Treatment Of Liver Cancer Research Articles

Hierarchical mesoporous silicon and albumin composite microparticles delivering DOX and FU for liver cancer treatment

Drug delivery systems based on hydrogel microcarriers have shown enormous achievements in tumor treatment. Current research direction mainly concentrated on the improvement of the structure and function of the microcarriers to effectively deliver drugs for enhanced cancer treatment with decreased general toxicity. Herein, we put forward novel hierarchical mesoporous silicon nanoparticles (MSNs) and bovine serum albumin (BSA) composite microparticles (MPMSNs@DOX/FU) delivering doxorubicin (DOX) and 5-fluorouracil (FU) for effective tumor therapy with good safety. The DOX and FU could be efficiently loaded in the MSNs, which were further encapsulated into methacrylate BSA (BSAMA) microparticles by applying a microfluidic technique. When transported to the tumor area, DOX and FU will be persistently released from the MPMSNs@DOX/FU and kept locally to lessen general toxicity. Based on these advantages, MPMSNs@DOX/FU could observably kill liver cancer cells in vitro, and evidently suppress the tumor development of liver cancer nude mice model in vivo. These results suggest that such hierarchical hydrogel microparticles are perfect candidates for liver cancer treatment, holding promising expectations for impactful cancer therapy.

Knockout of LINC01134 as a potential treatment for Liver Cancer in HepG2 cells

Liver cancer, a major global health issue, continues to contribute significantly to global deaths. Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, remains a leading cause of cancer-related fatalities. This study explores the potential treatment for HCC by investigating the role of LINC01134, an encoding gene for the LncRNA TLNC1, in mediating the nuclear export of p53. The hypothesis suggests that knocking out the LINC01134 gene in HepG2 cells will decrease p53 nuclear export, leading to increased p53 levels and enhanced cellular responses to DNA damage. The methods include CRISPR CAS-9 for gene knockout, RT-PCR for TLNC1 expression, Immunofluorescence for p53 within the nucleus, and xenograft mouse model for in vivo tumor size reduction. Statistical analysis will be performed using a one-sample T-test. This strategy might effectively improve the cell’s reaction to DNA damage, which could halt or slow the growth of HCC.

Liver cancer wars: plant-derived polyphenols strike back.

Liver cancer currently represents the leading cause of cancer-related death worldwide. The majority of liver cancer arises in the context of chronic inflammation and cirrhosis. Surgery, radiation therapy, and chemotherapy have been the guideline-recommended treatment options for decades. Despite enormous advances in the field of liver cancer therapy, an effective cure is yet to be found. Plant-derived polyphenols constitute a large family of phytochemicals, with pleiotropic effects and little toxicity. They can drive cellular events and modify multiple signaling pathways which involves initiation, progression and metastasis of liver cancer and play an important role in contributing to anti-liver cancer drug development. The potential of plant-derived polyphenols for treating liver cancer has gained attention from research clinicians and pharmaceutical scientists worldwide in the last decades. This review overviews hepatic carcinogenesis and briefly discusses anti-liver cancer mechanisms associated with plant-derived polyphenols, specifically involving cell proliferation, apoptosis, autophagy, angiogenesis, oxidative stress, inflammation, and metastasis. We focus on plant-derived polyphenols with experiment-based chemopreventive and chemotherapeutic properties against liver cancer and generalize their basic molecular mechanisms of action. We also discuss potential opportunities and challenges in translating plant-derived polyphenols from preclinical success into clinical applications.

Advances in the Study of Liver Cancer Stem Cells

Liver cancer is one of the deadliest cancers in the world, and liver cancer stem cells (LCSCs) is a key factor in liver cancer pathogenesis, treatment resistance and disease recurrence. Despite significant advances in the understanding of LCSCs over the past few years, their role in liver cancer pathology remains a challenge. This review addresses the characterization of LCSCs in hepatocellular carcinoma, methods of identification, therapeutic strategies, and how they affect disease progression and patient prognosis. This paper pays special attention to recent studies on molecular markers, signaling pathways, and gene expression characterization of LCSCs. The paper also evaluates a variety of potential therapeutic approaches, including targeted drug therapies against specific signaling pathways, cell surface markers, etc., immunotherapeutic strategies such as CAR-T cell therapy, and tumor vaccines. Although most of these therapeutic strategies are still in the research phase, they offer new hope for the treatment of liver cancer. Finally, this paper discusses the challenges faced in translating these laboratory studies into clinical treatments, as well as potential directions for future research.

