatlas.org). The expression of RRN3 was ubiquitously detected in whole tissues and cell lines, indicating the low tissue specificity of RRN3 expression profiles. (TIF 2007 KB)

10147_2023_2342_MOESM5_ESM.tif

Supplementary file5 Supplementary Figure 4. Relationship between RRN3 and MYC expression in 178 pancreatic cancer samples from the transcriptomic data in the TCGA dataset. The expression of RRN3 was positively correlated with that of MYC. (TIF 1002 KB)

10147_2023_2342_MOESM6_ESM.tif

Supplementary file6 Supplementary Figure 5. Relationship between RRN3, LKB1, and MTOR expression in 178 pancreatic cancer samples from the transcriptomic data in the TCGA dataset. Left panel: Expression of LKB1 was inversely correlated with that of MTOR. Middle panel: Expression of RRN3 was inversely correlated with that of LKB1. Right panel: Expression of RRN3 was positively correlated with that of MTOR. (TIF 1648 KB)

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Batbayar, C., Ishii, N., Harimoto, N. et al. High RRN3 expression is associated with malignant characteristics and poor prognosis in pancreatic cancer. Int J Clin Oncol 28, 901–912 (2023). https://doi.org/10.1007/s10147-023-02342-w

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  • DOI: https://doi.org/10.1007/s10147-023-02342-w

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