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Hepatocellular carcinoma (HCC) is the most common malignant hepatobiliary disease; it is responsible for about 1 million deaths per year. Risk factors include hepatitis B and C, hepatic cirrhosis, including alcohol related hepatitis, metabolic and nutritional hepatic damage. The main modality of diffusion is intrahepatic in the natural course of th...
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Primary liver cancer is one of the commonest causes of death. Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers. For patients with unresectable or metastatic HCC, conventional chemotherapy is of limited or no benefit. Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall surviv...
ADVANCED HEPATOCELLULAR CARCINOMA (HCC) IS A MALIGNANCY OF GLOBAL IMPORTANCE: it is the sixth most common cancer and the third most common cause of cancer-related mortality worldwide. Despite decades of efforts by many investigators, systemic chemotherapy or hormone therapy has failed to demonstrate improved survival in patients with HCC.. Ongoing...
Citations
... Hepatocellular carcinoma (HCC) is an invasive type of cancer that leads to over 700,000 deaths annually worldwide (1). This tragedy occurs due to lack of effective diagnostic tools as well as efficient therapeutic approaches (2,3). Although surgical removal, liver transplants, and chemotherapeutic agents are the most commonly used treatments for HCC, they are ineffective in many cases due to multifocal development and distant metastasis caused by late diagnosis (4,5). ...
Hepatocellular carcinoma (HCC) is one of the deadliest cancers due to multifocal development and distant metastasis resulting from late diagnosis. Consequently, new approaches to HCC diagnosis and treatment are required to reduce mortality rates. A large body of evidence suggests that non-coding RNAs (ncRNAs) are important in cancer initiation and progression. Cancer cells release many of these ncRNAs into the blood or urine, enabling their use as a diagnostic tool. Circular RNAs (CircRNAs) are as a members of the ncRNAs that regulate cancer cell expansion, migration, metastasis, and chemoresistance through different mechanisms such as the Wnt/β-catenin Signaling pathway. The Wnt/β-catenin pathway plays prominent roles in several biological processes including organogenesis, stem cell regeneration, and cell survival. Aberrant signaling of both pathways mentioned above could affect the progression and metastasis of many cancers, including HCC. Based on several studies investigated in the current review, circRNAs have an effect on HCC formation and progression by sponging miRNAs and RNA-binding proteins (RBPs) and regulating the Wnt/β-catenin signaling pathway. Therefore, circRNAs/miRNAs or RBPs/Wnt/β-catenin signaling pathway could be considered promising prognostic and therapeutic targets in HCC.
... Chemotherapeutic agents may be used in lower as well as higher doses, but the higher dosages provide a better efficacy profile, while the lower dosages give a better safety profile (Rossi et al., 2010;Al-Zubairi, 2017). Therefore, it is urgent to develop probable therapeutic agents for better efficacy as well as a safety profile to sustain the clinical benefits in cancerous patients. ...
Background:
The natural compound's alternative and complementary uses have increased hopes for hepatocellular cancer treatment (HCC).
Objects:
The goal of this study was to see if Piceatannol (PIC) in combination with cisplatin has a synergistic effect on N, N-nitrosodiethylamine (DEN)-induced HCC in rats.
Methods:
Tissue antioxidant enzymes, malondialdehyde (MDA), and nuclear factor erythroid 2 related factors 2 (Nrf2) and tumor necrosis factor α (TNF-α) gene expression were all measured. Nuclear Factor Kabba B (NF-κB) was also tested, as well as hepatic caspase 3 and NAD (P) H quinone oxidoreductase 1 (NQO1). Liver specimens were subjected to histopathological analysis.
Results:
When compared to the HCC group, piceatannol and/or cisplatin caused a significant improvement in liver function tests, as well as a significant modulation in Nrf2 gene expression and antioxidant enzyme activities, as well as a significant decrease in tissue MDA, TNF-α, NF-κB levels, NQO1 activity, and prompt and caspase-3 activities. When the PIC and/or cisplatin combination was compared to each of these compounds alone, the results were substantial.
Conclusion:
PIC in combination with cisplatin has been shown to have a synergistic anticancer impact through modulating Nrf2 and redox state. In addition, adding PIC to an HCC therapy plan that includes chemotherapeutic medicines may boost the efficacy of cisplatin while reducing its negative effects.
... Risk factors include hepatitis B and hepatitis C infections, smoking, alcohol use, obesity, cirrhosis, aflatoxin exposure, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and hemochromatosis [17]. Several systemic and local drug therapies have been developed, yet surgical resection and liver transplantation remain the single realistic possibility of cure [18]. Exploring new molecules for the treatment of HCC and revealing their efficacy could, therefore, reveal alternative treatment strategies for patients who cannot be treated surgically and allow the development of combination treatments for advanced HCC patients [19]. ...
