Anti HCV activity and expression inhibition of HCC markers by protein extract from Iberis gibraltarica / Atividade anti-HCV e inibição da expressão de marcadores HCC por extrato de proteína de Iberis gibraltarica

Hepatitis C virus infection (HCV) is the foremost reason of progressive hepatic fibrosis and cirrhosis, with an elevated risk of hepatocellular carcinoma (HCC) development. Medicinal plants have been used for human health benefits for several years, but their therapeutic potential needs to be explored. The main objective of this study was to figure out the in vitro antiviral and anticancer characteristics of total crude protein of Iberis gibraltarica against HCV and HCC. Total crude protein of Iberis gibraltarica was isolated and quantified. The level of cytotoxicity was measured against the HepG2 cell line and it shows no significant cytotoxicity at the concentration of 504µg/ml. The anti-HCV effect was determined by absolute quantification via real time RT-PCR method and viral titer was reduced up to 66% in a dose dependent manner against the total protein of Iberis gibraltarica. The anticancer potential of Iberis gibraltarica was also examined through mRNA expression studies of AFP and GPC3 genes against the total protein of Iberis gibraltarica-treated HepG2 cells. The results show up to 90% of the down-regulation expression of AFP and GPC3. The obtained results indicate the therapeutic potential of total protein of Iberis gibraltarica against HCV and hepatocellular carcinoma in vitro.

A infecção pelo vírus da hepatite C (HCV) é a principal causa de fibrose hepática progressiva e cirrose, com risco elevado de desenvolvimento de carcinoma hepatocelular (HCC). As plantas medicinais vêm sendo utilizadas para benefícios à saúde humana há vários anos, mas seu potencial terapêutico precisa ser explorado. O principal objetivo deste estudo foi descobrir as características antivirais e anticancerígenas in vitro da proteína bruta total de Iberis gibraltarica contra HCV e HCC. A proteína bruta total de Iberis gibraltarica foi isolada e quantificada. O nível de citotoxicidade foi medido contra a linha celular HepG2 e não apresenta citotoxicidade significativa na concentração de 504µg/ml. O efeito anti-HCV foi determinado por quantificação absoluta através do método RT-PCR em tempo real e o título viral foi reduzido em até 66% de forma dose-dependente contra a proteína total de Iberis gibraltarica. O potencial anticancerígeno de Iberis gibraltarica também foi examinado através de estudos de expressão de mRNA dos genes AFP e GPC3 contra a proteína total de células HepG2 tratadas com Iberis gibraltarica. Os resultados mostram até 90% da expressão de regulação negativa de AFP e GPC3. Os resultados obtidos indicam o potencial terapêutico da proteína total de Iberis gibraltarica contra HCV e carcinoma hepatocelular in vitro.

Assessment of YME1L and mitofusin2 as a possible diagnostic and/or therapeutic target in hepatocellular carcinoma

Mitochondrial dynamics are a contraversal issue in hepatocellular carcinoma. The present study tries to illustrate the role of mitochondrial dynamics proteins (mitofusin-2 (Mfn2) and YME1L) in hepatocarcinogenesis. Five groups were used: the control group and three HCC groups (after 8, 16, and 24 weeks from DENA induction). The last group was treated with Sorafenib (SP) (10 mg/kg), via oral gavage for 4 weeks after cancer induction. This study revealed that Mfn-2 was downregulated and YME1l was overexpressed in different HCC groups. This dysregulation of mitochondrial dynamics proteins was associated with high hepatic levels of cyclin D1, MMP-9, and MDA and overexpression of ki67 as well as decreasing the hepatic expression of tissue inhibitor of matrix metalloproteinase-3 (Timp-3) and Bax. To confirm the possible role of Mfn2 and YME1L in HCC, we assessed the effect of sorafenib on these parameters and its related HCC characteristics. Sorafenib corrected the level of Mfn2 and YME1L and decreased tumor cell proliferation as well. We also elucidated that mitochondrial dynamics proteins (Mfn2 and YME1L) could be a good therapeutic target for HCC.

