Journal of Liver Cancer

Articles in E-pub version are posted online ahead of regular printed publication.

Original Article

Synergistic effects of L-arginine and argininosuccinate synthetase 1 in inducing apoptosis in hepatocellular carcinoma: Jin Sun Kim, Won-Mook Choi, Ha-Il Kim, Sung Won Chung, Jonggi Choi, Danbi Lee, Kang Mo Kim; Received October 9, 2024 Accepted December 27, 2024 Published online January 14, 2025; DOI: https://doi.org/10.17998/jlc.2024.12.27 [Accepted]

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Abstract PDF: Background/Aims
Hepatocellular carcinoma (HCC) is a malignant cancer with an increasing incidence worldwide. Although numerous efforts have been made to identify effective therapies for HCC, current strategies have limitations. We present a new approach for targeting L-arginine and argininosuccinate synthetase 1 (ASS1).
Methods
ASS1 expression in HCC cell lines and primary hepatocytes was detected using PCR and western blotting. Proliferation, migration, signaling pathways, and nitric oxide production in HCC cell lines were measured using MTS, colony formation, wound healing, western blot, and Griess assays.
Results
ASS1 expression varied among the HCC cell lines, and cisplatin cytotoxicity was ASS1-dependent. L-arginine alone induced apoptosis in HCC cell lines, regardless of ASS1 expression; however, its effect was enhanced in ASS1-expressing HCC cell lines. Cisplatin cytotoxicity also increased, suggesting that L-arginine acts as a sensitizer to cisplatin in HCC cell lines. ASS1 and L-arginine produced nitric oxide and inhibited key proliferation- and survival-related signaling pathways such as PI3K/Akt and MAPK. Additionally, ASS1 and L-arginine reduced the expression of PKM1 and PKM2 in the glycolysis pathway.
Conclusions
Our study revealed that ASS1 and L-arginine exhibited anticancer effects in HCC and sensitized cisplatin-resistant HCC cells to chemotherapy. The combination of ASS1 and L-arginine significantly enhanced the anticancer effects, even in HCC cell lines with low or absent ASS1 expression. These findings highlight the critical roles of arginine and ASS1 in HCC and suggest that increasing arginine availability could be a promising therapeutic strategy.

Review Article

Molecular and immune landscape of hepatocellular carcinoma for therapeutic development: Hiroyuki Suzuki, Sumit Mishra, Subhojit Paul, Yujin Hoshida; Received October 30, 2024 Accepted December 2, 2024 Published online December 6, 2024; DOI: https://doi.org/10.17998/jlc.2024.12.02 [Accepted]

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Abstract PDF: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with an estimated 750,000 deaths in 2022. Recent emergence of molecular targeted agents (MTAs) and immune checkpoint inhibitors (ICIs) and their combination therapies have been transforming HCC care, but their prognostic impact in advanced-stage disease remains unsatisfactory. In addition, their application to early-stage disease is still an unmet need. Omics profiling studies have elucidated recurrent and heterogeneously present molecular aberrations involved in pro-cancer tumor (immune) microenvironment that may guide therapeutic strategies. Recurrent aberrations such somatic mutations in TERT promoter and TP53 have been regarded undruggable, but recent studies have suggested that these may serve as new classes of therapeutic targets. HCC markers such as alpha-fetoprotein (AFP), glypican-3 (GPC3), and epithelial cell adhesion molecule (EpCAM) have also been explored as therapeutic targets. These molecular features may be utilized as biomarkers to guide the application of new approaches as companion biomarkers to maximize therapeutic benefits in patients who are likely to benefit from the therapies, while minimizing unnecessary harm in patients who will not respond. The explosive number of new agents in the pipelines have posed challenges in their clinical testing. Novel clinical trial designs guided by predictive biomarkers have been proposed to enable their efficient and cost-effective evaluation. These new developments collectively facilitate clinical translation of personalized molecular-targeted therapies in HCC and substantially improve prognosis of HCC patients.

Editorial

Evolving trends in epidemiology, etiology, and treatment patterns for hepatocellular carcinoma in South Korea: Soo Young Hwang, Ju Dong Yang; Received November 30, 2024 Accepted December 4, 2024 Published online December 5, 2024; DOI: https://doi.org/10.17998/jlc.2024.12.04 [Accepted]

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PDF

Case Report

Durable complete response after discontinuation of atezolizumab-bevacizumab therapy in patients with hepatocellular carcinoma with portal vein tumor thrombosis: the first report: Pramod Kumar, Pradeep Krishna, Rohit Maidur, Naveen Chandrashekhar, Suresh Raghavaiah; Received June 14, 2024 Accepted September 26, 2024 Published online November 5, 2024; DOI: https://doi.org/10.17998/jlc.2024.09.26 [Accepted]

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Abstract PDF: Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is associated with a dismal prognosis. Atezolizumab plus bevacizumab (atezo-bev) is the recommended palliative treatment, and approximately 10% of the patients may experience a complete response (CR), according to the mRECIST criteria. The treatment duration is until disease progression or unacceptable side effects occur. Long-term continuation can cause potential toxicities and a substantial financial burden, making early treatment discontinuation a viable option. This report describes durable CR after discontinuing atezo-bev treatment in three patients with HCC and PVTT.

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