Background
Imidazole nucleus has been used efficiently in the development of many drug molecules due to its therapeutic effects. Many derivatives of it have been produced particularly for use in cancer treatment. However, the anti-cancer effects of imidazole nucleus in liver cancer cells are as yet unclear. In this study, we aimed to investigate the anti-cancer effects of imidazole nucleus in hepatocellular carcinoma (HCC) cell lines.
Methods and results
Anti-cancer effect of imidazole nucleus was investigated using cell viability assay, apoptosis analysis, cell migration analysis, cell morphology analysis, colony formation assay and 3D cell culture techniques in HuH-7 and Mahlavu cell lines. Also, effect of imidazole on AKT and ERK1/2 pathways were determined using by western blot analysis. Imidazole decreased cell viability in both HCC cell lines in a dose and time-dependent manner and also suppressed the colony forming ability of the cells (p < 0.05). Imidazole increased the cleaved caspase 3 protein levels and thus induced apoptosis (p < 0.05). Imidazole induced morphological alterations and autophagy by increasing intracellular vacuolization. Also, imidazole decreased the viability and dimensions of HCC cell tumor spheroids produced in 3D cell cultures (p < 0.05). Moreover, it was observed that all of these effects, are defined above, appeared in parallel with suppression of AKT and ERK1/2 signaling pathways by imidazole nucleus.
Conclusions
The findings of this present study established the anti-cancer effects of imidazole nucleus in HCC cell lines and showed that it could be a potential molecule in the treatment of HCC via inhibition of AKT and ERK1/2 signaling pathways.
... The Barcelona-Clinic Liver Cancer Classification (BCLC) is currently a useful method for staging patients and recommending treatments depending on the number and size of the tumor nodules, liver function, the presence of vascular invasion, and extrahepatic metastasis [3,4]. While ablation, resection, and orthotopic liver transplantation are indicated at very early and early stages of the disease [5,6], Sfb is the current most administered drug for the treatment of patients advanced HCC [6][7][8]. Unfortunately, Sfb only provides very limited clinical benefit to patients, the five-year survival rate remaining extremely low [7,8]. ...
Simple Summary
Hepatocellular carcinoma (HCC) is the fourth most frequent cause of cancer-related mortality worldwide. While ablation, resection and orthotopic liver transplantation are indicated at an early stage of the disease, Sorafenib (Sfb) is the current most administrated first-line treatment for advanced HCC, even though its therapeutic benefit is limited due to the appearance of resistance. Deep knowledge on the molecular consequences of Sfb-treatment is essentially required for optimizing novel therapeutic strategies to improve the outcomes for patients with advanced HCC. In this study, we analyzed differential gene expression changes in two well characterized liver cancer cell lines upon a Sfb-treatment, demonstrating that both lines responded similarly to the treatment. Our results provide valuable information on the molecular action of Sfb on diverse cellular fundamental processes such as DNA repair, translation and proteostasis and identify rationalization issues that could provide a different therapeutic perspective to Sfb.
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent and essentially incurable cancers in its advanced stages. The tyrosine kinase inhibitor Sorafenib (Sfb) remains the globally accepted treatment for advanced HCC. However, the extent of its therapeutic benefit is limited. Sfb exerts antitumor activity through its cytotoxic, anti-proliferative and pro-apoptotic roles in HCC cells. To better understand the molecular mechanisms underlying these effects, we used RNA sequencing to generate comprehensive transcriptome profiles of HepG2 and SNU423, hepatoblastoma- (HB) and HCC-derived cell lines, respectively, following a Sfb treatment at a pharmacological dose. This resulted in similar alterations of gene expression in both cell lines. Genes functionally related to membrane trafficking, stress-responsible and unfolded protein responses, circadian clock and activation of apoptosis were predominantly upregulated, while genes involved in cell growth and cycle, DNA replication and repair, ribosome biogenesis, translation initiation and proteostasis were downregulated. Our results suggest that Sfb causes primary effects on cellular stress that lead to upregulation of selective responses to compensate for its negative effect and restore homeostasis. No significant differences were found specifically affecting each cell line, indicating the robustness of the Sfb mechanism of action despite the heterogeneity of liver cancer. We discuss our results on terms of providing rationalization for possible strategies to improve Sfb clinical outcomes.
... So far, early-stage HCC patients are amenable to curative therapy. The available treatment approaches for HCC include resection, liver transplantation, image-guided tumor ablation, and systemic therapy [4]. However, the prognosis of HCC patients is still not satisfactory, owing to tumor recurrence and metastasis with high frequency [5]. ...
