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Induction of Kallikrein-Related Peptidase 13 and TET2/3 by Anticancer Drugs and Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma After Preoperative Treatment

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

Abstract

Background

Preoperative chemotherapy/chemoradiotherapy has been generally considered for the treatment of esophageal squamous cell carcinoma (ESCC) to improve prognosis. We examined the effects of anticancer drugs on the expression of kallikrein-related peptidase 13 (KLK13), a potential ESCC prognostic marker, and its clinical relevance in patients who received chemotherapy/chemoradiotherapy for ESCC.

Methods

Overall, 105 patients with ESCC who received chemotherapy or chemoradiotherapy before esophagectomy were enrolled. The expression of KLK13 in biopsy samples obtained before chemotherapy/chemoradiotherapy and resected ESCC tumors was assessed by immunohistochemical staining. The effects of 5-fluorouracil (5-FU) and/or cisplatin (CDDP) exposure on the expressions of KLK13 and ten-eleven translocation dioxygenases (TET) in ESCC cells were examined by reverse transcription-polymerase chain reaction.

Results

Immunohistochemical staining of paired ESCC specimens before (biopsy samples) and after (resected specimens) chemotherapy/chemoradiotherapy demonstrated a change in KLK13 expression. KLK13 and TET2/3 transcriptions were induced when human ESCC cell lines were treated with 5-FU and/or CDDP. Among patients with KLK13-negative status before chemotherapy/chemoradiotherapy, those with KLK13-positive resected tumors had a significantly poorer prognosis than those with KLK13-negative resected tumors (p = 0.0477). By using tumor cells isolated from ESCC biopsy tissues obtained before chemotherapy/chemoradiotherapy, we established a primary culture system and detected the induction of KLK13 expression by anticancer drugs.

Conclusions

Preoperative treatments alter KLK13 expression in ESCC. The conversion of KLK13 expression from a negative status in biopsy samples to a positive status in resected tumor samples is a predictor of poor prognosis. KLK13 status is a potential marker for decision making to avoid harmful chemotherapy/chemoradiotherapy in patients with ESCC.

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Acknowledgment

The authors thank Drs. Miwa Tamura-Nakano and Chinatsu Oyama in the NCGM EM Support Unit for their technical support for histological analysis. They would also like to thank Enago for the English language review, and Ms. Yasuko Nozaki for her technical assistance. This work was supported by JSPS KAKENHI Grant Numbers JP15K10124, JP19K08457, and by grants from the National Center for Global Health and Medicine (26-117, 29-1019, 20A1017 and 20A3002).

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Author notes

  1. Masayoshi Terayama MD, PhD

    Present address: Department of Gastroenterological Surgery, Gastroenterological Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

Authors and Affiliations

  1. Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan

    Akira Shimomura MD & Chizu Yokoi MD, PhD

  2. Department of General Internal Medicine, National Center for Global Health and Medicine, Tokyo, Japan

    Akira Shimomura MD

  3. Clinical Research Advancement Section, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan

    Akira Shimomura MD, Teruki Hagiwara MS, Masayoshi Terayama MD, PhD & Yuki I. Kawamura PhD

  4. Course of Advanced and Specialized Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Akira Shimomura MD & Kazuhiko Yamada MD, PhD, FACS

  5. Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan

    Kazuhiko Yamada MD, PhD, FACS, Masayoshi Terayama MD, PhD & Kyoko Nohara MD, PhD

  6. Pathology Division of Clinical Laboratory, National Center for Global Health and Medicine, Tokyo, Japan

    Toru Igari MD

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  1. Akira Shimomura MD
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Corresponding author

Correspondence to Yuki I. Kawamura PhD.

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Disclosures

Akira Shimomura, Teruki Hagiwara, Kazuhiko Yamada, Chizu Yokoi, Masayoshi Terayama, Kyoko Nohara, Toru Igari, and Yuki I. Kawamura have no financial or other relations that could lead to a commercial interest.

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Shimomura, A., Hagiwara, T., Yamada, K. et al. Induction of Kallikrein-Related Peptidase 13 and TET2/3 by Anticancer Drugs and Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma After Preoperative Treatment. Ann Surg Oncol 31, 251–261 (2024). https://doi.org/10.1245/s10434-023-14364-9

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  • DOI: https://doi.org/10.1245/s10434-023-14364-9

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