Mukia maderaspatana (L.) M. Roem. phytoconstituents: Unveiling their anticancer potentials against hepatocellular carcinoma cells

Globally, hepatocellular carcinoma poses significant health challenges due to its higher incidence and mortality rates. Further adverse effects of synthetic drugs prompted research into herbal plants as safer, more effective and alternative treatments. Mukia maderaspatana (L.) M. Roem. is a traditional medicinal renowned for its therapeutic properties. This study explores the anticancer property of hydroalcoholic leaf extract of M. maderaspatana (HLEMM) against liver carcinoma (HepG2) cells and further unveils the active phytoconstituents. Purification and characterization of HLEMM through spectroscopic analysis (HPLC, UV-Vis, MS, FT-IR, NMR) evidenced 3,3′,4′,5,5′,7–Hexahydroxyflavone (Myricetin) as the active phytoconstituent. Cytotoxicity of HLEMM on HepG2 cells showed a significantly dose-dependent reduction in cell viability with an IC50 of 128.6 ± 0.4 μg/ml. Cell cycle analysis revealed that HLEMM effectively inhibited HepG2 cells at the G2/M phase. Results of the Annexin-V/PI staining study inferred HLEMM-induced apoptosis in the early and late phases of HepG2 cells. Flow cytometry results confirmed the up-regulation of caspase-3 and caspase-9 along with the simultaneous down regulation of Bcl-2, substantiating the activation of apoptosis, a controlled process of programmed cell death due to cellular stress or damage. Depolarization of the mitochondrial membrane in HepG2 cells was confirmed by a decrease in JC-1 fluorescence, as observed under a confocal fluorescent microscope. This tends to indicate the alteration in membrane potential and interference in energy metabolites. In silico biodegradability pattern of Myricetin by BIOWINTM models showed its rapid biodegradation under aerobic conditions and further emphasized its environmental sustainability. In conclusion, this is the first report spotlighting Myricetin as the active compound from M. maderaspatana and further suggests that it could serve as a potential anti-cancer agent for treating liver cancer.

Cryoablation with KCl Solution Enhances Necrosis and Apoptosis of HepG2 Liver Cancer Cells.

Cryoablation has become a valuable treatment modality for the management of liver cancer. However, one of the major challenges in cryosurgery is the incomplete cryodestruction near the edge of the iceball. This issue can be addressed by optimizing cryoablation parameters and administering thermotropic drugs prior to the procedure. These drugs help enhance tumor response, thereby strengthening the destruction of the incomplete frozen zone in liver cance. In the present study, the feasibility and effectiveness of a thermophysical agent, KCl solution, were investigated to enhance the cryodestruction of HepG2 human liver cancer cells. All cryoablation parameters were simultaneously optimized in order to significantly improve the effect of cryoablation, resulting in an increase in the lethal temperature from - 25°C to - 17°C. Subsequently, it was found that the application of KCl solution prior to freezing significantly decreased cell viability post-thaw compared to cryoablation treatment alone. This effect was attributed to the eutectic effect of KCl solution. Importantly, it was found that the combination of KCl solution and freezing was less effective when applied to LO2 human liver normal cells. The data revealed that the ratio of mRNA levels of Bcl-2 and bax decreased significantly more in HepG2 cells than in LO2 cells when cryoablation was used with KCl solution. In conclusion, the results of this study demonstrate the effectiveness of KCl solution in promoting cryoablation and describe a novel therapeutic model for the treatment of liver cancer that may distinguish between cancer and normal cells.

