Driver gene KRAS aggravates cancer-associated stroke outcomes

Yan, Haomin; Sasaki, Tsutomu; Gon, Yasufumi; Nishiyama, Kumiko; Kanki, Hideaki; Mochizuki, Hideki

doi:https://doi.org/10.1016/j.thromres.2023.11.015

Driver gene KRAS aggravates cancer-associated stroke outcomes

Yan, Haomin; Sasaki, Tsutomu; Gon, Yasufumi et al.

Thrombosis Research, 2024, 233(5), 55-68

アクセス数:825件（2025-09-01 20:46 集計）

固定URL: https://hdl.handle.net/11094/93386

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タイトル	Driver gene KRAS aggravates cancer-associated stroke outcomes
著者	著者名 Yan, Haomin
	NRID 1000020534879 1000020534879 ORCID 0000-0001-8726-978X 0000-0001-8726-978X researchmap permalink tsutomusasaki1111 tsutomusasaki1111 Scopus Author ID 7407394272 7407394272 著者名 Sasaki, Tsutomu
	NRID 1000070751311 1000070751311 researchmap permalink y-gon y-gon Scopus Author ID 56565092900 56565092900 著者名 Gon, Yasufumi
	著者名 Nishiyama, Kumiko
	NRID 1000010774218 1000010774218 researchmap permalink kan1 kan1 著者名 Kanki, Hideaki
	NRID 1000090230044 1000090230044 ORCID 0000-0002-0874-7542 0000-0002-0874-7542 researchmap permalink read0207787 read0207787 Scopus Author ID 7202006099 7202006099 著者名 Mochizuki, Hideki
キーワード等	Cancer-associated stroke
	KRAS mutation
	Neuroinflammation
内容	Yan Haomin, Sasaki Tsutomu, Gon Yasufumi, et al. Driver gene KRAS aggravates cancer-associated stroke outcomes. Thrombosis Research 233, 55 (2023); https://doi.org/10.1016/j.thromres.2023.11.015.
抄録	The incidence of cancer-associated stroke has increased with the prolonged survival times of cancer patients. Recent genetic studies have led to progress in cancer therapeutics, but relationships between oncogenic mutations and stroke remain elusive. Here, we focused on the driver gene KRAS, which is the predominant RAS isoform mutated in multiple cancer types, in cancer associated stroke study. KRASG13D/− and parental human colorectal carcinoma HCT116 cells were inoculated into mice that were then subjected to a photochemically-induced thrombosis model to establish ischemic stroke. We found that cancer inoculation exacerbated neurological deficits after stroke. Moreover, mice inoculated with KRASG13D/− cells showed worse neurological deficits after stroke compared with mice inoculated with parental cells. Stroke promoted tumor growth, and the KRASG13D/− allele enhanced this growth. Brain RNA sequencing analysis and serum ELISA showed that chemokines and cytokines mediating pro-inflammatory responses were upregulated in mice inoculated with KRASG13D/− cells compared with those inoculated with parental cells. STAT3 phosphorylation was promoted following ischemic stroke in the KRASG13D/− group compared with in the parental group, and STAT3 inhibition significantly ameliorated stroke outcomes by mitigating microglia/macrophage polarization. Finally, we compared the prognosis and mortality of colorectal cancer patients with or without stroke onset between 1 January 2007 and 31 December 2020 using a hospital-based cancer registry and found that colorectal cancer patients with stroke onset within 3 months after cancer diagnosis had a worse prognosis. Our work suggests an interplay between KRAS and ischemic stroke that may offer insight into future treatments for cancer-associated stroke.
出版者	Elsevier BV
収録物名	Thrombosis Research
巻(号)	233(5)
ページ	55-68
刊行年月	2024-01-01
言語	英語
ハンドルURL	https://hdl.handle.net/11094/93386
PISSN	00493848
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1016/j.thromres.2023.11.015
アクセス権	open access
権利情報	© 2023. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
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	Thrombosis Research. 2024, 233(5), p. 55-68
DC.title	Driver gene KRAS aggravates cancer-associated stroke outcomes
DC.creator	Yan, Haomin
	Sasaki, Tsutomu
	Gon, Yasufumi
	Nishiyama, Kumiko
	Kanki, Hideaki
	Mochizuki, Hideki
DC.publisher	Elsevier BV
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-01-01
DC.identifier	https://doi.org/10.1016/j.thromres.2023.11.015
DC.subject	Cancer-associated stroke
	KRAS mutation
	Neuroinflammation
DC.description	Yan Haomin, Sasaki Tsutomu, Gon Yasufumi, et al. Driver gene KRAS aggravates cancer-associated stroke outcomes. Thrombosis Research 233, 55 (2023); https://doi.org/10.1016/j.thromres.2023.11.015.
DCTERMS.abstract	The incidence of cancer-associated stroke has increased with the prolonged survival times of cancer patients. Recent genetic studies have led to progress in cancer therapeutics, but relationships between oncogenic mutations and stroke remain elusive. Here, we focused on the driver gene KRAS, which is the predominant RAS isoform mutated in multiple cancer types, in cancer associated stroke study. KRASG13D/− and parental human colorectal carcinoma HCT116 cells were inoculated into mice that were then subjected to a photochemically-induced thrombosis model to establish ischemic stroke. We found that cancer inoculation exacerbated neurological deficits after stroke. Moreover, mice inoculated with KRASG13D/− cells showed worse neurological deficits after stroke compared with mice inoculated with parental cells. Stroke promoted tumor growth, and the KRASG13D/− allele enhanced this growth. Brain RNA sequencing analysis and serum ELISA showed that chemokines and cytokines mediating pro-inflammatory responses were upregulated in mice inoculated with KRASG13D/− cells compared with those inoculated with parental cells. STAT3 phosphorylation was promoted following ischemic stroke in the KRASG13D/− group compared with in the parental group, and STAT3 inhibition significantly ameliorated stroke outcomes by mitigating microglia/macrophage polarization. Finally, we compared the prognosis and mortality of colorectal cancer patients with or without stroke onset between 1 January 2007 and 31 December 2020 using a hospital-based cancer registry and found that colorectal cancer patients with stroke onset within 3 months after cancer diagnosis had a worse prognosis. Our work suggests an interplay between KRAS and ischemic stroke that may offer insight into future treatments for cancer-associated stroke.
DC.rights	© 2023. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
DC.format	93386
citation_title	Driver gene KRAS aggravates cancer-associated stroke outcomes
citation_author	Yan, Haomin
	Sasaki, Tsutomu
	Gon, Yasufumi
	Nishiyama, Kumiko
	Kanki, Hideaki
	Mochizuki, Hideki
citation_publisher	Elsevier BV
citation_language	英語
citation_date	2024-01-01
citation_journal_title	Thrombosis Research
citation_volume	233
citation_issue	5
citation_firstpage	55
citation_lastpage	68
citation_doi	https://doi.org/10.1016/j.thromres.2023.11.015
citation_public_url	https://hdl.handle.net/11094/93386

Driver gene KRAS aggravates cancer-associated stroke outcomes

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