Chiao-Fang Teng

Introduction: Although resection surgery is a curative treatment for hepatocellular carcinoma (HCC), high HCC recurrence leads to poor patient survival. Chronic hepatitis B virus (HBV) infection is an important risk factor for HCC. Deletion mutation in HBV pre-S2 gene results in expression of pre-S2 mutant oncoprotein and represents an independent prognostic biomarker for HCC recurrence. MicroRNAs (miRNAs) are small non-coding RNAs that play key roles in HBV-related HCC. Methods: This study aimed to identify the miRNAs whose expression levels in tumor tissues were correlated with pre-S2 gene deletion mutation and post-resection HCC recurrence and investigate their potential in combination with pre-S2 gene deletion mutation to predict HCC recurrence in a retrospective cohort of patients. Results: The results showed that the expression level of miR-369-3p was decreased in tumor tissues of patients with pre-S2 gene deletion mutation or HCC recurrence. miR-369-3p was identified as a prognostic biomarker for HCC recurrence. Patients with pre-S2 gene deletion mutation combined with a low level of miR-369-3p had a higher risk of HCC recurrence than patients with either one or none of these two biomarkers. The combination of pre-S2 gene deletion mutation and miR-369-3p expression level showed a greater prognostic potential for HCC recurrence than either biomarker alone. Conclusion: Collectively, miR-369-3p held exploratory promise in serving as a combination biomarker with pre-S2 gene deletion mutation to provide a better potential in predicting HBV-related HCC recurrence after curative surgical resection. Plain Language Summary: This study provided preliminary evidence indicating a negative association between HBV pre-S2 gene deletion mutation and miR-369-3p expression level in tumor tissues of HCC patients and demonstrating a superior prognostic potential of combining these two biomarkers for post-resection HCC recurrence.

Background & Aims: Discovery of therapeutic targets for hepatocellular carcinoma (HCC) is urgently needed. As an important hepatitis B virus (HBV) oncoprotein, pre‐S2 mutant activates multiple signalling pathways to induce HCC development. Methods: This study investigated the effect of pre‐S2 mutant on regulating microRNA (miRNA) expression and the role of miRNAs in mediating pre‐S2 mutant's oncogenic functions. Results: The results showed that 9 miRNAs were downregulated in both tumour tissues of pre‐S2 mutant‐positive HCC patients and pre‐S2 mutant‐expressed human HCC cell lines, contributing to pre‐S2 mutant‐promoted cell proliferation, anchorage‐independent cell growth, cell cycle progression, and tumour growth and malignancy. Moreover, pre‐S2 mutant downregulated miRNA expression at the epigenetic levels through suppression of lysine acetyltransferase 3B (KAT3B)‐ and KAT5‐mediated histone H3 lysine 9 acetylation (H3K9ac) and H4K5ac modifications. The decreased levels of pre‐S2 mutant‐dysregulated miRNAs could also be detected in blood exosomes of patients. Conclusions: Collectively, this study provided new mechanistic insights and therapeutic perspectives for pre‐S2 mutant‐associated HCC tumorigenesis.

Objectives: High recurrence rates of hepatocellular carcinoma (HCC) after curative surgical resection severely limit patient survival, highlighting the need for reliable prognostic biomarkers and therapeutic targets. This study aimed to investigate the clinical significance and oncogenic mechanisms of microRNA-548b-5p (miR-548b-5p) in HCC. Methods: This retrospective study analyzed paired tumor (T) and adjacent non-tumor (NT) tissue samples from 68 patients with hepatitis B virus-related HCC from a single medical center. Cellular functions and target genes were investigated in HuH-7 and HepG2 cells using RT-qPCR, Western blot, cell malignant phenotype assays, and luciferase reporter assays. In vivo effects were validated using a computer-randomized NOD/SCID xenograft mouse model (n = 6 per group). Results: An increased miR-548b-5p T/NT ratio independently predicted shorter recurrence-free survival in patients (p < 0.01). Zinc finger and BTB domain containing 38 (ZBTB38) was identified as a direct downstream target. ZBTB38 expression was significantly suppressed in patients with high miR-548b-5p levels (T/NT ratio > 2.54). Functionally, miR-548b-5p inhibitor significantly reduced cell proliferation (p < 0.05), anchorage-independent growth (p < 0.001), migration (p < 0.01), and invasion (p < 0.001), which was fully reversed by ZBTB38 silencing (p < 0.05). Consistently, in vivo tumor growth, Ki-67 expression, and epithelial-to-mesenchymal transition phenotypes were significantly suppressed by the miR-548b-5p inhibitor (p < 0.001) but effectively restored upon ZBTB38 knockdown (p < 0.001). Conclusion: The miR-548b-5p/ZBTB38 signaling axis promotes tumorigenesis, and an elevated tissue miR-548b-5p T/NT ratio serves as an independent prognostic indicator for post-resection HCC recurrence. Targeting this axis represents a promising therapeutic strategy.