Long-term outcome of adjuvant radiotherapy upon postoperative relapse of centrally located hepatocellular carcinoma: a real-world study

Despite that surgical resection is widely regarded as the most effective approach to the treatment of liver cancer, its safety and efficacy upon centrally located hepatocellular carcinoma (HCC) remain unsatisfactory. In consequence, seeking an integrated treatment, like combined with adjuvant radiotherapy, to enhance the prognosis of patients is of critical importance. By recruiting patients undergoing surgical resection for centrally located HCC ranging from June 2015 to 2020, they were divided into liver resection combined with adjuvant radiotherapy (LR + RT) and mere liver resection (LR) groups. The calculation of propensity score and model of Cox proportional hazards regression were utilized. 193 patients were recruited in aggregation, containing 88 ones undergoing LR + RT, while 105 handled with LR. RT was verified to be an independent factor of prognosis for relapse (HR 0.60). In propensity-score analyses, significant association existed between adjuvant radiotherapy and better disease-free survival (DFS) (Matched, HR 0.60; Adjustment of propensity score, HR 0.60; Inverse probability weighting, HR 0.63). The difference of DFS was apparent within two groups (p value = 0.022), and RT significantly down-regulated early relapse (p value < 0.05) in subgroup analysis. The calculation of E-value revealed robustness of unmeasured confounding. The combination of liver surgical resection with RT is safe and effective towards patients with centrally located HCC, which would notably enhance the prognosis and decrease the early relapse of HCC.

Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression.

Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.

Effects of the nutraceutical myricetin on liver health: a systematic review

This article presents a systematic review addressing the effects of the nutraceutical myricetin on liver health. Nutraceuticals are natural or bioactive substances known for their health benefits and their crucial role in the prevention and treatment of liver diseases. In this context, myricetin, a flavonoid found in various food sources, emerges as a relevant nutraceutical for liver health. This review analyzes 20 preclinical studies demonstrating the benefits of myricetin on liver health, including improvement in Non-Alcoholic Fatty Liver Disease (NAFLD), attenuation of liver injuries, and even its therapeutic potential in the treatment of liver cancer in animal models. However, it was observed that there is a lack of clinical trials that fully explore the potential of myricetin as a nutraceutical. Most existing research is based on preclinical studies, such as animal or cell experiments. Therefore, there is a need for clinical studies to assess the efficacy of myricetin in humans. Furthermore, future research approaches are suggested, including investigating the mechanisms of action of myricetin, determining optimal doses and long-term safety, and developing dietary supplements.

TDF and TAF inhibit liver cancer cell migration, invasion via p7TP3

Tenofovir disoproxil fumarate (TDF) seems to prevent hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV). However, the mechanism is still little known. This study aimed to investigate the the roles and mechanisms of TDF, tenofovir alafenamide fumarate (TAF), and entecavir (ETV) on the malignant characteristics of liver cancer cells. Using the wound-healing assays, transwell assays, matrigel transwell assays, and cell counting kit-8 (CCK-8) assays, it was possible to identify that TDF/TAF, inhibited migration, invasion, and proliferation of HepG2 cells and Huh7 cells. To investigate the mechanisms, we performed TOP/FOP-Flash system, Western blot, and RT-qPCR assays of liver cancer cells cultured with TDF/TAF and found a lower activity of Wnt/β-catenin signaling pathway compared with control cells. Finally, Hepatitis C virus p7 trans-regulated protein 3 (p7TP3), a tumor suppressor in liver cancers, was significantly increased in HepG2 cells and Huh7 cells that treated with TDF/TAF. However, entecavir (ETV)-treated liver cancer cells showed no significant difference in the malignant characteristics of liver cancer cells, activity of Wnt/β-catenin signaling pathway, and expression of p7TP3, compared with the control groups. To conclude, TDF/TAF maybe novel promising therapeutic strategy for liver cancers, including HCC and hepatoblastoma, via Wnt/β-catenin signaling pathway, by up-regulating expression of the tumor suppressor, p7TP3.