... HCC accounts for >80% of primary liver cancers and is also the fourth main cause of cancer mortality worldwide [3]. Although the available treatment approaches for earlystage HCC include resection, liver transplantation has been developed [4]. The prognosis of HCC patients is still not satisfactory, owing to tumor recurrence and metastasis with high frequency [5]. ...
Recently, accumulating evidence has supported that circular RNA (circRNA) plays important roles in tumorigenesis by regulating gene expression at transcriptional and post-transcriptional levels. Expression of circRNAs can be epigenetically silenced by DNA methylation; however, the underlying regulatory mechanisms of circRNAs by DNA methylation remains largely unknown. We explored this regulation in hepatocellular carcinoma (HCC) using genome-wide DNA methylation and RNA sequencing data of the primary tumor and matched adjacent normal tissues from 20 HCC patients. Our pipeline identified 1012 upregulated and 747 downregulated circRNAs (collectively referred to as differentially expressed circRNAs, or DE circRNAs) from HCC RNA-seq data. Among them, 329 DE circRNAs covered differentially methylated sites (adjusted p-value < 0.05, |ΔM| > 0.5) in circRNAs’ interior and/or flanking regions. Interestingly, the corresponding parental genes of 46 upregulated and 31 downregulated circRNAs did not show significant expression change in the HCC tumor versus normal samples. Importantly, 34 of the 77 DE circRNAs (44.2%) had significant correlation with DNA methylation change in HCC (Spearman’s rank-order correlation, p-value < 0.05), suggesting that aberrant DNA methylation might regulate circular RNA expression in HCC. Our study revealed genome-wide differential circRNA expression in HCC. The significant correlation with DNA methylation change suggested that epigenetic regulation might act on both mRNA and circRNA expression. The specific regulation in HCC and general view in other cancer or disease requires further investigation.
... 34 The Wnt/β-catenin pathway extensively participates in tumor growth, but the reason it is overactivated in HCC is still unknown. 35 A recent study showed that circ-0004194 (circβ-catenin) encodes a new protein, β-catenin-370aa, which is a subtype of β-catenin. 36 Additionally, circβ-catenin regulates the expression of β-catenin at the protein level, not at the transcription level. ...
Circular RNAs (circRNAs) constitute a class of covalently closed RNA molecules. With the continuous advancement of high‐throughput sequencing technology and bioinformatics tools, many circRNAs have been identified in various human tissues and cell lines. Notably, recent studies have indicated that some circRNAs have translational functions. Internal ribosome entry sites and the N6‐methyladenosine modification mediate cap‐independent translation. This review describes these two translation mechanisms and verification methods at the molecular level. Databases (including ORF Finder, Pfam, BLASTp, CircRNADb, CircBase, CircPro, CircCode, IRESite, IRESbase) were used to analyze whether circRNAs have the structural characteristic of translation. CircRNA minigene reporter system containing green fluorescent protein (GFP) confirmed the translation potential of circRNAs. Also, we briefly summarize the roles of proteins/peptides encoded by circRNAs (circFBXW7, circFNDC3B, circLgr4, circPPP1R12A, circMAPK1, circβ‐catenin, circGprc5a, circ‐SHPRH, circPINTexon2, circAKT3) that have been verified thus far in human cancers (triple‐negative breast cancer, colon cancer, gastric cancer, hepatocellular carcinoma, bladder cancer, glioblastoma). Those findings suggest circRNAs have a great implication in translation of the human genome.
... .Major intracellular enzymatic pathways are involved in the process of hepatocancerogenesis; and the enzymatic cascade activated by the binding of epidermal growth factor (EGF) to its receptor11 1. Wnt/ ß-catenin (Aflatoxin, Alcohol HBV, Growth factors (EGF/TGF-ß)8. p53 (Aflatoxin,HBV) 9. Hemachromatosis (HBV HBV, HCV A)12 ...
Hepatocellular carcinoma is the leading cause of death in cirrhosis. Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. To review the risk factors, causes, morphology, enzymatic pathways and management strategies involved in hepatocellular carcinoma. A literature search was performed using PubMed for publications with a predetermined search string to identify relevant studies. The diagnosis and treatment schedule used for the successful management of hepatocellular carcinoma. Studies combining sorafenib with locoregional or other targeted molecular therapies are likely to improve responses and outcome.
... (HCC), liver metastasis (LM), and cholangiocarcinoma (CC). Although surgical resection remains the mainstay of liver tumor intervention, less than 25% of patients are candidates for resection due to tumor burden, location, or comorbid disease [2,3]. For example, a prior study found that only 15% of intrahepatic CC tumors and 56% of distal tumors were deemed resectable [4]. ...
