C/EBP homologous protein (CHOP) triggers the death of multiple cancers via endoplasmic reticulum (ER) stress. However, the function and regulatory mechanism of CHOP in liver cancer remain elusive. We have reported that late endosomal/lysosomal adapter, mitogen-activated protein kinase and mTOR activator 5 (LAMTOR5) suppresses apoptosis in various cancers. Here, we show that the transcriptional and posttranscriptional inactivation of CHOP mediated by LAMTOR5 accelerates liver cancer growth. Clinical bioinformatic analysis revealed that the expression of CHOP was low in liver cancer tissues and that its increased expression predicted a good prognosis. Elevated CHOP contributed to destruction of LAMTOR5-induced apoptotic suppression and proliferation. Mechanistically, LAMTOR5-recruited DNA methyltransferase 1 (DNMT1) to the CpG3 region (-559/-429) of the CHOP promoter and potentiated its hypermethylation to block its interaction with general transcription factor IIi (TFII-I), resulting in its inactivation. Moreover, LAMTOR5-enhanced miR-182/miR-769 reduced CHOP expression by targeting its 3\'UTR. Notably, lenvatinib, a first-line targeted therapy for liver cancer, could target the LAMTOR5/CHOP axis to prevent liver cancer progression. Accordingly, LAMTOR5-mediated silencing of CHOP via the regulation of ER stress-related apoptosis promotes liver cancer growth, providing a theoretical basis for the use of lenvatinib for the treatment of liver cancer.

Metabolic changes play a crucial role in determining the status and function of macrophages, but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood. Here, we investigated the phenotype, contribution, and regulatory mechanisms of lipid droplet (LD)-laden macrophages (LLMs) in hepatocellular carcinoma (HCC). Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC patients. The LLMs displayed immunosuppressive phenotypes (with extensive expression of TREM2, PD-L1, CD206, and CD163) and attenuated the antitumor activities of CD8+ T cells. Mechanistically, tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in macrophages. LDs prolong LLM survival and promote CCL20 secretion, which further recruits CCR6+ Tregs to HCC tissue. Inhibiting LLM formation by targeting DGAT1 and DGAT2, which catalyze the synthesis of triglycerides, significantly reduced Treg recruitment, and delayed tumor growth in a mouse hepatic tumor model. Our results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.

Personalized medicine has emerged as a revolutionary approach to healthcare in the 21st century. By understanding a patient\'s unique genetic and biological characteristics, it aims to tailor treatments specifically to the individual. This approach takes into account factors such as an individual\'s lifestyle, genetic makeup, and environmental factors to provide targeted therapies that have the potential to be more effective and lower the risk of side reactions or ineffective treatments. It is a paradigm shift from the traditional \"one size fits all\" approach in medicine, where patients with similar symptoms or diagnoses receive the same standard treatments regardless of their differences. It leads to improved clinical outcomes and more efficient use of healthcare resources. Drug repurposing is a strategy that uses existing drugs for new indications and aims to take advantage of the known safety profiles, pharmacokinetics, and mechanisms of action of these drugs to accelerate the development process. Precision medicine may undergo a revolutionary change as a result, enabling the rapid development of novel treatment plans utilizing drugs that traditional methods would not otherwise link to. In this chapter, we have focused on a few strategies wherein drug repurposing has shown great success for precision medicine. The approach is particularly useful in oncology as there are many variations induced in the genetic material of cancer patients, so tailored treatment approaches go a long way. We have discussed the cases of breast cancer, glioblastoma and hepatocellular carcinoma. Other than that, we have also looked at drug repurposing approaches in anxiety disorders and COVID-19.

Liver transplantation (LT) is considered the ideal treatment for hepatocellular carcinoma (HCC) concurrent with underlying cirrhotic liver disease. As well-known, LT for HCC based on the Milan criteria has shown satisfactory outcomes. However, numerous expanded transplantation criteria were proposed to benefit more patients for LT and showed comparable survivals as well. In addition, a modest expansion of transplantation criteria for HCC may be acceptable on the basis of the consensus within the transplantation community. Nonetheless, LT in patients with advanced HCC and portal vein tumor thrombosis (PVTT) recently has received attention and has been reported by many transplantation centers despite being contraindicated. Of those, the LT outcomes in certain HCC patients with PVTT were favorable. Additionally, the advancement of multimodality treatments and the evolution of systemic therapies have emerged as promising therapeutic options for downstaging advanced HCC prior to LT. Somehow, advanced HCC with PVTT could be downstaged to become eligible for LT through these multidisciplinary approaches. Although the available evidence of LT for HCC with PVTT is limited, it is hoped that LT may soon be more widely indicated for these patients. Nevertheless, several unknown factors associated with LT for HCC remain to be explored. Herein, this review aimed to update the developments in LT for patients with advanced HCC.