Hypobaric hypoxia exposure regulates tissue distribution of nanomedicine for enhanced cancer therapy

BackgroundEffective drug delivery of nanomedicines to targeted sites remains challenging. Given that hypobaric hypoxia and hyperbaric oxygen exposure can significantly change pharmacokinetics of drugs, it is interesting to determine whether they can regulate tissue distribution of nanomedicine, especially in tumor, for enhanced cancer therapy.ResultsHypobaric hypoxia exposure improved the pharmacokinetics of paclitaxel-loaded liposomes and facilitated their distribution in the heart and liver, whereas hyperbaric oxygen exposure did not benefit and even impaired the pharmacokinetics and distribution. Particularly, both hypobaric hypoxia and hyperbaric oxygen exposure could not improve the distribution in subcutaneous tumor. Thus, we constructed orthotopic liver tumor model and discussed whether high distribution of the liposomal nanomedicine in the liver, facilitated by hypobaric hypoxia exposure, could ensure their effective accumulation in liver tumor for enhanced cancer therapy.ConclusionsThe liposomal nanomedicine with adjuvant hypobaric hypoxia exposure significantly inhibited the growth of orthotopic liver tumor for prolonged survival time, achieved by hypobaric hypoxia-promoted accumulation at tumor sites of the liver. It might be the first example of the application of adjuvant intermittent hypobaric hypoxia exposure in treating liver cancer.

Analysing the Anticancer Properties of Pterostilbene Through Absorption, Distribution, Metabolism, and Excretion (ADME) and Molecular Docking Studies.

Aim The aim of this study is to examine the possible therapeutic effect of pterostilbene (PTS), a chemical present in grapes and blueberries, in the treatment of liver cancer by analysing its interactions with important proteins linked to the wingless/integrated (Wnt) signaling system. Objective Using computational techniques like molecular docking and absorption, distribution, metabolism, and excretion (ADME) studies, this research focuses on examining the pharmacokinetics and molecular interactions of PTS with proteins such as vimentin (Vim), glycogen synthase kinase 3 beta (GSK3-β), epithelial cadherin (E-cadherin), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), c-Jun N-terminal kinase (JNK), and Wnt, all of which are connected to the Wnt signaling pathway in liver cancer. Methods The study includes the synthesis of proteins and ligands, ADME investigations for PTS, and AutoDock Vina molecular docking simulations to evaluate binding affinities and interactions. PTS is obtained from PubChem, while protein structures are obtained from the Protein Data Bank. Results Strong binding affinities between PTS and essential proteins in the Wnt signaling cascade are shown by molecular docking, which also highlights noteworthy hydrogen bonds, hydrophobic interactions, and electrostatic contacts. According to an ADME study, PTS has advantageous pharmacokinetic properties, such as moderate solubility, membrane permeability, and a minimal chance of drug interactions. Conclusion The extensive study highlights PTS's potential as a viable treatment option for liver cancer. The study promotes its investigation in cutting-edge liver cancer therapy approaches and urges more investigation into the molecular mechanisms, underpinning its anticancer properties. This paper sheds important light on the role of natural chemicals in cancer therapy and emphasizes the need for computational methods in drug discovery.

Stigmatization of drinking patients with liver cancer: The role of socioeconomic status

Patients with liver cancer may face stigmatization due to cancer, alcohol consumption, or both. This study addresses gaps in the existing literature regarding stigmatization of alcohol-related liver cancer patients, particularly its connection with socioeconomic status (SES). The study explores whether the SES of a fictional character with alcohol addiction and liver cancer influences stigma levels reported by participants. Additionally, it investigates how participants' personal characteristics, such as alcohol consumption and healthcare professional status, impact stigmatization. This study aims to provide new insights regarding the role of stigmatization in liver cancer treatment and management, emphasizing in socioeconomic determinants. The method is based on three scenarios describing a woman character with alcohol abuse and liver cancer. The scenarios depicted a woman character with either low, medium or high SES. Each participant (N = 991) was randomly assigned to one of the three scenarios. After reading it, each participant answered questionnaires assessing negative attitudes towards the character. Four scales were used: “Negative attributions about people with health problems”, “Causality of cancer”, “Controllability of drinking” and “Reluctance to helping behavior”. Data were analyzed using ANOVA and t-tests. The scenario describing a character with a low SES significantly received more “Negative attributions about people with health problems” than the character with medium or high SES. Participants having higher alcohol consumption themselves showed lower stigma scores for three out of four scales than participants with lower consumption. In addition, participants identified as health professionals had lower stigma scores regarding the scales “Negative attributions about people with health problems” and “Controllability of drinking”, and higher scores for the subscale “Reluctance to helping behavior”, compared with non-professionals. A character with low SES received more negative attributions than the one with higher SES. Participants’ own alcohol consumption and professional status (being health professional or not), influenced their stigmatizing attitudes.

