GULP1, a multifaceted diagnostic biomarker and potential therapeutic target in hepatocellular carcinoma: Editorial on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”

Currently, hepatocellular carcinoma (HCC) is still a global health challenge, which is a leading cause of cancer-related deaths worldwide [1]. The high morbidity and mortality of HCC are due to late diagnosis, high recurrence rates, and limited therapeutic regimens [2]. As the most common primary liver cancer, early detection, and intervention are crucial for increasing treatment outcomes [2,3]. However, current diagnosing methods, including imaging technologies and serum biomarkers, such as alpha-fetoprotein (AFP), still have limitations in terms of sensitivity and specificity [4]. Thus, the need for novel tools or biomarkers to improve early detection and diagnosis of HCC is urgent and necessary.

In this edition of Clinical and Molecular Hepatology, the recent study performed by Kim et al. [5] presents a novel candidate biomarker, GULP PTB domain-containing engulfment adaptor 1 (GULP1). In this multi-omics study, Kim et al. merge genomic, transcriptomic, and proteomic analyses with functional validation and identify GULP1 as a dual-purpose biomarker and oncogenic driver in HCC progression and recurrence, which has a crucial diagnostic and predictive role in personalized medicine [5]. In general, this work provides not only a better understanding of HCC biology but also new insight into clinical translation.

First, based on the recurrence status following HCC surgical resection, Kim et al. classified the patients into distinct study cohorts. 50 overlapping differentially expressed genes were identified between recurrent and non-recurrent cohorts. After that, scientists conducted some machine learning-driven analyses in three HCC cohorts, such as Elastic Net and LASSO, and yielded a 15-gene risk score (RS) model. The risk scores correlated with patients’ survival data, making the model appropriate for predicting HCC recurrence. Among these DEGs, GULP1 demonstrated consistent overexpression in recurrent HCC. Notably, as an independent biomarker, its accuracy in patient stratification was comparable to that of comprehensive predictive models. These findings led Kim et al. [5] to identify GULP1 as a prominent candidate gene. However, unlike its oncogenic role in HCC, GULP1 frequently functions as a tumor suppressor in other malignancies, such as ovarian and urothelial cancers [6,7]. This finding underscores the critical importance of tissue specificity in biomarker development.

Subsequent histopathological analyses by Kim et al. [5] revealed significantly elevated GULP1 levels in HCC tissues compared to normal liver and hepatitis samples. Spatial transcriptomics and single-cell RNA sequencing further validated that GULP1 expression progressively increased with disease progression, peaking in malignant hepatocytes. This specific enrichment aligned with pathways associated with HCC aggressiveness, including KRAS signaling, epithelial-mesenchymal transition (EMT), and hypoxia. To confirm genomic findings, serum-based analyses were conducted using quantitative reverse transcription- polymerase chain reaction and enzyme-linked immunosorbent assay. Results showed markedly higher serum GULP1 levels in HCC patients than in non-tumor controls. Time-dependent receiver operating characteristic curve analysis indicated an area under the curve of 0.85 for serum GULP1, significantly outperforming α-fetoprotein. These results further indicated that GULP1 has more significant and excellent potential as a serum biomarker for the detection of HCC. Strikingly, combining GULP1 with AFP increased HCC diagnostic sensitivity to 81%, offering new hope for detecting complex cancer phenotypes in clinical settings.

Functional assays, both in vitro and in vivo models, further illustrated GULP1’s mechanistic roles [5]. In in vitro studies, knockdown of GULP1 in HCC cell lines (e.g., Huh-7 and PLC/PRF/5) suppressed proliferation, colony formation, migration, and invasion, while overexpression restored these malignant phenotypes. In subsequent orthotopic xenograft and subcutaneous metastatic mouse models, GULP1 depletion attenuated tumor growth and reduced the expression of proliferation markers, such as Ki-67 and PCNA. Immunohistochemical analyses linked GULP1 to β-catenin signaling—a key oncogenic driver in HCC and other types of cancers [8]. Mechanistically, GULP1 promotes tumor progression and metastasis by: 1) stabilizing ARF6-GTP, 2) facilitating β-catenin nuclear translocation, and 3) enhancing EMT-related gene transcription. Chromatin immunoprecipitation assays showed that the cascade reaction of the β-catenin signaling pathway facilitates the binding of transcription factor TCF3 to the GULP1 promoter, indicating that TCF3 serves as a direct regulator of the GULP1 promoter. This driving effect amplifies oncogenic signaling transduction through a positive feedback mechanism during carcinogenesis. Overall, these findings reveal the potential mechanism by which GULP1 functions as a proto-oncogene in the pathogenesis of HCC, demonstrating that β-catenin signaling is a critical pathway in HCC progression, where GULP1 plays a dual role as both an upstream regulator and a downstream effector.

In summary, the study by Kim et al. [5] provides robust evidence demonstrating that GULP1 serves not only as a diagnostic and prognostic biomarker for HCC, but also as a critical driver factor of tumor recurrence and metastasis. GULP1 exhibits superior diagnostic properties as a serum biomarker compared to the conventional biomarker AFP. The discovery of GULP1, whether used independently or combined with AFP, brings considerable potential for advancing early detection and risk stratification in HCC management. From a therapeutic perspective, GULP1 represents a promising therapeutic target that facilitates novel approaches in personalized medicine. Developing small-molecule inhibitors or monoclonal antibodies targeting the GULP1-ARF6-β-catenin axis could effectively prevent postresection recurrence and metastasis, improving survival rates and quality of life for HCC patients. Future research should focus on integrating GULP1 with other novel biomarkers to enhance diagnostic accuracy, particularly for AFP-negative HCC patients. Additionally, investigation into GULP1-associated oncogenic signaling pathways, such as the Notch signaling pathway, represents another promising research frontier. Understanding GULP1’s mechanistic roles in these pathways may also facilitate the development of novel targeted therapies. Overall, this groundbreaking work by Kim et al. [5] marks significant progress in the HCC research area and brings new hope for precision medicine in liver cancer. The discovery of GULP1 underscores the transformative potential of molecular biology in enhancing cancer diagnostics and therapeutics. Continued exploration in this field remains crucial for fully harnessing GULP1’s clinical potential and ultimately improving HCC treatment outcomes.

Abbreviations

AFP

α-fetoprotein

EMT

epithelial-mesenchymal transition

GULP1

GULP PTB domain-containing engulfment adaptor 1

HCC

hepatocellular carcinoma

RS

risk score