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Peer-reviewedCC BYCancers

SPINT2 Is Associated with Dual-Phenotype Hepatocellular Carcinoma and Aggressive Tumor Features.

  • Jie Zhang1,2
  • Minjun Li1,2
  • Taixin Yang1,2
  • Ning Ma3
  • Yaohong Liu4
  • Chunye Fang4
  • Chenglei Yang1,2
  • Bangde Xiang1,2
4 affiliations
  1. 1Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China.
  2. 2Guangxi Key Laboratory of Early Prevention and Treatment of Regional High Frequency Tumors, Nanning 530021, China.
  3. 3Division of Health Science, Graduate School of Health Science, Suzuka University of Medical Science, Suzuka 510-0293, Japan.
  4. 4School of Oncology, Guangxi Medical University, Nanning 530021, China.
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Abstract

Background: Hepatocellular carcinoma (HCC) heterogeneity, particularly the presence of tumor cells co-expressing hepatocytic and cholangiocytic markers, contributes to therapeutic resistance and poor prognosis, yet its molecular correlates remain incompletely understood. This study aimed to characterize dual-phenotype HCC (DPHCC) and investigate the association and functional relevance of SPINT2 in tumor progression. Methods: We integrated multiplex immunofluorescence, CyTOF mass cytometry, single-cell RNA sequencing, and functional assays across clinical cohorts and cell lines. Results: Multiplex staining identified DPHCC in 22.89% of patients, correlating significantly with younger age, elevated AFP, and inferior recurrence-free and overall survival compared to non-DPHCC cases. Parallel scRNA-seq and CyTOF analyses showed that DPHCC-associated cells were enriched for stemness- and EMT-related features, with SPINT2 emerging as a top candidate gene in the transcriptomic analysis. Immunohistochemistry showed higher SPINT2 expression in DPHCC tissues, and high SPINT2 expression was associated with shorter overall survival in univariate Kaplan-Meier analysis and frequently co-localized with CK19. Functionally, SPINT2 modulation produced context-dependent changes in invasion, proliferation-related CCK-8 readouts, wound closure, sphere formation, and xenograft tumor growth in MHCC-97H and MHCC-LM3 cells. Collectively, these findings characterize DPHCC as a clinically relevant dual-lineage phenotypic state associated with aggressive tumor features and identify SPINT2 as a candidate molecule associated with this phenotype. Conclusions: SPINT2 is associated with the DPHCC-related state and aggressive tumor-cell phenotypes, but its mechanistic and clinical significance requires further validation.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026spint2,
  title = {{SPINT2 Is Associated with Dual-Phenotype Hepatocellular Carcinoma and Aggressive Tumor Features.}},
  author = {Jie Zhang and Minjun Li and Taixin Yang and Ning Ma and Yaohong Liu and Chunye Fang and Chenglei Yang and Bangde Xiang},
  journal = {Cancers},
  year = {2026},
  month = sep,
  doi = {10.3390/cancers18193102},
  url = {https://europepmc.org/article/MED/42882797},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - SPINT2 Is Associated with Dual-Phenotype Hepatocellular Carcinoma and Aggressive Tumor Features.
AU  - Jie Zhang
AU  - Minjun Li
AU  - Taixin Yang
AU  - Ning Ma
AU  - Yaohong Liu
AU  - Chunye Fang
AU  - Chenglei Yang
AU  - Bangde Xiang
PY  - 2026
DA  - 2026/09/24
JO  - Cancers
DO  - 10.3390/cancers18193102
UR  - https://europepmc.org/article/MED/42882797
AB  - Background: Hepatocellular carcinoma (HCC) heterogeneity, particularly the presence of tumor cells co-expressing hepatocytic and cholangiocytic markers, contributes to therapeutic resistance and poor prognosis, yet its molecular correlates remain incompletely understood. This study aimed to characterize dual-phenotype HCC (DPHCC) and investigate the association and functional relevance of SPINT2 in tumor progression. Methods: We integrated multiplex immunofluorescence, CyTOF mass cytometry, single-cell RNA sequencing, and functional assays across clinical cohorts and cell lines. Results: Multiplex staining identified DPHCC in 22.89% of patients, correlating significantly with younger age, elevated AFP, and inferior recurrence-free and overall survival compared to non-DPHCC cases. Parallel scRNA-seq and CyTOF analyses showed that DPHCC-associated cells were enriched for stemness- and EMT-related features, with SPINT2 emerging as a top candidate gene in the transcriptomic analysis. Immunohistochemistry showed higher SPINT2 expression in DPHCC tissues, and high SPINT2 expression was associated with shorter overall survival in univariate Kaplan-Meier analysis and frequently co-localized with CK19. Functionally, SPINT2 modulation produced context-dependent changes in invasion, proliferation-related CCK-8 readouts, wound closure, sphere formation, and xenograft tumor growth in MHCC-97H and MHCC-LM3 cells. Collectively, these findings characterize DPHCC as a clinically relevant dual-lineage phenotypic state associated with aggressive tumor features and identify SPINT2 as a candidate molecule associated with this phenotype. Conclusions: SPINT2 is associated with the DPHCC-related state and aggressive tumor-cell phenotypes, but its mechanistic and clinical significance requires further validation.
SN  - 2072-6694
ER  -