VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix

Kobayashi, Mariya; Nakagawa, Satoshi; Ishii, Yusuke; Kamei, Yuji; Kanda, Mizuki; Masuda, Tatsuo; Kakuda, Mamoru; Hiramatsu, Kosuke; Iwamiya, Tadashi; Egawa-Takata, Tomomi; Matsuzaki, Shinya; Uematsu, Hiroyuki; Onuma, Kunishige; Inoue, Masahiro; Ueda, Yutaka; Kimura, Tadashi; Kodama, Michiko

doi:https://doi.org/10.1111/cas.70211

VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix

Kobayashi, Mariya; Nakagawa, Satoshi; Ishii, Yusuke et al.

Cancer Science, 2025

アクセス数:753件（2026-02-15 20:22 集計）

固定URL: https://hdl.handle.net/11094/103279

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タイトル	VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix
著者	ORCID 0000-0002-3658-4541 0000-0002-3658-4541 researchmap permalink mariya.k mariya.k Scopus Author ID 57269826700 57269826700 著者名 Kobayashi, Mariya
	NRID 1000030650593 1000030650593 ORCID 0000-0001-6540-9040 0000-0001-6540-9040 researchmap permalink snakagawa snakagawa Scopus Author ID 56514567200 56514567200 著者名 Nakagawa, Satoshi
	著者名 Ishii, Yusuke
	著者名 Kamei, Yuji
	著者名 Kanda, Mizuki
	NRID 1000050886629 1000050886629 researchmap permalink t_masuda t_masuda 著者名 Masuda, Tatsuo
	NRID 1000030923031 1000030923031 ORCID 0000-0003-2768-8848 0000-0003-2768-8848 researchmap permalink mamorukakuda mamorukakuda Scopus Author ID 56692693900 56692693900 著者名 Kakuda, Mamoru
	NRID 1000010650591 1000010650591 ORCID 0000-0001-7569-7875 0000-0001-7569-7875 researchmap permalink K12T029771F K12T029771F Scopus Author ID 55371955600 55371955600 著者名 Hiramatsu, Kosuke
	NRID 1000040790936 1000040790936 著者名 Iwamiya, Tadashi
	NRID 1000030437420 1000030437420 著者名 Egawa-Takata, Tomomi
	NRID 1000000467565 1000000467565 ORCID 0000-0001-5725-9994 0000-0001-5725-9994 researchmap permalink shinya.matsuzaki shinya.matsuzaki Scopus Author ID 35201668600 35201668600 著者名 Matsuzaki, Shinya
	著者名 Uematsu, Hiroyuki
	NRID 1000090597890 1000090597890 著者名 Onuma, Kunishige
	NRID 1000010342990 1000010342990 著者名 Inoue, Masahiro
	NRID 1000010346215 1000010346215 ORCID 0000-0001-8760-6379 0000-0001-8760-6379 researchmap permalink read0092318 read0092318 Scopus Author ID 55087087500 55087087500 著者名 Ueda, Yutaka
	NRID 1000090240845 1000090240845 著者名 Kimura, Tadashi
	NRID 1000070791391 1000070791391 ORCID 0000-0003-4046-7572 0000-0003-4046-7572 researchmap permalink mkyh mkyh Scopus Author ID 35422516200 35422516200 著者名 Kodama, Michiko
キーワード等	cervical cancer
	in vivo
	mitochondria
	small cell neuroendocrine carcinoma
	VRK1
内容	Kobayashi M., Nakagawa S., Ishii Y., et al. VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix. Cancer Science (2025); https://doi.org/10.1111/cas.70211.
抄録	Small cell neuroendocrine carcinoma of the cervix (SCNEC) is classified as a high-grade neuroendocrine carcinoma with a worse prognosis than other major histological types of cervical cancer. Identifying novel therapeutic targets based on its molecular characteristics is highly desirable but challenging due to the rarity of SCNEC and the resulting lack of research resources. In this study, we identified vaccinia-related kinase 1 (VRK1) as a potential therapeutic target for SCNEC. VRK1 was prioritized based on our previously reported proteomic analysis of patient-derived organoids. Immunohistochemistry of patient samples consistently revealed high VRK1 expression in SCNEC, as opposed to its variable expression in other cervical carcinomas. Although VRK1 knockdown in SCNEC had only a limited effect on cell proliferation in two-dimensional cultures, it significantly suppressed cell proliferation in three-dimensional cultures and inhibited xenograft tumor growth in vivo. Gene set enrichment analysis of RNA-sequencing data from mouse xenograft models demonstrated that VRK1 is associated with mitochondrial-related pathways. Furthermore, under oxidative stress conditions, VRK1 knockdown resulted in a reduction of mitochondrial membrane potential, an indicator of mitochondrial integrity, and decreased expression of cytochrome c oxidase subunit IV (COX IV), a nuclear-encoded subunit of cytochrome c oxidase, the terminal enzyme complex of the mitochondrial respiratory chain. These findings suggest that VRK1 knockdown indirectly impaired mitochondrial function. Collectively, these anti-tumor effects highlight VRK1 as a promising therapeutic target for SCNEC.