Synthesis and anti-HCC activity of full 2ʹ-F/OMe-siRNA encapsulated with neutral cytidinyl/cationic lipid / 药学学报

A variety of full 2ʹ-F/OMe-modified siRNAs were designed and synthesized, and the activity against hepatocellular carcinoma Huh-7 and HepG2 cells was evaluated. K&A DNA/RNA H-8 synthesizer was used to synthesize siRNAs, and neutral cytidinyl lipid DNCA mixed with cationic lipid CLD were used to transfect siRNA. By RT-qPCR and CCK-8 assay, the target gene silence and the proliferation of Huh-7 and HepG2 cells were detected. The siRNAs loading into Ago2 protein was detected by RNA-binding protein immunoprecipitation. Drug uptake and cell apoptosis were detected by flow cytometry, and the expression of PLK1 protein was detected by Western blot. Partial full 2ʹ-F/OMe modified siRNAs, especial siPLK1A3, increased the uptake of Huh-7 cells, enhanced their binding to Ago2 and gene silencing activity, down-regulated PLK1 protein, as well as induced more Huh-7 cell apoptosis and proliferation inhibition activity. It provides important data for the development of novel siRNA modification patterns and anti-HCC formulations.

Expression and functions of transient receptor potential channels in liver diseases

Liver diseases constitute a major healthcare burden globally, including acute hepatic injury resulted from acetaminophen overdose, ischemia-reperfusion or hepatotropic viral infection and chronic hepatitis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Attainable treatment strategies for most liver diseases remain inadequate, highlighting the importance of substantial pathogenesis. The transient receptor potential (TRP) channels represent a versatile signalling mechanism regulating fundamental physiological processes in the liver. It is not surprising that liver diseases become a newly explored field to enrich our knowledge of TRP channels. Here, we discuss recent findings revealing TRP functions across the fundamental pathological course from early hepatocellular injury caused by various insults, to inflammation, subsequent fibrosis and hepatoma. We also explore expression levels of TRPs in liver tissues of ALD, NAFLD and HCC patients from Gene Expression Omnibus (GEO) or The Cancer Genome Atlas (TCGA) database and survival analysis estimated by Kaplan-Meier Plotter. At last, we address the therapeutical potential and challenges by pharmacologically targeting TRPs to treat liver diseases. The aim is to provide a better understanding of the implications of TRP channels in liver diseases, contributing to the discovery of novel therapeutic targets and efficient drugs.

Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Accumulating evidence has confirmed the links between transfer RNA (tRNA) modifications and tumor progression. The present study is the first to explore the role of tRNA methyltransferase 5 (TRMT5), which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma (HCC) progression. Here, based on bioinformatics and clinical analyses, we identified that TRMT5 expression was upregulated in HCC, which correlated with poor prognosis. Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro, which may be partially explained by declined extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Mechanistically, we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1 (HIF-1) signaling pathway by preventing HIF-1α stability through the enhancement of cellular oxygen content. Moreover, our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-‍1α. In conclusion, our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs. Thus, TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.

TumorFisher CTC detection technology for the treatment decision of anti-PD-1/PD-L1 in advanced hepatocellular carcinoma and its efficacy evaluation：a case report and literature review / 中国肿瘤生物治疗杂志

@#[摘 要] 肝细胞癌（HCC）的发病率和病死率正在逐年增长，严重威胁人类的健康和生命。近年来，以PD-1/PD-L1抑制剂为代表的免疫治疗迅速发展，但对晚期HCC疗效有限。治疗中实时监测循环肿瘤细胞（CTC）PD-L1表达，是评估免疫治疗有效性的重要指标之一。本案例通过TumorFisher检测技术实时监测1例HCC患者免疫治疗前后总CTC数及PD-L1+ CTC个数，结合影像学和血清学检查结果进一步评估患者免疫治疗疗效。患者治疗前总CTC数为5个/2 mL，PD-L1+ CTC为5个/2 mL，PD-L1+ CTC/总CTC为100%。用PD-1/PD-L1抑制剂行3周期免疫治疗后，PD-L1+ CTC/总CTC逐渐降低，肿瘤缩小，血清AFP及PIVKA-Ⅱ逐渐下降，PD-L1+ CTC/总CTC变化与肿瘤标志物、MRI检查结果一致。PD-L1+ CTC/总CTC可作为HCC免疫治疗疗效评估的辅助指标。

