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Inhibition of Clusterin Represses Proliferation by Inducing Cellular Senescence in Pancreatic Cancer

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

Abstract

Background

The outcome of pancreatic ductal adenocarcinoma (PDAC) is unsatisfactory, and the identification of novel therapeutic targets is urgently needed. Clinical studies on the antisense oligonucleotide that targets clusterin (CLU) expression have been conducted and have shown efficacy in other cancers. We aimed to investigate the effects of CLU in PDAC and the underlying mechanisms with a view to the clinical application of existing drugs.

Methods

We knocked down CLU in PDAC cells and evaluated changes in cell proliferation. To elucidate the mechanism responsible for these changes, we performed western blot analysis, cell cycle assay, and senescence-associated β-galactosidase (SA-β-gal) staining. To evaluate the clinical significance of CLU, immunohistochemistry was performed, and CLU expression was analyzed in specimens resected from PDAC patients not treated with preoperative chemotherapy.

Results

Knockdown of CLU significantly decreased cell proliferation and did not induce apoptosis, but did induce cellular senescence by increasing the percentage of G1-phase and SA-β-gal staining-positive cells. A marker of DNA damage such as γH2AX and factors related to cellular senescence, such as p21 and the senescence-associated secretory phenotype, were upregulated by knockdown of CLU. CLU expression in resected PDAC specimens was located in the cytoplasm of tumor cells and revealed significantly better recurrence-free survival and overall survival in the CLU-low group than in the CLU-high group.

Conclusions

We identified that CLU inhibition leads to cellular senescence in PDAC. Our findings suggest that CLU is a novel therapeutic target that contributes to the prognosis of PDAC by inducing cellular senescence.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    Suguru Mitsufuji MD, Yoshifumi Iwagami MD, PhD, Shogo Kobayashi MD, PhD, Kazuki Sasaki MD, PhD, Daisaku Yamada MD, PhD, Yoshito Tomimaru MD, PhD, Hirofumi Akita MD, PhD, Tadafumi Asaoka MD, PhD, Takehiro Noda MD, PhD, Kunihito Gotoh MD, PhD, Hidenori Takahashi MD, PhD, Masahiro Tanemura MD, PhD, Yuichiro Doki MD, PhD & Hidetoshi Eguchi MD, PhD

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  1. Suguru Mitsufuji MD
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  2. Yoshifumi Iwagami MD, PhD
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Correspondence to Shogo Kobayashi MD, PhD.

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Mitsufuji, S., Iwagami, Y., Kobayashi, S. et al. Inhibition of Clusterin Represses Proliferation by Inducing Cellular Senescence in Pancreatic Cancer. Ann Surg Oncol 29, 4937–4946 (2022). https://doi.org/10.1245/s10434-022-11668-0

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