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High Expression of Bloom Syndrome Helicase is a Key Factor for Poor Prognosis and Advanced Malignancy in Patients with Pancreatic Cancer: A Retrospective Study

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

Abstract

Background

Bloom syndrome helicase (BLM) is overexpressed in multiple types of cancers and its overexpression may induce genomic instability. This study aimed to determine the function of BLM expression in pancreatic cancer.

Methods

BLM messenger RNA (mRNA) expression was analyzed using public datasets to determine its relationship with pancreatic cancer prognosis. Overall, 182 patients with pancreatic cancer who underwent radical resection at our institution were enrolled. BLM expression was evaluated by immunohistochemistry (IHC). We explored the effect of BLM on the proliferation, invasion, migration, and chemoresistance of pancreatic cancer cells via small-interfering RNAs and performed pathway analysis using gene set enrichment analysis.

Results

BLM mRNA expression was higher in tumor tissue than in normal tissue and had a prognostic effect on overall survival (OS) and recurrence-free survival. The same results were validated by IHC. Multivariate analysis showed that high BLM expression was an independent poor prognostic factor for OS (hazard ratio [HR] 1.678, p = 0.029). In subgroup analysis, the effect of high BLM expression was more significant on OS in patients with younger age (HR 2.27, p = 0.006), male sex (HR 2.39, p = 0.002), high cancer antigen 19-9 level (HR 2.44, p = 0.001), advanced tumor stage (HR 2.25, p = 0.001), lymph node metastasis (HR 2.51, p = 0.001), nerve invasion (HR 2.07, p = 0.002), and adjuvant chemotherapy (HR 2.66, p < 0.001). In vitro, BLM suppression resulted in reduced tumor proliferation, invasion, migration, and chemoresistance. Mechanistically, BLM expression may be associated with E2F1 and E2F2.

Conclusion

BLM expression is a prognostic factor for patients with pancreatic cancer, especially in those with advanced malignancies and receiving chemotherapy.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.

    Article  Google Scholar 

  2. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359-386.

    Article  CAS  Google Scholar 

  3. Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7(4):e1000267.

    Article  Google Scholar 

  4. Winter JM, Brennan MF, Tang LH, et al. Survival after resection of pancreatic adenocarcinoma: results from a single institution over three decades. Ann Surg Oncol. 2012;19(1):169–75.

    Article  Google Scholar 

  5. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310(14):1473–81.

    Article  CAS  Google Scholar 

  6. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  Google Scholar 

  7. Sharma S, Doherty KM, Brosh RM Jr. Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability. Biochem J. 2006;398(3):319–37.

    Article  CAS  Google Scholar 

  8. Brosh RM Jr. DNA helicases involved in DNA repair and their roles in cancer. Nat Rev Cancer. 2013;13(8):542–58.

    Article  CAS  Google Scholar 

  9. Croteau DL, Popuri V, Opresko PL, Bohr VA. Human RecQ helicases in DNA repair, recombination, and replication. Annu Rev Biochem. 2014;83:519–52.

    Article  CAS  Google Scholar 

  10. Cheok CF, Bachrati CZ, Chan KL, Ralf C, Wu L, Hickson ID. Roles of the Bloom’s syndrome helicase in the maintenance of genome stability. Biochem Soc Trans. 2005;33(Pt 6):1456–9.

    Article  CAS  Google Scholar 

  11. Kaur E, Agrawal R, Sengupta S. Functions of BLM helicase in cells: is it acting like a double-edged sword? Front Genet. 2021;12:634789.

    Article  CAS  Google Scholar 

  12. Ledet EM, Antonarakis ES, Isaacs WB, Lotan TL, Pritchard C, Sartor AO. Germline BLM mutations and metastatic prostate cancer. Prostate. 2020;80(2):235–7.

