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ARTICLE

Serum Extracellular Vesicle-Associated GULP1 Is a Key Indicator of Hepatocellular Carcinoma

Hyung Seok Kim1,#, Ju A Son2,#, Minji Kang3,4,#, Soon Sun Kim3, Geum Ok Baek3, Moon Gyeong Yoon3, Se Ha Jang3,4, Dokyung Jung5, Ji Eun Han3, Jae Youn Cheong3,*, Jung Woo Eun3,*
1 Department of Biochemistry, Kosin University College of Medicine, Seo-gu, Busan, 49267, Republic of Korea
2 Department of Molecular Diagnostics, Ugenecell, Songpa-gu, Seoul, 05557, Republic of Korea
3 Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, 16499, Republic of Korea
4 Department of Biomedical Sciences, Ajou University Graduate School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, 16499, Republic of Korea
5 Department of Molecular Medicine, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Daegu, 41944, Republic of Korea
* Corresponding Author: Jae Youn Cheong. Email: email; Jung Woo Eun. Email: email
# These authors contributed equally to this work

Oncology Research https://doi.org/10.32604/or.2025.070392

Received 15 July 2025; Accepted 12 November 2025; Published online 05 December 2025

Abstract

Objectives: Early detection of hepatocellular carcinoma (HCC) is a significant challenge due to the limited sensitivity of alpha-fetoprotein (AFP). This study aimed to assess serum-derived extracellular vesicle-encapsulated GULP PTB domain-containing engulfment adaptor 1 (EV-GULP1) as a novel, noninvasive biomarker for HCC detection and prognosis, leveraging the potential of tumor-specific molecules carried by small extracellular vesicles (EVs). Methods: The study utilized both internal and external cohorts of HCC patients and controls. Small EVs were isolated from serum samples, then characterized and validated to confirm their identity. The expression levels of EV-GULP1 were quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: EV-GULP1 expression was found to be significantly higher in HCC patients, including those with early-stage disease, when compared to control groups. It demonstrated superior diagnostic accuracy over AFP, achieving an area under the curve (AUC) of 0.919, and was particularly effective in detecting AFP-negative cases. Furthermore, high EV-GULP1 expression correlated with worse overall and disease-free survival outcomes. Conclusion: These findings highlight EV-GULP1 as a highly promising noninvasive biomarker for hepatocellular carcinoma. It offers improved diagnostic accuracy for early detection and better risk stratification for prognosis compared to the current standard, AFP.

Keywords

Extracellular vesicles; GULP PTB domain-containing engulfment adaptor 1; hepatocellular carcinoma; liquid biopsy; biomarker

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