出版者	John Wiley and Sons Inc
収録物名	Cancer Science
刊行年月	2025-10-20
言語	英語
ハンドルURL	https://hdl.handle.net/11094/103279
PISSN	13479032
eISSN	13497006
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1111/cas.70211
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	Cancer Science. 2025
DC.title	VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix
DC.creator	Kobayashi, Mariya
	Nakagawa, Satoshi
	Ishii, Yusuke
	Kamei, Yuji
	Kanda, Mizuki
	Masuda, Tatsuo
	Kakuda, Mamoru
	Hiramatsu, Kosuke
	Iwamiya, Tadashi
	Egawa-Takata, Tomomi
	Matsuzaki, Shinya
	Uematsu, Hiroyuki
	Onuma, Kunishige
	Inoue, Masahiro
	Ueda, Yutaka
	Kimura, Tadashi
	Kodama, Michiko
DC.publisher	John Wiley and Sons Inc
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-10-20
DC.identifier	https://doi.org/10.1111/cas.70211
DC.subject	cervical cancer
	in vivo
	mitochondria
	small cell neuroendocrine carcinoma
	VRK1
DC.description	Kobayashi M., Nakagawa S., Ishii Y., et al. VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix. Cancer Science (2025); https://doi.org/10.1111/cas.70211.
DCTERMS.abstract	Small cell neuroendocrine carcinoma of the cervix (SCNEC) is classified as a high-grade neuroendocrine carcinoma with a worse prognosis than other major histological types of cervical cancer. Identifying novel therapeutic targets based on its molecular characteristics is highly desirable but challenging due to the rarity of SCNEC and the resulting lack of research resources. In this study, we identified vaccinia-related kinase 1 (VRK1) as a potential therapeutic target for SCNEC. VRK1 was prioritized based on our previously reported proteomic analysis of patient-derived organoids. Immunohistochemistry of patient samples consistently revealed high VRK1 expression in SCNEC, as opposed to its variable expression in other cervical carcinomas. Although VRK1 knockdown in SCNEC had only a limited effect on cell proliferation in two-dimensional cultures, it significantly suppressed cell proliferation in three-dimensional cultures and inhibited xenograft tumor growth in vivo. Gene set enrichment analysis of RNA-sequencing data from mouse xenograft models demonstrated that VRK1 is associated with mitochondrial-related pathways. Furthermore, under oxidative stress conditions, VRK1 knockdown resulted in a reduction of mitochondrial membrane potential, an indicator of mitochondrial integrity, and decreased expression of cytochrome c oxidase subunit IV (COX IV), a nuclear-encoded subunit of cytochrome c oxidase, the terminal enzyme complex of the mitochondrial respiratory chain. These findings suggest that VRK1 knockdown indirectly impaired mitochondrial function. Collectively, these anti-tumor effects highlight VRK1 as a promising therapeutic target for SCNEC.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
DC.format	103279
citation_title	VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix
citation_author	Kobayashi, Mariya
	Nakagawa, Satoshi
	Ishii, Yusuke
	Kamei, Yuji
	Kanda, Mizuki
	Masuda, Tatsuo
	Kakuda, Mamoru
	Hiramatsu, Kosuke
	Iwamiya, Tadashi
	Egawa-Takata, Tomomi
	Matsuzaki, Shinya
	Uematsu, Hiroyuki
	Onuma, Kunishige
	Inoue, Masahiro
	Ueda, Yutaka
	Kimura, Tadashi
	Kodama, Michiko
citation_publisher	John Wiley and Sons Inc
citation_language	英語
citation_date	2025-10-20
citation_journal_title	Cancer Science
citation_doi	https://doi.org/10.1111/cas.70211
citation_public_url	https://hdl.handle.net/11094/103279

VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix

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