    Article  CAS  Google Scholar 

  13. Ruan Y, Xu H, Ji X, Zhao J. BLM interaction with EZH2 regulates MDM2 expression and is a poor prognostic biomarker for prostate cancer. Am J Cancer Res. 2021;11(4):1347–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Alzahrani FA, Ahmed F, Sharma M, et al. Investigating the pathogenic SNPs in BLM helicase and their biological consequences by computational approach. Sci Rep. 2020;10(1):12377.

    Article  CAS  Google Scholar 

  15. Votino C, Laudanna C, Parcesepe P, et al. Aberrant BLM cytoplasmic expression associates with DNA damage stress and hypersensitivity to DNA-damaging agents in colorectal cancer. J Gastroenterol. 2017;52(3):327–40.

    Article  CAS  Google Scholar 

  16. Arora A, Abdel-Fatah TM, Agarwal D, et al. Transcriptomic and protein expression analysis reveals clinicopathological significance of bloom syndrome helicase (BLM) in breast cancer. Mol Cancer Ther. 2015;14(4):1057–65.

    Article  CAS  Google Scholar 

  17. Mills CC, Kolb EA, Sampson VB. Development of chemotherapy with cell-cycle inhibitors for adult and pediatric cancer therapy. Cancer Res. 2018;78(2):320–5.

    Article  CAS  Google Scholar 

  18. Slupianek A, Gurdek E, Koptyra M, et al. BLM helicase is activated in BCR/ABL leukemia cells to modulate responses to cisplatin. Oncogene. 2005;24(24):3914–22.

    Article  CAS  Google Scholar 

  19. Nakagawa S, Okabe H, Sakamoto Y, et al. Enhancer of zeste homolog 2 (EZH2) promotes progression of cholangiocarcinoma cells by regulating cell cycle and apoptosis. Ann Surg Oncol. 2013;20(Suppl 3):S667-675.

    Article  Google Scholar 

  20. Okabe H, Beppu T, Ueda M, et al. Identification of CXCL5/ENA-78 as a factor involved in the interaction between cholangiocarcinoma cells and cancer-associated fibroblasts. Int J Cancer. 2012;131(10):2234–41.

    Article  CAS  Google Scholar 

  21. Nakao Y, Nakagawa S, Yamashita YI, et al. High ARHGEF2 (GEF-H1) expression is associated with poor prognosis via cell cycle regulation in patients with pancreatic cancer. Ann Surg Oncol. 2021;28(8):4733–43.

    Article  Google Scholar 

  22. Du X, Zhang C, Yin C, et al. High BLM expression predicts poor clinical outcome and contributes to malignant progression in human cholangiocarcinoma. Front Oncol. 2021;11:633899.

    Article  Google Scholar 

  23. Morkel M, Wenkel J, Bannister AJ, Kouzarides T, Hagemeier C. An E2F-like repressor of transcription. Nature. 1997;390(6660):567–8.

    Article  CAS  Google Scholar 

  24. Attwooll C, Lazzerini Denchi E, Helin K. The E2F family: specific functions and overlapping interests. EMBO J. 2004;23(24):4709–16.

    Article  CAS  Google Scholar 

  25. Ren B, Cam H, Takahashi Y, et al. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev. 2002;16(2):245–56.

    Article  CAS  Google Scholar 

  26. Xie L, Li T, Yang LH. E2F2 induces MCM4, CCNE2 and WHSC1 upregulation in ovarian cancer and predicts poor overall survival. Eur Rev Med Pharmacol Sci. 2017;21(9):2150–6.

    CAS  PubMed  Google Scholar 

  27. Liang B, Zhao J, Wang X. Clinical performance of E2Fs 1–3 in kidney clear cell renal cancer, evidence from bioinformatics analysis. Genes Cancer. 2017;8(5–6):600–7.

    Article  CAS  Google Scholar 

  28. Sun CC, Li SJ, Hu W, et al. Comprehensive analysis of the expression and prognosis for E2Fs in human breast cancer. Mol Ther. 2019;27(6):1153–65.

    Article  CAS  Google Scholar 

  29. Zhan L, Huang C, Meng XM, et al. Promising roles of mammalian E2Fs in hepatocellular carcinoma. Cell Signal. 2014;26(5):1075–81.

