High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer

Ryotaro Ohkuma; Erica Yada; Shumpei Ishikawa; Daisuke Komura; Hidenobu Ishizaki; Koji Tamada; Yutaro Kubota; Kazuyuki Hamada; Hiroo Ishida; Yuya Hirasawa; Hirotsugu Ariizumi; Etsuko Satoh; Midori Shida; Makoto Watanabe; Rie Onoue; Kiyohiro Ando; Junji Tsurutani; Kiyoshi Yoshimura; Takehiko Yokobori; Tetsuro Sasada; Takeshi Aoki; Masahiko Murakami; Tomoko Norose; Nobuyuki Ohike; Masafumi Takimoto; Masahiko Izumizaki; Shinichi Kobayashi; Takuya Tsunoda; Satoshi Wada

doi:10.1371/journal.pone.0226707

High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer

PLoS One. 2020 Jan 10;15(1):e0226707. doi: 10.1371/journal.pone.0226707. eCollection 2020.

Authors

Ryotaro Ohkuma^{1

2

3}, Erica Yada⁴, Shumpei Ishikawa⁵, Daisuke Komura⁵, Hidenobu Ishizaki⁶, Koji Tamada⁷, Yutaro Kubota², Kazuyuki Hamada², Hiroo Ishida², Yuya Hirasawa^{2

8}, Hirotsugu Ariizumi², Etsuko Satoh², Midori Shida^{1

9}, Makoto Watanabe^{1

9}, Rie Onoue^{1

9}, Kiyohiro Ando^{1

9}, Junji Tsurutani^{2

10}, Kiyoshi Yoshimura^{2

8

9}, Takehiko Yokobori¹¹, Tetsuro Sasada⁴, Takeshi Aoki¹², Masahiko Murakami¹², Tomoko Norose¹³, Nobuyuki Ohike¹³, Masafumi Takimoto¹³, Masahiko Izumizaki³, Shinichi Kobayashi⁹, Takuya Tsunoda², Satoshi Wada^{1

2

9}

Affiliations

¹ Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology & Therapeutics, Showa University, Tokyo, Japan.
² Department of Medicine, Division of Medical Oncology, School of Medicine, Showa University, Tokyo, Japan.
³ Department of Physiology, Graduate School of Medicine, Showa University, Tokyo, Japan.
⁴ Kanagawa Cancer Center Research Institute, Kanagawa, Japan.
⁵ Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁶ Noile-Immune Biotech, Inc., Tokyo, Japan.
⁷ Department of Immunology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan.
⁸ Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology & Therapeutics, Showa University, Tokyo, Japan.
⁹ Clinical Research Institute for Clinical Pharmacology & Therapeutics, Showa University, Tokyo, Japan.
¹⁰ Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan.
¹¹ Department of Innovative Immune-Oncology Therapeutics, Graduate School of Medicine, Gunma University, Gunma, Japan.
¹² Department of Surgery, Division of General and Gastroenterological Surgery, School of Medicine, Showa University, Tokyo, Japan.
¹³ Department of Pathology and Laboratory Medicine, School of Medicine, Showa University, Tokyo, Japan.

Abstract

Pancreatic cancer has an extremely poor prognosis, and identification of novel predictors of therapeutic efficacy and prognosis is urgently needed. Chemoresistance-related molecules are correlated with poor prognosis and may be effective targets for cancer treatment. Here, we aimed to identify novel molecules correlated with chemoresistance and poor prognosis in pancreatic cancer. We established 10 patient-derived xenograft (PDX) lines from patients with pancreatic cancer and performed next-generation sequencing (NGS) of tumor tissues from PDXs after treatment with standard drugs. We established a gene-transferred tumor cell line to express chemoresistance-related molecules and analyzed the chemoresistance of the established cell line against standard drugs. Finally, we performed immunohistochemical (IHC) analysis of chemoresistance-related molecules using 80 pancreatic cancer tissues. From NGS analysis, we identified olfactomedin-4 (OLFM4) as having high expression in the PDX group treated with anticancer drugs. In IHC analysis, OLFM4 expression was also high in PDXs administered anticancer drugs compared with that in untreated PDXs. Chemoresistance was observed by in vitro analysis of tumor cell lines with forced expression of OLFM4. In an assessment of tissue specimens from 80 patients with pancreatic cancer, Kaplan-Meier analysis showed that patients in the low OLFM4 expression group had a better survival rate than patients in the high OLFM4 expression group. Additionally, multivariate analysis showed that high expression of OLFM4 was an independent prognostic factor predicting poor outcomes. Overall, our study revealed that high expression of OLFM4 was involved in chemoresistance and was an independent prognostic factor in pancreatic cancer. OLFM4 may be a candidate therapeutic target in pancreatic cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Transformation, Neoplastic
Drug Resistance, Neoplasm / genetics*
Gene Expression Regulation, Neoplastic*
Granulocyte Colony-Stimulating Factor / genetics*
HeLa Cells
Humans
Kaplan-Meier Estimate
Mice
Pancreatic Neoplasms / diagnosis*
Pancreatic Neoplasms / genetics*
Prognosis

Substances

OLFM4 protein, human
Granulocyte Colony-Stimulating Factor

Grants and funding

This study was funded by Noile-Immune Biotech, Inc. All funding was performed as the collaborative research project and was only used to purchase the reagents and equipment needed for the experiment. The funder had no additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funder also provided support in the form of salaries to HI. The specific roles of these authors are articulated in the ‘author contributions’ section support in the form of salaries to HI. The specific roles of these authors are articulated in the ‘author contributions’ section.