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EV013/#470  VRK1 as a promising therapeutic target in small cell neuroendocrine carcinoma of the uterine cervix through mitochondrial dysfunction
  1. Mariya Kobayashi1,
  2. Satoshi Nakagawa1,
  3. Mizuki Kanda2,
  4. Yuji Kamei3,
  5. Tatsuo Masuda1,
  6. Mamoru Kakuda1,
  7. Kosuke Hiramatsu1,
  8. Tadashi Iwamiya1,
  9. Shinya Matsuzaki1 and
  10. Yutaka Ueda1
  1. 1The University of Osaka, Department of Obstetrics and Gynecology, Suita-shi, Osaka, Japan
  2. 2Sakai City Medical Center, Department of Obstetrics and Gynecology, Sakai-shi, Japan
  3. 3Higashiosaka City Medical Center, Department of Obstetrics and Gynecology, Higashi-Osaka-shi, Japan

Abstract

Introduction Our previous proteomic analysis identified higher expression of Vaccinia-related kinase 1 (VRK1) in small cell neuroendocrine carcinoma of the uterine cervix (SCNEC) compared to other cervical cancers. VRK1 is expected a potential synthetic-lethal drug target in VRK2-low/null cancers. This study aimed to investigate the potential of VRK1 as a therapeutic target for SCNEC and to elucidate its mechanisms.

Methods The mRNA and/or protein expression levels of VRK1 and VRK2 in SCNEC were compared to those in other histological cervical cancer using clinical samples, cancer tissue-originated organoids, and cell lines. The effect of VRK1 on tumor growth in 2D and 3D cell cultures and in subcutaneous mouse models was evaluated using shRNA-mediated knockdown of VRK1. Gene Set Enrichment Analysis (GSEA) was performed using RNA-seq data from subcutaneous mouse tumors, and the results were validated in 2D cell cultures using hydrogen peroxide (H2O2).

Results VRK1 expression was higher and VRK2 expression was lower in SCNEC compared to other histological types. VRK1-knockdown significantly suppressed tumor growth in 3D cell cultures and in subcutaneous mouse models, although its effects were limited in 2D cell cultures. GSEA suggested suppression of the mitochondrial pathway in VRK1-knockdown and a relationship between VRK1 and responses to external stimuli. In 2D cell cultures, as the concentration of H2O2 increased, the resistance to H2O2 decreased more significantly in VRK1-knockdown compared to the control. Furthermore, VRK1-knockdown suppressed mitochondrial activity in response to H2O2.

Conclusion/Implications VRK1-knockdown significantly suppressed SCNEC tumor growth through mitochondrial dysfunction, suggesting that VRK1 is a promising therapeutic target in SCNEC.

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