Value of dynamic subtraction MRI in assessing HCC response to image-guided loco-regional therapy

Background: Hepatocellular carcinoma (HCC) is considered one of the foremost cancers worldwide. Although the hepatic resection of HCC has a high existence in the clinical scenarios, locoregional management is preferred owing to the preservation of hepatic parenchyma with lower morbidity and mortality. Dynamic contrast-enhanced MR with subtraction imaging improves the evaluation of managed HCC with easy detection of residual or recurrent viable lesions. Patients and methods: This study was designed in a retrospective pattern from December 2020 to December 2022. Forty patients were referred to our radiology department with solitary HCC, underwent therapeutic intervention, then underwent follow-up by dynamic MRI study. Results: Forty patients with solitary HCC were conducted during our study; all underwent locoregional therapy with follow-up by dynamic MRI with subtraction technique one month later. The subtraction image has a sensitivity of 100%, specificity of 100%, PPV of 100%, NPV of 100%, and 100% accuracy, compared to 90.91%, 77.78%, 83.33%, 87.5%, and 85% for conventional dynamic images, 45.45%, 100%, 100%, 60% and 70% for diffusion-weighted images. Analysis of those results exhibited a considerable additive value of the subtraction technique to the dynamic MRI to detect the response of HCC after management. Conclusions: Subtraction MRI is a pivotal tool to assess the interventional treatment of HCC, particularly in lesions having pre-contrast high signal intensity with distinguished radiologists' confidence

Methyl rosmarinate induces cell apoptosis in human hepatocellular carcinoma cells via inhibiting the Akt/mTOR signaling pathways / 西安交通大学学报(医学版)

【Objective】 To investigate the cell death-inducing effect of methyl rosmarinate (MR) on human hepatoma Hep-3B and SK-Hep1 cells and their potential mechanisms. 【Methods】 The effects of MR on the viability of Hep-3B, SK-Hep1 and MIHA cells were determined by cell counting kit-8 (CCK-8) assay. The morphological changes of three kinds of cells treated with different concentrations of MR were observed by optical microscopy. EdU assay and flow cytometry were used to detect the proliferation and apoptosis of Hep-3B and SK-Hep1 cells. Transwell assay was used to study the effects of MR on the migration and invasion of Hep-3B and SK-Hep1 cells. Western blotting was used to evaluate the protein expression levels of apoptosis, EMT and Akt/mTOR signaling pathways. 【Results】 After treated with different concentrations of MR (0~200 μmol/L) for 48 h, Hep-3B and SK-Hep1 cells activities were significantly decreased in a concentration-dependent manner (P<0.01), while there was no significant effect on MIHA cell activity (P>0.05), and the IC50 of Hep-3B and SK-Hep1 cells were 102.5 and 99.3 μmol/L, respectively. MR treatment (0-150 μmol/L) significantly inhibited the proliferation of Hep-3B and SK-Hep1 cells (P<0.05), while cell detachment and shrinkage were observed by optical microscopy on the Hep-3B and SK-Hep1 cells, while the morphology of MIHA cells was not changed. Compared with the control group, MR (100, 150 μmol/L) induced apoptosis in Hep-3B and SK-Hep1 cells, the expression levels of the pro-apoptotic proteins Bax and cleaved PARP were significantly increased (P<0.05), while the expression level of the anti-apoptotic protein Bcl-2 was significantly decreased (P<0.05). MR (100, 150 μmol/L) also inhibited the migration and invasion of HCC cells, significantly increased the expression of E-cadherin and decreased the expression of N-cadherin and Vimentin compared with the control group (P<0.05). Finally, Western blotting results showed that the expressions of p-Akt and p-mTOR in Hep-3B and SK-Hep1 treated by MR were significantly reduced in a dose-dependent manner, suggesting that MR may play an anti-cancer role by inhibiting Akt/mTOR signaling pathway. 【Conclusion】 MR can promote apoptosis in Hep-3B and SK-Hep1 cells, which may be closely related to the inhibition of Akt/mTOR signaling pathway.