Preparation and Evaluation of Chitosan Coated PLGA Nanoparticles Encapsulating Ivosidenib with Enhanced Cytotoxicity Against Human Liver Cancer Cells.

Ivosidenib (IVO), an isocitrate dehydrogenase-1 (IDH1) used for treatment of acute myeloid leukemia (AML) and cholangiocarcinoma. However, poor solubility, low bioavailability, high dose and side effects limit clinical application of IVO. Ivosidenib-loaded PLGA nanoparticles (IVO-PLGA-NPs) and Ivosidenib-loaded chitosan coated PLGA nanoparticles (IVO-CS-PLGA-NPs) were prepared using emulsification and solvent evaporation method for the treatment of liver cancer. The developed IVO-PLGA-NPs were evaluated for their particle size (171.7±4.9 nm), PDI (0.333), ZP (-23.0±5.8 mV), EE (96.3±4.3%), and DL (9.66±1.1%); similarly, the IVO-CS-PLGA-NPs were evaluated for their particle size (177.3±5.2 nm), PDI (0.311), ZP +25.9±5.7 mV, EE (90.8±5.7%), and DL (9.42±0.7%). The chitosan coating of IVO-PLGA-NPs was evidenced by an increase in mean particle size and positive ZP value. Because of the chitosan coating, the IVO-CS-PLGA-NPs showed a more stable and prolonged release of IVO than IVO-PLGA-NPs. In comparison to pure-IVO, the IVO-PLGA-NPs and IVO-CS-PLGA-NPs were found to be more effective against HepG2 cells, with IC50 values for the MTT assay being approximately half of those of pure-IVO. In HepG2 cells, the expressions of caspase-3, caspase-9, and p53 were significantly (p < 0.05) elevated. Overall, these findings suggest that chitosan coating of IVO-PLGA-NPs improves the delivery and efficacy of ivosidenib in liver cancer treatment.

Radiofrequency ablation versus microwave ablation for hepatocellular carcinoma with cirrhosis: a propensity score analysis.

Radiofrequency ablation (RFA) and microwave ablation (MWA) are the most frequently used percutaneous ablation techniques for the treatment of liver cancer. The aim of our study was to identify the ablation method that had a better long-term prognosis for patients with cirrhotic hepatocellular carcinoma (HCC). This retrospective study consisted of HCC patients with cirrhosis who underwent RFA and MWA between January 2014 to December 2021 at Beijing You'an Hospital. Patients were divided into two groups according to the therapeutic approaches: the RFA group and the MWA group. The prognosis was compared before and after 1:1 propensity score matching (PSM). A total of 800 HCC patients with cirrhosis who received interventional treatment from January 2014 to December 2021 were prospectively enrolled. After PSM, there were 268 patients in each of the RFA and MWA groups. The statistically significant differences in recurrence-free survival (RFS) and overall survival (OS) between RFA and MWA groups can be observed, both before and after PSM. Besides, 1-, 3-year RFS, and 5-year OS rates were higher in those the RFA group than in the MWA group. Age, tumor size, gamma glutamyl transferase (GGT), and hepatitis B surface antigen (HBsAg) were independent risk factors for RFS. Child-Pugh, lymphocyte (Lym), GGT, and treatment modality were independent risk factors for OS. For patients with HCC associated with cirrhosis, RFA can provide a better prognosis than MWA, with lower recurrence and mortality rate.