Immune checkpoint therapy (ICT) has been shown to produce durable responses in various cancer patients. However, its efficacy is notably limited in hepatocellular carcinoma (HCC), with only a small percentage of patients responding positively to treatment. The mechanism underlying resistance to ICT in HCC remains poorly understood. Here, we showed that combination treatment of ICG-001, an inhibitor of the Wnt/β-catenin signaling pathway, with anti-PD-1 antibody effectively suppresses tumor growth and promotes the infiltration of immune cells such as DCs and CD8+ T cells in the tumor microenvironment (TME). By inhibiting the activity of β-catenin and blocking its binding to the transcription factor IKAROS family zinc finger 1 (IKZF1), ICG-001 upregulated the expression of CCL5. Moreover, IKZF1 regulated the activity of the CCL5 promoter and its endogenous expression. Through inhibition of the WNT/β-catenin signaling pathway, upregulation of the expression of CCL5 was achieved, which subsequently recruited more DCs into the TME via C-C motif chemokine receptor 5 (CCR5). This, in turn, resulted in an increase in the infiltration of CD8+ T cells in the TME, thereby enhancing the antitumor immune response. Analysis of a tissue microarray derived from HCC patient samples revealed a positive correlation between survival rate and prognosis and the expression levels of CCL5/CD8. In conclusion, our findings suggest that combined application of ICG-001 and anti-PD-1 antibody exhibits significantly enhanced antitumor efficacy. Hence, combining a WNT/β-catenin signaling pathway inhibitor with anti-PD-1 therapy may be a promising treatment strategy for patients with HCC.

Alterations in signaling pathways and modulation of cell metabolism are associated with the pathogenesis of cancers, including hepatocellular carcinoma (HCC). Small ubiquitin-like modifier (SUMO) proteins and NF-κB family play major roles in various cellular processes. The current study aims to determine the expression profile of SUMO and NF-κB genes in HCC tumors and investigate their association with the clinical outcome of HCC. The expression of 5 genes - SUMO1, SUMO2, SUMO3, NF-κB p65, and NF-κB p50 - was quantified in tumor and adjacent non-tumor tissues of 58 HBV-related HCC patients by real-time quantitative PCR and was analyzed for the possible association with clinical parameters of HCC. The expression of SUMO2 was significantly higher in HCC tumor tissues compared to the adjacent non-tumor tissues (P = .01), while no significant difference in SUMO1, SUMO3, NF-κB p65, and NF-κB p50 expression was observed between HCC tumor and non-tumor tissues (P > .05). In HCC tissues, a strong correlation was observed between the expression of SUMO2 and NF-κB p50, between SUMO3 and NF-κB p50, between SUMO3 and NF-κB p65 (Spearman rho = 0.83; 0.82; 0.772 respectively; P < .001). The expression of SUMO1, SUMO2, SUMO3, NF-κB p65, and NF-κB p50 was decreased in grade 3 compared to grades 1 and 2 in HCC tumors according to the World Health Organization grades system. Our results highlighted that the SUMO2 gene is upregulated in tumor tissues of patients with HCC, and is related to the development of HCC, thus it may be associated with the pathogenesis of HCC.

Advancements in diagnostic modalities, such as enhanced magnetic resonance imaging, provide increased opportunities for identifying small hepatocellular carcinoma that is undetectable on preoperative ultrasonography. Whether it is acceptable to leave these lesions untreated is uncertain. This study aimed to evaluate the safety and efficacy of intraoperative magnetic resonance imaging-guided hepatectomy using new navigation systems. This study was conducted between July 2019 and January 2023. We retrospectively studied the clinicopathological features and prognoses of patients with small hepatocellular carcinoma who underwent curative intraoperative magnetic resonance imaging-guided hepatectomy. We evaluated 23 patients (median age, 75 years), among whom 20 (87.0%) were males. Seven (30.4%) and 15 (65.2%) patients had liver cirrhosis and a history of hepatectomy, respectively. The median size of the target lesions was 9 mm, with a median distance of 6 mm from the liver surface. Despite being undetectable preoperatively on contrast-enhanced ultrasonography, all lesions were identified using intraoperative magnetic resonance imaging. Based on pathological findings, 76.0% of the lesions were malignant. The complete resection rate was 100%, and tumor-free margins were confirmed in 96.0% of the patients. Intraoperative magnetic resonance imaging-guided hepatectomy is safe and effective in identifying and resecting small hepatocellular carcinoma lesions that are undetectable on preoperative ultrasonography.