Advances in Molecular Targeted Drugs for Hepatocellular Carcinoma / 中山大学学报(医学科学版)

Being the most common solid malignant tumor in the digestive system and the third leading cause of cancer-related death worldwide， hepatocellular carcinoma （HCC） is characterized by insidious onset， early recurrence/metastasis and poor prognosis. With the advantages of targeted precision， high specificity， minimal drug resistance， remarkable therapeutic efficacy and fewer side effects， molecular targeted drugs have become the hotspot and focus of tumor therapy research in recent years. As more is learned about the mechanism and clinical efficacy， some molecular targeted drugs have been recommended by HCC treatment guidelines. This paper reviewed the mechanism of HCC targeted therapy， molecular targeted drugs， relevant therapeutic protocols and outcomes so as to provide reference and evidence for subsequent research.

Research Progress on Glypican-3 Targeted Therapy in Hepatocellular Carcinoma / 药学实践杂志

Liver cancer is the second leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) being the most common form of primary liver cancer. Glypican-3 (GPC3) is a cell membrane proteoglycan which is rarely expressed in normal adult tissues but is specifically upregulated in HCC, which makes GPC3 a reliable target for the diagnosis and treatment of HCC. The role of GPC3 in the regulation of cancer development through Wnt, YAP, hedgehog and other signaling pathways were reviewed in this article. GPC3-targeted therapies, such as monoclonal antibodies, bispecific antibodies, tumor vaccines, immunotoxins, CAR-T cells, and photosensitizer therapy were also summarized. These treatment methods offered promising approaches for HCC treatment and future treatment strategies for HCC based on GPC3 were prospected in this paper.

Investigation of Hepatitis B Virus X Gene Mutations in Patients with and without Cirrhosis/Hepatocellular Carcinoma

Background: Chronic HBV (CH) infection and its consequences including cirrhosis (C) and Hepatocellular Carcinoma (HCC) still represent a major Global health. The relationship between HCC and various mutations of HBx gene has been reported. In the present study, we aimed to determine the sequence variation of HBx gene in patients with Chronic HBV infection or C/HCC. Materials and Methods : In this cross-sectional study, 15 patients with HBV chronic infection and 13 with C/HCC were included. After viral DNA extraction using commercial kit HBX gene was amplified using an in-house nestedPCR. Then, bi-directional sequencing was performed on the PCR product. The data resulting from sequencing were aligned with reference HBV sequence to identify the mutations. Results : The mean age of CH and C/HCC groups was 38.23�.46 and 50.67�.22 years old, respectively. We found 43 and 20 Amino acid substitutions inside the region of 88�4 from HBx protein in CH and C/HCC groups, respectively. In addition, K130M+V131I mutation was found in 13.34% (2/15) and 30.7% (4/13) of patients in the CH and C/HCC groups, respectively (P=0.36). Furthermore, 10 deletion mutations were observed in both groups with no significant difference (P=0.8). Conclusion : The results of the present study indicated the relatively high frequency of Amino acid substitutions and deletion, especially in part of region 88-154 from HBx Protein in patients with CH and C/HCC. The findings should be considered in a larger population

Quantification of cell-free circulating mitochondrial DNA copy number variation in hepatocellular carcinoma