    Article  CAS  Google Scholar 

  30. Ma L, Tian X, Wang F, et al. The long noncoding RNA H19 promotes cell proliferation via E2F–1 in pancreatic ductal adenocarcinoma. Cancer Biol Ther. 2016;17(10):1051–61.

    Article  CAS  Google Scholar 

  31. Schild C, Wirth M, Reichert M, Schmid RM, Saur D, Schneider G. PI3K signaling maintains c-myc expression to regulate transcription of E2F1 in pancreatic cancer cells. Mol Carcinog. 2009;48(12):1149–58.

    Article  CAS  Google Scholar 

  32. Yamazaki K, Yajima T, Nagao T, et al. Expression of transcription factor E2F–1 in pancreatic ductal carcinoma: an immunohistochemical study. Pathol Res Pract. 2003;199(1):23–8.

    Article  Google Scholar 

  33. Yao Z, Chen Q, Ni Z, et al. Long non-coding RNA differentiation antagonizing nonprotein coding RNA (DANCR) promotes proliferation and invasion of pancreatic cancer by sponging miR-214-5p to regulate E2F2 expression. Med Sci Monit. 2019;25:4544–52.

    Article  CAS  Google Scholar 

  34. Sun FB, Lin Y, Li SJ, Gao J, Han B, Zhang CS. MiR-210 knockdown promotes the development of pancreatic cancer via upregulating E2F3 expression. Eur Rev Med Pharmacol Sci. 2018;22(24):8640–8.

    PubMed  Google Scholar 

  35. Lin C, Hu Z, Yuan G, et al. MicroRNA-1179 inhibits the proliferation, migration and invasion of human pancreatic cancer cells by targeting E2F5. Chem Biol Interact. 2018;291:65–71.

    Article  CAS  Google Scholar 

  36. Cam H, Balciunaite E, Blais A, et al. A common set of gene regulatory networks links metabolism and growth inhibition. Mol Cell. 2004;16(3):399–411.

    Article  CAS  Google Scholar 

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Acknowledgment

The authors would like to acknowledge TCGA, GEO, Kaplan–Meier Plotter, GSEA, and GEPIA2 databases, which were used free of charge. They would also like to thank Editage (www.editage.cn) for English language editing, and Yoko Ogata, Noriko Yasuda, and Lingfeng Fu for their technical assistance.

Funding

This work was supported by the Youth Project of the University-level Scientific Research Development Fund of North Sichuan Medical College (grant no. XJ2021007001).

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan

    Chuan Lan MD, PhD, Yo-ichi Yamashita MD, PhD, Hiromitsu Hayashi MD, PhD, Shigeki Nakagawa MD, PhD, Katsunori Imai MD, PhD, Kosuke Mima MD, PhD, Takayoshi Kaida MD, PhD, Takashi Matsumoto MD, Masataka Maruno MD, Zhao Liu MD, Xiyu Wu MD, Feng Wei MD & Hideo Baba MD, PhD

  2. Department of Hepatobiliary Surgery and Center of Severe Acute Pancreatitis, The Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of China

    Chuan Lan MD, PhD

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  1. Chuan Lan MD, PhD
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Correspondence to Hideo Baba MD, PhD.

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Chuan Lan, Yo-ichi Yamashita, Hiromitsu Hayashi, Shigeki Nakagawa, Katsunori Imai, Kosuke Mima, Takayoshi Kaida, Takashi Matsumoto, Masataka Maruno, Zhao Liu, Xiyu Wu, Feng Wei, and Hideo Baba have declared no conflicts of interest.

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Lan, C., Yamashita, Yi., Hayashi, H. et al. High Expression of Bloom Syndrome Helicase is a Key Factor for Poor Prognosis and Advanced Malignancy in Patients with Pancreatic Cancer: A Retrospective Study. Ann Surg Oncol 29, 3551–3564 (2022). https://doi.org/10.1245/s10434-022-11500-9

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