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Background <p>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.</p> Methods <p>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.</p> Results <p>Compared with their parental cells, etoposide-resistant choriocarcinoma cells demonstrated significantly reduced proliferation (<i>p</i> &lt; 0.001), migration (<i>p</i> &lt; 0.05), and invasion (<i>p</i> &lt; 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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月31日

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  • Yuko Yasui,
  • Kosuke Yoshida,
  • Yuki Nishiko,
  • Hironori Suzuki,
  • Yusuke Yamamoto,
  • Kazumasa Mogi,
  • Masato Yoshihara,
  • Yukari Nagao,
  • Satoshi Tamauchi,
  • Akira Yokoi,
  • Nobuhisa Yoshikawa,
  • Kimihiro Nishino,
  • Eiko Yamamoto,
  • Kaoru Niimi,
  • Hiroaki Kajiyama

摘要

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.