SUMMARY OBJECTIVE: Hepatocellular carcinoma is the most common primary malignant liver tumor. Mitochondrial DNA copy number has been shown to be associated with various malignancies. However, there has not been any study on the absolute quantification of mtDNA copy number in hepatocellular carcinoma. The aim of this study was to develop a new method for absolute quantification of mtDNA copy number and to relatively quantify the variations in the mtDNA copy number in hepatocellular carcinoma patients in comparison with healthy individuals. METHODS: Venous blood samples were collected from both hepatocellular carcinoma patients (34) and healthy individuals (34). Circulating cell-free DNAs were isolated and the relative quantification of mtDNA copy number variation was determined using quantitative polymerase chain reaction and digital polymerase chain reaction. RESULTS: It was found that the relative mtDNA copy number was significantly decreased in hepatocellular carcinoma patients in comparison with the control group (p<0.05). The median (range) and average of relative mtDNA/β-actin gene of the patients were determined as 42.8 cp/μL (11.1-88.5) and 45.1 cp/μL, respectively, while the median (range) and average relative mtDNA/β-actin gene of the control group were determined as 102.8 cp/μL (55.1-291.8) and 138.7 cp/μL, respectively (p<0.05). When quantitative polymerase chain reaction and digital polymerase chain reaction were compared, mtDNA/β-actin gene copy number ratio of digital polymerase chain reaction results was found to be 1.76-fold more than that of quantitative polymerase chain reaction results. CONCLUSION: Circulating mtDNA copy number was decreased in hepatocellular carcinoma patients in comparison with healthy individuals, and we suggest that it can be used as a noninvasive biomarker for hepatocellular carcinoma diagnosis in the future.

Hepatocarcinoma sobre hígado ectópico intratorácico / Hepatocellular carcinoma in intrathoracic ectopic liver tissue

RESUMEN La presencia de tejido hepático ectópico es una situación inusual que se corresponde con alteraciones en la embriogénesis hepática. Suelen encontrarse de manera incidental y cobran particular importancia por su mayor potencial carcinogénico. El tratamiento de este tipo de patología es habitualmente quirúrgico. Se presenta el caso de una paciente femenina de 27 años que manifestó dolor torácico dorsal; por presentar además una formación evidenciable en la tomografía computarizada se decidió conducta quirúrgica. Asimismo se realiza una revisión bibliográfica del tema.

ABSTRACT Ectopic liver tissue is a rare finding due to aberrant migration of hepatic cells during embryonic development that is mostly found incidentally and has particular relevance because of its significant carcinogenic potential. Surgical management is usually indicated. We report the case of a 27-year-old female patient with thoracic back pain and a mass in the computed tomography scan who underwent surgery. A bibliographic review is also presented.

p53R72P polymorphisms in Mongolian patients with hepatocellular carcinoma / Монголын Анагаах Ухаан

Introduction@#Hepatocellular carcinoma incidence and mortality per 100,000 population in Mongolia is the highest in the world. The individual’s genetic factors and new genetic changes are considered an important effect on the origin and development cancer. We aimed to investigate whether p53R72P polymorphisms were associated with the risk of hepatocellular carcinoma in Mongolian patients.@*Material and Method@#p53R72P polymorphisms were evaluated in 80 controls and 38 HCC cases using a PCRrestriction fragment length polymorphism assay.@*Results@#The mean age was 58.5±13.6 years in the case group and 63.2±8.1 years in the control group. Hepatocellular carcinoma is most common in 50-59 (n=14, 36.8%) and 60-69 (n=14, 36.8%) ages. Of the HCC group, 4 (10.8%) were diagnosed with tumor at stage II, 23 (62.2%) at stage III, and 11 (27%) at stage IV. </br>The results revealed that the heterozygous (Arg/Pro (PR)) genotype of p53R72P increased statistically significant the risk of hepatocellular carcinoma (OR=4.222, 95% CI 1.669-10.684) compared to the wildtype (R/R) genotype. (p=0.002). Moreover, the homozygous (Pro/Pro (P/P)) genotype of p53R72P increased the risk of carcinoma (OR=1.333, 95% CI 0.414-4.299) but not statistically significant. (p=0.63). Heterozygous (Arg/Pro (PR)) genotype of p53R72P in the tumor tissue was associated with a statistically significant (OR=3.3, 95% CI 1.274-8.57) increase in the risk of HCC (p=0.014). Pro/Pro (PP) genotype increased the risk of the carcinoma by 2.4 times (OR=2.44, 95% CI 0.865-6.908), but it was not significant. (p=0.092). Pro/Pro (PP) genotype of p53R72P in the tumor tissue compared to normal tissue of a case group increased the risk of cancer by 1.8 times (OR=1.833, 95% CI 0.472- 7.126), which was not statistically significant (p=0.382).@*Conclusion@#Taken together, Heterozygous (Arg/Pro (PR)) genotype of p53R72P increases the risk of hepatocellular carcinoma in Mongolians. Further studies with larger populations are needed to confirm these results.