Although there are various treatment modalities available for hepatocellular carcinoma (HCC), HCC is still among the most common causes of cancer‐related death globally. Identifying independent biomarkers of poor prognosis in HCC patients remains a critical goal to allow timely intervention and ameliorate patient survival. MicroRNAs (miRNAs), the most widely investigated small noncoding RNAs to date, play a crucial role in regulating the initiation and progression of HCC. The expression of numerous miRNAs is altered in tumor tissues and blood specimens of HCC patients, underscoring their potential as promising prognostic biomarkers. This review offers an exhaustive overview of the current literature examining tissue‐ and circulation‐derived miRNAs as single or combined independent prognostic biomarkers in HCC patients.

Although significant advances have been made in the prevention and therapy, hepatocellular carcinoma (HCC) is still one of the most frequent and fatal human cancers worldwide. Discovery of independent prognostic biomarkers for the early identification and timely treatment of HCC patients with poor prognosis remains a key goal to achieve better patient survival. Long non-coding RNA (lncRNA) is one of the most-investigated classes of non-coding RNAs and plays important roles in controlling the occurrence and development of HCC through regulation of oncogene and tumor suppressor gene expression. Moreover, alterations in the expression levels of many lncRNAs are frequently observed in tumor tissues and blood circulation of HCC patients. LncRNAs have emerged as potential independent biomarkers for predicting the prognosis of HCC patients. This review comprehensively summarizes the evidence in the literature validating a single or a combination of lncRNA biomarker(s) with independent prognostic value in HCC patients.

Background: Despite the significant progress in prevention and therapy, hepatocellular carcinoma (HCC) is still one of the most prevalent and lethal human cancers worldwide. Purpose: Recently, the combination of atezolizumab (an immune checkpoint inhibitor, anti-programmed death ligand 1 antibody) and bevacizumab (an antiangiogenic agent, anti-vascular endothelial growth factor antibody) has emerged as a new and effective first-line systemic therapy in the treatment of patients with unresectable HCC. However, the development of prognostic biomarkers for the early identification and timely intervention of HCC patients with poor prognosis after atezolizumab plus bevacizumab combination therapy remains a key goal to achieve better patient survival. Research Design: This review provides a comprehensive summary of the evidence in the literature validating a single or a combination of biomarker(s) in various sampling sources at diverse time points with prognostic value in predicting the outcomes of HCC patients receiving atezolizumab plus bevacizumab combination therapy. A plethora of promising prognostic biomarkers is identified here, and further studies to implement these biomarkers in clinical practices are urgently needed.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Although various therapeutic modalities have been established for HCC, the overall outcomes of patients after treatment remain unsatisfactory, highlighting the need for valuable independent prognostic biomarkers. Cytokines are a large group of multifunctional secretory proteins and play critical roles in regulating development and progression of many cancer types, including HCC. Moreover, the expression levels of many cytokines in tumor/peritumor tissues and serum/plasma samples have been validated as important biomarkers for independently predicting the prognosis of HCC patients. This review provides a comprehensive summary of literature evidence for the independent prognostic significance of cytokine biomarkers in HCC patients receiving different therapies.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Although many therapeutic modalities have been established for treating HCC patients, the outcomes of patients remain unsatisfactory. Development of independent prognostic biomarkers is thus an important need to allow for early diagnosis and timely treatment. MicroRNAs (miRNAs) are the most studied class of small non-coding RNAs. It has been shown that miRNAs play essential roles in the multiple steps of HCC tumorigenesis and progression. Furthermore, the baseline expression levels of many miRNAs are altered in tumor tissues and blood circulation of HCC patients. Therefore, miRNAs have emerged as independent biomarkers for the prediction of HCC prognosis. This review provides a comprehensive literature-based summary of tissue and circulating miRNA biomarkers with independent prognostic significance in HCC.

Background Dendritic cell (DC) vaccine is a promising immunotherapy for hepatocellular carcinoma (HCC) via triggering antigen-specific anti-tumor immunity. Hypoxia contributes to higher level and broader spectrum of antigen expression in tumor cells. Methods This study aims to compare immunological activity and therapeutic efficacy between hypoxic and normoxic HCC cell line lysate-pulsed DC vaccines. Results The results showed that hypoxic HCC cell line lysate-pulsed DC vaccines exhibited a stronger activity in producing interleukin-12 and promoting T cell proliferation and cytotoxicity in vitro. In HCC mice, hypoxic HCC cell line lysate-pulsed DC vaccines displayed a better efficacy in improving survival time and tumor volume and inducing intratumoral cytotoxic T cell infiltration and activation as well as tumor cell apoptosis. Adenylate kinase 4-derived antigens were important for hypoxic HCC cell line lysate-pulsed DC vaccine-elicited T cell killing. Conclusions In conclusion, this study demonstrated hypoxic HCC cell line lysate-pulsed DC vaccine as a potential therapeutic strategy for HCC.