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Peer-reviewedCC BY-NC-ND 4.0BMC Cancer

Characterization of etoposide-resistant choriocarcinoma cells and contribution of MAPK7 to etoposide resistance

  • Yuko Yasui1,2
  • Kosuke Yoshida1,3
  • Yuki Nishiko1,2
  • Hironori Suzuki1,4
  • Yusuke Yamamoto4
  • Kazumasa Mogi1,5
  • Masato Yoshihara1
  • Yukari Nagao1
  • Satoshi Tamauchi1
  • Akira Yokoi1,3
  • Nobuhisa Yoshikawa1
  • Kimihiro Nishino6
3 more authors
  • Eiko Yamamoto6
  • Kaoru Niimi1
  • Hiroaki Kajiyama1
6 affiliations
  1. 1Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Tsuruma-Cho 65, Showa-Ku, Nagoya, 466-8550 Japan
  2. 2Department of Obstetrics and Gynecology, Aichi Medical University School of Medicine, Nagakute, Japan
  3. 3Institute for Advanced Research, Nagoya University, Nagoya, Japan
  4. 4Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan
  5. 5Department of Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan
  6. 6Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Abstract

Background: Gestational choriocarcinoma is an aggressive gynecologic malignancy that can occur with various pregnancy events. Although typically highly sensitive to combination chemotherapy, this malignancy, in a subset of patients, develops resistance to etoposide-containing regimens, leading to therapeutic failure. We aimed to elucidate the molecular mechanisms that confer resistance to etoposide, a central component of choriocarcinoma chemotherapy.

Methods: Etoposide-resistant JAR and JEG-3 choriocarcinoma cell lines were established by continuous stepwise exposure of parental cells to increasing concentrations of etoposide. Phenotypic comparisons with the parental cells were then performed. RNA sequencing and upstream regulator analyses were conducted to identify key regulatory molecules and signaling pathways associated with etoposide resistance. Candidate molecules were further evaluated by siRNA-mediated knockdown to assess their effects on etoposide sensitivity.

Results: Compared with their parental cells, etoposide-resistant choriocarcinoma cells demonstrated significantly reduced proliferation (p < 0.001), migration (p < 0.05), and invasion (p < 0.01). RNA sequencing and pathway analyses revealed suppression of pathways related to cell cycle progression and DNA replication. In addition, upstream regulator analysis focusing on kinases suggested the involvement of MAPK-related molecules, including MAPK9, MAP2K5, and MAPK7. siRNA-mediated suppression of MAPK7 in resistant cells restored sensitivity to etoposide, suggesting a role for MAPK7 in the maintenance of etoposide resistance.

Conclusion: Our findings indicate that the MAPK signaling pathway, particularly MAPK7, contributes to etoposide resistance in choriocarcinoma, based on RNA sequencing and functional analyses of resistant cell models.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12885-026-16640-9.

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Cite

BibTeXRIS
BibTeX
@article{yasui2026characterization,
  title = {{Characterization of etoposide-resistant choriocarcinoma cells and contribution of MAPK7 to etoposide resistance}},
  author = {Yuko Yasui and Kosuke Yoshida and Yuki Nishiko and Hironori Suzuki and Yusuke Yamamoto and Kazumasa Mogi and Masato Yoshihara and Yukari Nagao and Satoshi Tamauchi and Akira Yokoi and Nobuhisa Yoshikawa and Kimihiro Nishino and Eiko Yamamoto and Kaoru Niimi and Hiroaki Kajiyama},
  journal = {BMC Cancer},
  year = {2026},
  month = jul,
  doi = {10.1186/s12885-026-16640-9},
  url = {https://doi.org/10.1186/s12885-026-16640-9},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Characterization of etoposide-resistant choriocarcinoma cells and contribution of MAPK7 to etoposide resistance
AU  - Yuko Yasui
AU  - Kosuke Yoshida
AU  - Yuki Nishiko
AU  - Hironori Suzuki
AU  - Yusuke Yamamoto
AU  - Kazumasa Mogi
AU  - Masato Yoshihara
AU  - Yukari Nagao
AU  - Satoshi Tamauchi
AU  - Akira Yokoi
AU  - Nobuhisa Yoshikawa
AU  - Kimihiro Nishino
AU  - Eiko Yamamoto
AU  - Kaoru Niimi
AU  - Hiroaki Kajiyama
PY  - 2026
DA  - 2026/07/31
JO  - BMC Cancer
DO  - 10.1186/s12885-026-16640-9
UR  - https://doi.org/10.1186/s12885-026-16640-9
AB  - Background: Gestational choriocarcinoma is an aggressive gynecologic malignancy that can occur with various pregnancy events. Although typically highly sensitive to combination chemotherapy, this malignancy, in a subset of patients, develops resistance to etoposide-containing regimens, leading to therapeutic failure. We aimed to elucidate the molecular mechanisms that confer resistance to etoposide, a central component of choriocarcinoma chemotherapy.  Methods: Etoposide-resistant JAR and JEG-3 choriocarcinoma cell lines were established by continuous stepwise exposure of parental cells to increasing concentrations of etoposide. Phenotypic comparisons with the parental cells were then performed. RNA sequencing and upstream regulator analyses were conducted to identify key regulatory molecules and signaling pathways associated with etoposide resistance. Candidate molecules were further evaluated by siRNA-mediated knockdown to assess their effects on etoposide sensitivity.  Results: Compared with their parental cells, etoposide-resistant choriocarcinoma cells demonstrated significantly reduced proliferation (p < 0.001), migration (p < 0.05), and invasion (p < 0.01). RNA sequencing and pathway analyses revealed suppression of pathways related to cell cycle progression and DNA replication. In addition, upstream regulator analysis focusing on kinases suggested the involvement of MAPK-related molecules, including MAPK9, MAP2K5, and MAPK7. siRNA-mediated suppression of MAPK7 in resistant cells restored sensitivity to etoposide, suggesting a role for MAPK7 in the maintenance of etoposide resistance.  Conclusion: Our findings indicate that the MAPK signaling pathway, particularly MAPK7, contributes to etoposide resistance in choriocarcinoma, based on RNA sequencing and functional analyses of resistant cell models.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12885-026-16640-9.
SN  - 1471-2407
ER  -