Clinical study of pre-transplant immunotherapy effects on the prognosis of recipients with hepatocellular carcinoma after liver transplantation / 中华器官移植杂志

Objective:To explore the effect of pre-transplant immunotherapy on the prognosis of transplant recipients with hepatocellular carcinoma(HCC).Methods:From June 2018 to September 2021, retrospective analysis was conducted for clinical data of 19 HCC-liver transplant recipients receiving pre-transplant immunotherapy in affiliated Huashan Hospital of Fudan University. Pre-transplant immunotherapy regimen, adverse reactions, post-transplant acute rejection, tumor recurrence and metastasis and other complications were recorded. According to the preoperative tumor imaging and the changes of alpha-fetoprotein level, tumor change during recipient waiting period was judged by the mRECIST standard. According to whether or not there was partial tumor remission, they were divided into two groups of non-remission( n=13)and remission( n=6). Postoperative conditions of two groups were compared. Kaplan-Meier method was used for calculating the survival rate of recipients after transplantation and survival curve and Log-rank test utilized for comparing the recurrence-free and overall survival rates of recipients at 1 and 2 years post-operation. Results:A total of 19 liver transplant recipients received immunotherapy plus targeted and transcatheter arterial chemoembolization(TACE) before transplant. In non-remission group, tumor was stable( n=9)and progressive( n=4); 6 cases in remission group had tumor partial remission. Two recipients in non-remission group were pathologically confirmed by liver biopsy to have acute rejection(2/19, 10.5%)and both recovered after glucocorticoid + rATG and glucocorticoid therapy. In non-remission group, 2 patients died from septic shock post-operation. Among 3 patients of tumor recurrence and metastasis post-operation, 2 cases survived with tumor and 1 died after tumor recurrence and metastasis. In remission group( n=6), none had postoperative tumor recurrence and metastasis. The recurrence-free survival rates of non-remission group recipients at 1 and 2 years post-operation were 76.9% and 76.9% and recurrence-free survival rates in remission group were 100% and 100% respectively and inter-group difference in RFS was not statistically significant( χ2=1.468, P=0.226). The overall survival rates of recipients in non-remission group at 1 and 2 years post-operation were 76.9% and 76.9% respectively. And recipients in remission group were 100% and 100% respectively and no statistically significant inter-group difference existed in OS( χ2=1.292, P=0.256). Conclusions:Without a significantly higher risk of acute rejection after transplant, immunotherapy may be an effective option for bridging treatment before liver transplantation for HCC. And it remains necessary to expand the sample size for verifications and supports.

Mechanism of HBx Protein Inhibiting DKK4 Expression and Its Effect on Proliferation and Migration of Hepatocarcinoma Cell Lines / 肿瘤防治研究

Objective To explore the mechanism of hepatitis B virus X protein down-regulating DKK4 and its effect on the proliferation, migration of HCC cell lines. Methods HCC cell lines HepG2 and SMMC7721 cells were infected with adenovirus encoding hepatitis B virus X protein (Ad-HBx), and GFP adenovirus (Ad-GFP) was designed as a control group. We used deacetylase inhibitor (TSA) to treat HCC cell lines and transfected HCC cell lines with small interfering RNA-histone deacetylase 1 (si-HDAC1) and lentivirus overexpressing DKK4. Western blot was used to detect the expression of DKK4, HDAC1 and SIRT1. The proliferation and migration ability of HCC lines were assessed using MTT, crystal violet experiment and Transwell experiment. Results DKK4 expression level was significantly downregulated after Ad-HBx infection (P < 0.05), and its expression level was recovered after TSA treatment (P < 0.05). After silencing HDAC1 with small interfering RNA, the expression of DKK4 could be restored (P < 0.05), the proliferation and migration of HDAC1-silencing or/and DKK4-overexpressing cells decreased (P < 0.05). Conclusion Hepatitis B virus X protein inhibits the expression of DKK4 protein by up-regulating HDAC1 and SIRT1. Silencing HDAC1 and over expressing DKK4 protein could inhibit the proliferation and migration of HCC cell lines infected with Ad-HBx.

