Folate receptor 1 is a stemness trait-associated diagnostic and prognostic marker for hepatocellular carcinoma

Shiode, Yuto; Kodama, Takahiro; Sato, Yu; Takahashi, Ryo; Matsumae, Takayuki; Shirai, Kumiko; Doi, Akira; Tahata, Yuki; Hikita, Hayato; Tatsumi, Tomohide; Fukai, Moto; Taketomi, Akinobu; Ruchirawat, Mathuros; Wang, Xin Wei; Takehara, Tetsuo

doi:https://doi.org/10.1186/s40364-025-00752-8

Folate receptor 1 is a stemness trait-associated diagnostic and prognostic marker for hepatocellular carcinoma

Shiode, Yuto; Kodama, Takahiro; Sato, Yu et al.

Biomarker Research, 2025, 13(1), 37

Number of Access:1,875（2025-12-05 07:16 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/101065

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Title	Folate receptor 1 is a stemness trait-associated diagnostic and prognostic marker for hepatocellular carcinoma
Creator	NRID 1000010838840 1000010838840 CreatorName Shiode, Yuto
	NRID 1000010623275 1000010623275 ORCID 0000-0002-6250-1324 0000-0002-6250-1324 researchmap permalink takahirokodama takahirokodama Scopus Author ID 35193885800 35193885800 CreatorName Kodama, Takahiro
	CreatorName Sato, Yu
	NRID 1000010546865 1000010546865 CreatorName Takahashi, Ryo
	CreatorName Matsumae, Takayuki
	NRID 1000020992267 1000020992267 researchmap permalink u987841f u987841f CreatorName Shirai, Kumiko
	CreatorName Doi, Akira
	NRID 1000000838047 1000000838047 researchmap permalink yuki.tahata yuki.tahata Scopus Author ID 56755390400 56755390400 ORCID 0000-0002-9116-7054 0000-0002-9116-7054 CreatorName Tahata, Yuki
	NRID 1000020623044 1000020623044 researchmap permalink hikitahayato hikitahayato Scopus Author ID 23667454900 23667454900 ORCID 0000-0003-2488-7315 0000-0003-2488-7315 CreatorName Hikita, Hayato
	NRID 1000020397699 1000020397699 researchmap permalink read0140669 read0140669 Scopus Author ID 7202112131 7202112131 CreatorName Tatsumi, Tomohide
	CreatorName Fukai, Moto
	CreatorName Taketomi, Akinobu
	CreatorName Ruchirawat, Mathuros
	CreatorName Wang, Xin Wei
	NRID 1000070335355 1000070335355 CreatorName Takehara, Tetsuo
Subject	Biomarker
	Diagnosis
	FOLR1
	HCC
	Prognosis
Description	Shiode Y., Kodama T., Sato Y., et al. Folate receptor 1 is a stemness trait-associated diagnostic and prognostic marker for hepatocellular carcinoma. Biomarker Research 13, 37 (2025); https://doi.org/10.1186/s40364-025-00752-8.
Abstract	Background : Hepatocellular carcinoma (HCC) can be classified into several subtypes based on molecular traits, aiding in prognostic stratification. The subtype with a poor prognosis is often associated with stem/progenitor features. This study focused on identifying circulating biomarkers for aggressive HCC. Methods : We searched for secretory proteins whose expression was positively associated with the stem/progenitor markers KRT19, EPCAM, and PROM1 in 2 independent HCC cohorts. Serum folate receptor 1 (FOLR1) levels were measured in 238 chronic liver disease and 247 HCC patients, evaluating their diagnostic and prognostic capabilities. Results : FOLR1 was identified as a secretory protein that was positively correlated with all 3 stem/progenitor markers and a poor prognosis in both the discovery and validation cohorts. Higher FOLR1 expression was detected in tumor than nontumor tissues and was associated with aggressive subtypes, and activation of p53, DNA repair, Myc, E2F, and PI3K/AKT/mTOR pathways. Serum FOLR1 levels correlated with tumoral FOLR1 expression in HCC patients and were significantly elevated compared with those in patients with chronic hepatitis or nonliver disease. Serum FOLR1 levels demonstrated diagnostic performance for HCC comparable to that of alpha-fetoprotein (AFP), and their combination increased the diagnostic accuracy. Elevated serum FOLR1 levels were associated with poor prognosis in HCC patients, regardless of treatment, especially in patients with early-stage disease. The multivariate analysis revealed that the serum FOLR1 level and the Gender, Age, AFP-L3, AFP, and Des-gamma-carboxy prothrombin (GALAD) score were independent predictors of a poor prognosis with their combination further stratifying prognosis. Conclusions: FOLR1 is a stemness-associated biomarker for HCC, with serum levels serving as a diagnostic marker for HCC and a prognostic indicator for early-stage disease.