MiR-122-3p targets UBE2I to regulate the immunosuppression of liver cancer and the intervention of Liujunzi formula

Ethnopharmacological relevanceLiujunzi formula has been used to treat liver cancer in China for many years, but its underlying mechanism remains unclear. We previously found that decreased expression of miR-122-3p was associated with liver cancer. In this study, we aimed to explore the target of miR-122-3p and the effect of the Liujunzi formula on miR-122-3p and its downstream events in liver cancer. Material and methodsBioinformatics pinpointed potential targets of miR-122-3p. The actual target was confirmed by miRNA mimic/inhibitor transfections and a dual-luciferase reporter assay. RNA-seq looked at downstream genes impacted by this target. Flow cytometry checked for changes in T cell apoptosis levels after exposing them to liver cancer cells. Gene expression was measured by RT-qPCR, western blotting, and immunofluorescence staining. ResultsCell experiments found the Liujunzi extract (LJZ) upregulated miR-122-3p and in a dose-dependent manner. Bioinformatics analysis found UBE2I was a potential target of miR-122-3p, which was validated through experiments using miRNA mimics/inhibitors and a dual-luciferase reporter assay. RNA-seq data implicated the NF-κB pathway as being downstream of the miR-122-3p/UBE2I axis, further confirmed by forcing overexpression of UBE2I. Bioinformatic evidence suggested a link between UBE2I and T cell infiltration in liver cancer. Given that the NF-κB pathway drives PD-L1 expression, which can inhibit T cell infiltration, we investigated whether PD-L1 is a downstream effector of miR-122-3p/UBE2I. This was corroborated through mining public databases, UBE2I overexpression studies, and tumor-T cell co-culture assays. In addition, we also confirmed that LJZ downregulates UBE2I and NF-κB/PD-L1 pathways through miR-122-3p. LJZ also suppressed SUMOylation in liver cancer cells and protected PD-1+ T cells from apoptosis induced by co-culture with tumor cells. Strikingly, a miR-122-3p inhibitor abrogated LJZ's effects on UBE2I and PD-L1, and UBE2I overexpression rescued the LJZ-mediated effects on NF-κB and PD-L1. ConclusionsmiR-122-3p targets UBE2I, thereby suppressing the NF-κB signaling cascade and downregulating PD-L1 expression, which potentiates anti-tumor immune responses. LJZ bolsters anti-tumor immunity by modulating the miR-122-3p/UBE2I/NF-κB/PD-L1 axis in liver cancer cells.

Sterigmatocystin induces autophagic and apoptotic cell death of liver cancer cells via downregulation of XIAP

XIAP, or the X-linked Inhibitor of Apoptosis Protein, is the most extensively studied member within the IAP gene family. It possesses the capability to impede apoptosis through direct inhibition of caspase activity. Various kinds of cancers overexpress XIAP to enable cancer cells to avoid apoptosis. Consequently, the inhibition of XIAP holds significant clinical implications for the development of anti-tumor medications and the treatment of cancer. In this study, sterigmatocystin, a natural compound obtained from the genus asperigillus, was demonstrated to be able to induce apoptotic and autophagic cell death in liver cancer cells. Mechanistically, sterigmatocystin induces apoptosis by downregulation of XIAP expression. Additionally, sterigmatocystin treatment induces cell cycle arrest, blocks cell proliferation, and slows down colony formation in liver cancer cells. Importantly, sterigmatocystin exhibits a remarkable therapeutic effect in a nude mice model. Our findings revealed a novel mechanism through which sterigmatocystin induces apoptotic and autophagic cell death of liver cancer cells by suppressing XIAP expression, this offers a promising therapeutic approach for treating liver cancer patients.

Therapeutic targeting at genome mutations of liver cancer by the insertion of HSV1 thymidine kinase through Cas9-mediated editing.

Liver cancer is one of the most lethal malignancies for humans. The treatment options for advanced-stage liver cancer remain limited. A new treatment is urgently needed to reduce the mortality of the disease. In this report, we developed a technology for mutation site insertion of a suicide gene (herpes simplex virus type 1- thymidine kinase) based on type II CRISPR RNA-guided endonuclease Cas9-mediated genome editing to treat liver cancers. We applied the strategy to 3 different mutations: S45P mutation of catenin beta 1, chromosome breakpoint of solute carrier family 45 member 2-alpha-methylacyl-CoA racemase gene fusion, and V235G mutation of SAFB-like transcription modulator. The results showed that the herpes simplex virus type 1-thymidine kinase insertion rate at the S45P mutation site of catenin beta 1 reached 77.8%, while the insertion rates at the breakpoint of solute carrier family 45 member 2 - alpha-methylacyl-CoA racemase gene fusion were 95.1%-98.7%, and the insertion at V235G of SAFB-like transcription modulator was 51.4%. When these targeting reagents were applied to treat mouse spontaneous liver cancer induced by catenin beta 1S45P or solute carrier family 45 member 2-alpha-methylacyl-CoA racemase, the mice experienced reduced tumor burden and increased survival rate. Similar results were also obtained for the xenografted liver cancer model: Significant reduction of tumor volume, reduction of metastasis rate, and improved survival were found in mice treated with the targeting reagent, in comparison with the control-treated groups. Our studies suggested that mutation targeting may hold promise as a versatile and effective approach to treating liver cancers.