Mechanism and Role of circRNA in Occurrence and Development of Hepatocellular Carcinoma / 肿瘤防治研究

Hepatocellular carcinoma (HCC) is the most common pathological type of primary liver cancer, with high fatality rate. The pathogenesis of HCC is complex, and the specific occurrence and development mechanism is still in the exploratory stage. CircRNA is a special endogenous noncoding RNA and mainly participates in the regulation of gene expression at the transcriptional and posttranscriptional levels. By regulating gene transcription, it acts as a molecular sponge of miRNA, participates in protein translation, and interacts with RNA binding protein (RBP). CircRNA is involved in the occurrence and development of HCC. Its abnormal expression in HCC cells is related to the pathological characteristics of HCC tissue, regulates the expression of downstream target genes, miRNA and proteins, participates in the proliferation, migration, invasion and apoptosis of HCC cells, and regulates tumor microenvironment and signal pathways, suggesting that circRNA may be a potential novel biomarker and therapeutic target for the diagnosis and prognosis of HCC. This paper reviews the biological mechanism of circRNA, its role in HCC, and research progress in diagnosis and treatment.

27-P-CAUA induces apoptosis and mitochondrial autophagy in breast cancer cells by inhibiting HER2/PI3K/AKT signaling pathway / 南方医科大学学报

OBJECTIVE@#To investigate the inhibitory effect of 27-P-coumayl-ursolic acid (27-P-CAUA), the active ingredient in triterpenoids from the leaves of Ilex latifolia Thunb, against breast cancer cells and explore the underlying mechanism.@*METHODS@#CCK-8 assay was used to assess the changes in viability of breast cancer HCC-1806 cells after 27-P-CAUA treatment for 24, 48, or 72 h. The inhibitory effect of 27-P-CAUA on proliferation of the cells was determined by clonogenic assay. JC-1 was used to detect the changes in mitochondrial membrane potential and flow cytometry was performed for analyzing cell apoptosis following 27-P-CAUA treatment. Immunofluorescence assay was used to observe the expression of cl-caspase-3 and P62 in the treated cells. Western blotting was performed to observe the effect of 27-P-CAUA and chloroquine pretreatment on the expressions of LC3I/II, P62 and HER2 signaling pathway proteins in the cells.@*RESULTS@#The results of CCK-8 and clonogenic assays showed that 27-P-CAUA treatment significantly inhibited the proliferation of HCC-1806 cells (P < 0.01) with IC50 values of 81.473, 48.392 and 18.467 μmol/L at 24, 48, and 72 h, respectively. 27-P-CAUA treatment also caused obvious changes in mitochondrial membrane potential (P < 0.01) and induced cell apoptosis in HCC-1806 cells with a 3.34% increase of the early apoptosis rate. Immunofluorescence assay revealed a significant increase of cl-caspase3 expression in 27-P-CAUA-treated HCC-1806 cells, and treatment with 40 μmol/L 27-P-CAUA resulted in significant cell apoptosis (P < 0.01). 27-P-CAUA obviously reduced the expression of LC3II, caused P62 degradation and induced autophagy in HCC-1806 cells. Chloroquine pretreatment obviously blocked the autophagy-inducing effect of 27-P-CAUA. 27-P-CAUA treatment also inhibited the phosphorylation of HER2 and AKT proteins and progressively lowered the expressions of HER2 and phosphorylated AKT protein in HCC-1806 cells (P < 0.01).@*CONCLUSION@#27-P-CAUA can inhibit the proliferation and induce mitochondrial autophagy and apoptosis of HCC-1806 cells by inhibiting the HER2/PI3K/AKT signaling pathway.