Histotripsy is a non-invasive, non-ionizing, and non-thermal focused ultrasound ablation method that is currently being developed for the treatment of liver cancer. Promisingly, histotripsy has been shown for ablating primary (hepatocellular carcinoma, HCC) and metastatic (colorectal liver metastasis, CLM) liver tumors in preclinical and early clinical studies. The feasibility of treating cholangiocarcinoma (CC), a less common primary liver tumor that arises from the bile ducts, has not been explored previously. Given that prior work has established that histotripsy susceptibility is based on tissue mechanical properties, there is a need to explore histotripsy as a treatment for CC due to their dense fibrotic stromal components. In this work, we first investigated the feasibility of histotripsy for ablating CC tumors in vivo in a patient-derived xenograft mouse model. The results showed that histotripsy could generate CC tumor ablation using a 1 MHz small animal histotripsy system with treatment doses of 250, 500, and 1000 pulses/point. A second set of experiments compared the histotripsy doses required to ablate CC tumors to HCC and CLM tumors ex vivo. For this, human tumor samples were harvested after surgery and treated ex vivo with a 700 kHz clinical histotripsy transducer. Results demonstrated significantly higher treatment doses were required to ablate CC and CLM tumors compared to HCC, with the highest treatment dose required for CC tumors. Overall, the results of this study suggest that histotripsy has the potential to be used for the ablation of CC tumors while also highlighting the need for tumor-specific treatment strategies.
... Locoregional therapy has demonstrated improved disease-free and overall survival in patients who cannot undergo resection and is used as a bridge to transplantation or for downstaging borderlineeligible patients for transplant [13]. However, each form of locoregional therapy has different limitations based on tumor location and extent of disease, as well as morbidity based on the degree of underlying liver dysfunction secondary to cirrhosis [4,[14][15][16]. ...
... MRI has been utilized to characterize tumor response and to quantify tumor necrosis in pre-clinical animal and human tumor models as well as for the clinical assessment of locoregional therapies [16,32]. In this study, post-histotripsy MRI results of partially ablated tumors demonstrated clear delineation between treated tumor and residual viable tumor, as seen by differences in their T2 signal (Figures 2(b), 2(c), and 2(d)). ...
Objective and impact statement:
This is the first longitudinal study investigating the effects of histotripsy on local tumor progression in an in vivo orthotopic, immunocompetent rat hepatocellular carcinoma (HCC) model.
Introduction:
Histotripsy is the first noninvasive, nonionizing, nonthermal, mechanical ablation technique using ultrasound to generate acoustic cavitation to liquefy the target tissue into acellular debris with millimeter accuracy. Previously, histotripsy has demonstrated in vivo ablation of noncancerous liver tissue.
Methods:
N1-S1 HCC tumors were generated in the livers of immunocompetent rats (n = 6, control; n = 15, treatment). Real-time ultrasound-guided histotripsy was applied to ablate either 100% tumor volume + up to 2mm margin (n = 9, complete treatment) or 50-75% tumor volume (n = 6, partial treatment) by delivering 1-2 cycle histotripsy pulses at 100 Hz PRF (pulse repetition frequency) with p - ≥30MPa using a custom 1MHz transducer. Rats were monitored weekly using MRI (magnetic resonance imaging) for 3 months or until tumors reached ~25mm.
Results:
MRI revealed effective post-histotripsy reduction of tumor burden with near-complete resorption of the ablated tumor in 14/15 (93.3%) treated rats. Histopathology showed <5mm shrunken, non-tumoral, fibrous tissue at the treatment site at 3 months. Rats with increased tumor burden (3/6 control and 1 partial treatment) were euthanized early by 2-4 weeks. In 3 other controls, histology revealed fibrous tissue at original tumor site at 3 months. There was no evidence of histotripsy-induced off-target tissue injury.
Conclusion:
Complete and partial histotripsy ablation resulted in effective tumor removal for 14/15 rats, with no evidence of local tumor progression or recurrence.
... Hepatocellular carcinoma (HCC) is the sixth leading cause of cancer and the third leading cause of cancer death worldwide. It is the number one oncologic cause of death in cirrhotic patients, with approximately one million deaths/year [1,2] . According to the Barcelona Clinic Liver Cancer (BCLC) staging classification, liver resection (LR), radiofrequency ablation (RFA), and liver transplantation (LT) are potentially curative treatments for HCC [3,4] . ...
... Target lesion responseChi-squared test.1 Likelihood ratio test. ...
To compare the outcomes of 64 patients with HCC undergoing DEB-TACE downstaging to fit into Milan criteria(MC) with 136 patients listed for liver transplantation(LT) with HCC undergoing DEB-TACE for bridging.