Development of an aptamer capable of multidrug resistance reversal for tumor combination chemotherapy

Multidrug resistance (MDR) is a major factor in the failure of many forms of tumor chemotherapy. Development of a specific ligand for MDR-reversal would enhance the intracellular accumulation of therapeutic agents and effectively improve the tumor treatments. Here, an aptamer was screened against a doxorubicin (DOX)-resistant human hepatocellular carcinoma cell line (HepG2/DOX) via cell-based systematic evolution of ligands by exponential enrichment. A 50 nt truncated sequence termed d3 was obtained with high affinity and specificity for HepG2/DOX cells. Multidrug resistance protein 1 (MDR1) is determined to be a possible recognition target of the selected aptamer. Aptamer d3 binding was revealed to block the MDR of the tumor cells and increase the accumulation of intracellular anticancer drugs, including DOX, vincristine, and paclitaxel, which led to a boost to the cell killing of the anticancer drugs and lowering their survival of the tumor cells. The aptamer d3-mediated MDR-reversal for effective chemotherapy was further verified in an in vivo animal model, and combination of aptamer d3 with DOX significantly improved the suppression of tumor growth by treating a xenograft HepG2/DOX tumor in vivo. This work demonstrates the feasibility of a therapeutic DNA aptamer as a tumor MDR-reversal agent, and combination of the selected aptamer with chemotherapeutic drugs shows great potential for liver cancer treatments.

Comprehensive prognostic and immune analysis of sterol O-acyltransferase 1 in patients with hepatocellular carcinoma.

Sterol O-acyltransferase 1 (SOAT1) is an important target in the diagnosis and treatment of liver cancer. However, the prognostic value of SOAT1 in patients with hepatocellular carcinoma (HCC) is still not clear. To investigate the correlation of SOAT1 expression with HCC, using RNA-seq and gene expression data of The Cancer Genome Atlas (TCGA)-liver hepatocellular carcinoma (LIHC) and pan-cancer. The correlation between SOAT1 expression and HCC was analyzed. Cox hazard regression models were conducted to investigate the prognostic value of SOAT1 in HCC. Overall survival and disease-specific survival were explored based on TCGA-LIHC data. Biological processes and functional pathways mediated by SOAT1 were characterized by gene ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes. In addition, the protein-protein interaction network and co-expression analyses of SOAT1 in HCC were performed to better understand the regulatory mechanisms of SOAT1 in this malignancy. SOAT1 and SOAT2 were highly expressed in unpaired samples, while only SOAT1 was highly expressed in paired samples. The area under the receiver operating characteristic curve of SOAT1 expression in tumor samples from LIHC patients compared with para-carcinoma tissues was 0.748, while the area under the curve of SOAT1 expression in tumor samples from LIHC patients compared with GTEx was 0.676. Patients with higher SOAT1 expression had lower survival rates. Results from GO/KEGG and gene set enrichment analyses suggested that the PI3K/AKT signaling pathway, the IL-18 signaling pathway, the calcium signaling pathway, secreted factors, the Wnt signaling pathway, the Jak/STAT signaling pathway, the MAPK family signaling pathway, and cell-cell communication were involved in such association. SOAT1 expression was positively associated with the abundance of macrophages, Th2 cells, T helper cells, CD56bright natural killer cells, and Th1 cells, and negatively linked to the abundance of Th17 cells, dendritic cells, and cytotoxic cells. Our findings demonstrate that SOAT1 may serve as a novel target for HCC treatment, which is helpful for the development of new strategies for immunotherapy and metabolic therapy.