Publisher	BioMed Central Ltd
Source Title	Biomarker Research
Volume (Issue)	13(1)
Page	37
Date of Issued	2025-12-01
Language	English
Handle URL	https://hdl.handle.net/11094/101065
eISSN	20507771
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1186/s40364-025-00752-8
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Biomarker Research. 2025, 13(1), p. 37
DC.title	Folate receptor 1 is a stemness trait-associated diagnostic and prognostic marker for hepatocellular carcinoma
DC.creator	Shiode, Yuto
	Kodama, Takahiro
	Sato, Yu
	Takahashi, Ryo
	Matsumae, Takayuki
	Shirai, Kumiko
	Doi, Akira
	Tahata, Yuki
	Hikita, Hayato
	Tatsumi, Tomohide
	Fukai, Moto
	Taketomi, Akinobu
	Ruchirawat, Mathuros
	Wang, Xin Wei
	Takehara, Tetsuo
DC.publisher	BioMed Central Ltd
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-12-01
DC.identifier	https://doi.org/10.1186/s40364-025-00752-8
DC.subject	Biomarker
	Diagnosis
	FOLR1
	HCC
	Prognosis
DC.description	Shiode Y., Kodama T., Sato Y., et al. Folate receptor 1 is a stemness trait-associated diagnostic and prognostic marker for hepatocellular carcinoma. Biomarker Research 13, 37 (2025); https://doi.org/10.1186/s40364-025-00752-8.
DCTERMS.abstract	Background : Hepatocellular carcinoma (HCC) can be classified into several subtypes based on molecular traits, aiding in prognostic stratification. The subtype with a poor prognosis is often associated with stem/progenitor features. This study focused on identifying circulating biomarkers for aggressive HCC. Methods : We searched for secretory proteins whose expression was positively associated with the stem/progenitor markers KRT19, EPCAM, and PROM1 in 2 independent HCC cohorts. Serum folate receptor 1 (FOLR1) levels were measured in 238 chronic liver disease and 247 HCC patients, evaluating their diagnostic and prognostic capabilities. Results : FOLR1 was identified as a secretory protein that was positively correlated with all 3 stem/progenitor markers and a poor prognosis in both the discovery and validation cohorts. Higher FOLR1 expression was detected in tumor than nontumor tissues and was associated with aggressive subtypes, and activation of p53, DNA repair, Myc, E2F, and PI3K/AKT/mTOR pathways. Serum FOLR1 levels correlated with tumoral FOLR1 expression in HCC patients and were significantly elevated compared with those in patients with chronic hepatitis or nonliver disease. Serum FOLR1 levels demonstrated diagnostic performance for HCC comparable to that of alpha-fetoprotein (AFP), and their combination increased the diagnostic accuracy. Elevated serum FOLR1 levels were associated with poor prognosis in HCC patients, regardless of treatment, especially in patients with early-stage disease. The multivariate analysis revealed that the serum FOLR1 level and the Gender, Age, AFP-L3, AFP, and Des-gamma-carboxy prothrombin (GALAD) score were independent predictors of a poor prognosis with their combination further stratifying prognosis. Conclusions: FOLR1 is a stemness-associated biomarker for HCC, with serum levels serving as a diagnostic marker for HCC and a prognostic indicator for early-stage disease.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	101065
citation_title	Folate receptor 1 is a stemness trait-associated diagnostic and prognostic marker for hepatocellular carcinoma
citation_author	Shiode, Yuto
	Kodama, Takahiro
	Sato, Yu
	Takahashi, Ryo
	Matsumae, Takayuki
	Shirai, Kumiko
	Doi, Akira
	Tahata, Yuki
	Hikita, Hayato
	Tatsumi, Tomohide
	Fukai, Moto
	Taketomi, Akinobu
	Ruchirawat, Mathuros
	Wang, Xin Wei
	Takehara, Tetsuo
citation_publisher	BioMed Central Ltd
citation_language	English
citation_date	2025-12-01
citation_journal_title	Biomarker Research
citation_volume	13
citation_issue	1
citation_firstpage	37
citation_doi	https://doi.org/10.1186/s40364-025-00752-8
citation_public_url	https://hdl.handle.net/11094/101065

Folate receptor 1 is a stemness trait-associated diagnostic and prognostic marker for hepatocellular carcinoma

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