High-intensity focused ultrasound (HIFU) represents a method employing high-intensity ultrasound energy to induce thermal ablation of cancerous cells. Regarded as minimally invasive, HIFU treatment offers reduced risk of complications and abbreviated recovery periods compared to surgical interventions. Although predominantly utilized in the management of pancreatic malignancies, ongoing investigations are exploring its viability in addressing hepatocellular carcinoma. Although HIFU may be employed independently in hepatocellular carcinoma treatment, its potential as a synergistic component within combination therapies is under scrutiny. Moreover, emerging research endeavors have explored the multifaceted utility of HIFU, encompassing not only localized thermal ablation but also functionalities like drug delivery and gene therapy, augmenting its therapeutic efficacy. Despite the promising outlook of HIFU in the management of hepatocellular carcinoma, existing constraints and challenges persist. Continued research initiatives and technological innovations are anticipated to propel HIFU into a pivotal and established therapeutic modality in the foreseeable future. This article provides an overview of HIFU therapy for hepatocellular carcinoma and presents a comprehensive update on its current clinical status.

Both atezolizumab (a PD-L1 inhibitor) plus bevacizumab (A+B) and sintilimab (a PD-1 inhibitor) plus bevacizumab (S+B) are recommended as the first-line regimen for advanced hepatocellular carcinoma (HCC) in China. Different efficacy between the two regimens combined with transvascular intervention for unresectable HCC (uHCC) remain unknown. We retrospectively analyzed uHCC patients treated in three centers by simultaneous combination of A+B or S+B with transarterial chemoembolization (TACE) and FOLFOX-based hepatic arterial infusion chemotherapy (HAIC). Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAEs) were compared. Totally 188 patients were included, with 92 and 96 administered A+B+TACE-HAIC (ABTH) and S+B+TACE-HAIC (SBTH), respectively. ORRs (62.0 vs. 70.8%, respectively; P = 0.257) and disease control rates (88.0 vs. 93.8%, P = 0.267) were similar between groups by the mRECIST criteria. ABTH showed no survival advantage over SBTH, with median PFS times of 11.7 months and 13.0 months, respectively (HR = 0.81, 95% CI, 0.52-1.26, P = 0.35) and similar OS times (HR = 1.19, 95% CI, 0.32-4.39, P = 0.8). No significant differences were observed in grade 3-4 TRAEs between groups. Either PD-L1 or PD-1 inhibitor plus bevacizumab combined with TACE-HAIC have similarly excellent therapeutic efficacy with manageable adverse events, representing promising treatment options for uHCC.

BACKGROUND: The senescence marker protein 30 (SMP30) is a calcium-binding protein whose expression decreases with age, and is closely associated with hepatocellular carcinoma (HCC) development. The primary goal of this study was to examine the mechanistic effect of SMP30 on HCC migration and invasion.
METHODS: Bioinformatic and immunohistochemical approaches were used to examine the expression of SMP30 in HCC tissues and its relationship to patient survival. We investigated the effects of SMP30 expression on HCC cell proliferation, migration, invasion, and cell cycle dynamics. cDNA microarray technology was used to determine the gene expression profile of SK-Hep-1 cells following recombinant SMP30 overexpression to identify genes downstream of SMP30 that regulate HCC cell migration and invasion. We identified SMP30 interacting proteins by affinity purification-mass spectrometry (AP-MS) and co-immunoprecipitation/western blotting (COIP-WB).
RESULTS: SMP30 expression was lower in HCC tissues compared with normal liver tissues, and its expression positively correlated with overall survival in HCC patients. Additionally, SMP30 overexpression effectively blocked the migratory and invasive properties of SK-Hep-1 cells, but did not affect either proliferation rates or cell cycle. cDNA microarray results confirmed that many of the differentially expressed genes identified are involved in the process of epithelial-mesenchymal transition (EMT). AP-MS and COIP-WB experiments confirmed that Rho-associated protein kinase 1 (ROCK1) interacts with SMP30 in SK-Hep-1 cells, and ROCK1 is known to intimately regulate the EMT process.
CONCLUSIONS: SMP30 inhibits HCC metastasis by influencing the expression of EMT-related proteins after interacting with ROCK1.