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. 2025 Aug 25;15(1):31229.
doi: 10.1038/s41598-025-15310-3.

Circulating galectin-9 as a novel prognosticator in patients with intrahepatic cholangiocarcinoma undergoing surgical resection

Makoto Kurimoto  1 , Tomoaki Yoh  2 , Yutaro Hori  1 , Hiroto Nishino  1 , Kohei Yoshimura  1 , Shuhei Kanda  1 , Keisuke Okura  1 , Yuichi Takamatsu  1 , Motohiko Satoh  1 , Takahiro Nishio  1 , Keiko Iwaisako  3 , Takamichi Ishii  1 , Etsuro Hatano  1
Affiliations

Circulating galectin-9 as a novel prognosticator in patients with intrahepatic cholangiocarcinoma undergoing surgical resection

Makoto Kurimoto et al. Sci Rep. .

Abstract

Background: Intrahepatic cholangiocarcinoma (ICC) is a rare but highly malignant liver cancer. Surgical resection provides the best long-term survival, yet poor prognosis requires improved treatments. Galectin-9 (GAL9) has gained attention for its role in tumor biology. This study investigated circulating galectin-9 (cGAL9) levels in ICC patients undergoing resection, along with tumor tissue characteristics.

Methods: GAL9 expression levels in circulating and tumor cells were measured using enzyme-linked immunosorbent assay and immunohistochemistry (IHC) in 91 ICC surgical patients. The mRNA expression levels of candidate genes were analyzed in 44 available frozen tissue samples.

Results: The optimal cGAL9 cutoff was 12.0 ng/ml using minimum P value approach. Higher cGAL9 levels linked to multiple tumors (P = 0.046), poorer overall survival (OS), and recurrence-free survival (RFS). Tumor cell GAL9 expression by IHC did not correlate with OS or RFS. cGAL9 levels did not correlate with tumor cell expression in IHC analyses or GAL9 mRNA in resected specimens. However, cGAL9 levels correlated with mRNA levels of glycolysis markers (glucose transporter 1 and hypoxia inducible factor 1 alpha).

Conclusions: Preoperative cGAL9 serves as a novel prognosticator for ICC patients after surgical resection. Its association with glycolysis highlights the potential for therapeutic guidance.

Keywords: Galectin 9; Glut1; Hif 1 alpha; Intrahepatic cholangiocarcinoma; Liver cancer.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The Opt-out informed consent was obtained to use the participant data for research. Informed consent was obtained from all participants and/or their legal guardians. This study was approved by the Ethics Committee of Kyoto University Hospital, Graduate School and Faculty of Medicine (Approval No. R3844), and performed in accordance with the Declaration of Helsinki. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Comparison of cGAL9 levels between ICC patients and healthy volunteers, and relations between cGAL9 levels and tumor factors. A, Comparison of cGAL9 levels between ICC patients (n = 91) and healthy volunteers (n = 16). B, ROC analysis of disease detection ability in the cohort of 91 ICC patients and 16 healthy volunteers. C. cGAL9 levels according to the significant tumor factors in ICC patients (n = 91). D. Relations between known tumor makers and cGAL9 in ICC patients (n = 91). * Significant difference P < 0.05. Abbreviations: cGAL9; circulating galectin-9, ICC; intrahepatic cholangiocarcinoma, ROC; receiver operating characteristic, CEA; carcinoembryonic antigen, CA19-9; carbohydrate antigen 19–9, AJCC; American Joint Commission on Cancer.
Fig. 2
Fig. 2
Prognostic impact of cGAL9 levels in ICC patients after surgical resection. A and B, Kaplan–Meier analyses for OS (A) and RFS (B) according to the cGAL9 levels. *Significant difference P < 0.05. Abbreviations: cGAL9; circulating galectin-9, ICC; intrahepatic cholangiocarcinoma, OS; overall survival, RFS; recurrence-free survival.
Fig. 3
Fig. 3
Tissue expression levels by IHC and prognostic value of GAL9 in resected specimens. A. IHC staining of GAL9 in surgical specimens of ICC. B. OS and RFS between the positive and negative groups of GAL9 IHC expression. C. OS and RFS between the positive and negative groups of GAL9 (LGALS9) mRNA expression in the GAL9 IHC negative cohort (n = 40). D. Comparison of cGAL9 levels according to GAL9 mRNA positivity in the GAL9 IHC negative cohort. * Significant difference P < 0.05. Abbreviations: GAL9; galectin-9, IHC; immunohistochemistry, cGAL9; circulating galectin-9, ICC; intrahepatic cholangiocarcinoma, OS; overall survival, RFS; recurrence-free survival.
Fig. 4
Fig. 4
Relations between cGAL9 and mRNA expression of genes related to tumor glycolysis and EMT. * Significant difference P < 0.05. Abbreviations: cGAL9; circulating galectin-9, EMT; epithelial-mesenchymal transition.
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