Hepatocellular carcinoma (HCC) in patients with Non-Alcoholic Fatty Liver Disease (NAFLD): screening, treatment and survival analysis in a Brazilian series

Abstract Objective: The aim of the present study was to evaluate the clinical features, Hepatocellular Carcinoma (HCC) screening, treatment modalities, and Overall Survival (OS) in a series of Non-Alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma (NAFLD-HCC) Brazilian patients. Methods: This was a cross-sectional study at the Instituto do Cancer do Estado de São Paulo, at the Faculdade de Medicina da Universidade de São Paulo with the approval of the local research ethics committee. NAFLD patients with HCC diagnosed, from May 2010 to May 2019, were included. Results: A total of 131 patients were included. Risk factors for NAFLD were present in 94.7% of the patients. Only 29% of patients were in the HCC screening program before diagnosis. HCC treatment was performed in 84.7% of patients. Cumulative survival at the end of the first year was 72%, second-year 52%, and fifth-year 32%. HCC screening before diagnosis was not significantly associated with higher cumulative survival. The independent factors associated with shorter general survival were BCLC C-D, p < 0.001, and the size of the largest nodule > 42 mm, p = 0.039. Conclusions: Although the efficacy of screening in our population regarding overall survival was hampered due to the sample size (29% had screening), BCLC stages C‒D and the size of the largest nodule larger than 42 mm were identified as independent factors of worse prognosis.

Clinical Study of Jiawei Xiaochaihutang Combined with Microwave Ablation in Treatment of Primary Hepatocellular Carcinoma / 中国实验方剂学杂志

ObjectiveTo observe the clinical efficacy of Jiawei Xiaochaihutang combined with microwave ablation （MWA） in the treatment of primary hepatocellular carcinoma （HCC） and its influence on tumor microenvironment. MethodA total of 128 patients were randomly divided into control group （64 cases： 2 cases of dropout，2 cases of elimination，and 60 cases of completion） and observation group （64 cases： 3 cases of dropout，2 cases of elimination，and 59 cases of completion）. Both groups were given comprehensive treatment after MWA surgery. Patients in control group took Biejiajian Wan orally （3 g/time，3 times/d）， and those in observation group took Jiawei Xiaochaihutang （1 dose/d）. The treatment lasted for 3 consecutive months. The size of solid tumor before and after treatment was evaluated to record the progression-free survival （PFS）. The alpha-fetoprotein-L13 （AFP-L3），des-γ-carboxy prothrombin （DCP），Golgi protein 73 （GP73），tumor necrosis factor-α （TNF-α），transforming growth factor-β （TGF-β），vascular endothelial growth factor （VEGF） and matrix metalloproteinase-2 （MMP-2） levels，as well as performance status （PS），liver function and syndrome of liver depression and Qi stagnation scores were also detected before and after treatment. In addition， the incidence of side effects of grade Ⅲ and above was compared. ResultThe total effective rate of solid tumor in observation group was 91.53% （54/59），higher than that （76.67%， 46/60） in control group（χ2=4.895，P<0.05）. The PFS in observation group was （7.16±0.95） months， longer than that （6.24±0.89 months） in control group （P<0.01）. The effective rate of traditional Chinese medicine （TCM） syndrome in observation and control groups were 88.14% （52/59）and 70.00% （42/60）， respectively （χ2=5.897，P<0.05）. The observation group （57.63%，34/59） had higher marked effective rate of TCM syndrome than control group （31.67%，19/60） （χ2=8.116，P<0.01）. The AFP-13，DCP，GP73，TNF-α，TGF-β，VEGF and MMP-2 levels and the PS，liver function and syndrome of liver depression and Qi stagnation scores in observation group were lower than those in control group （both P<0.01）. The cumulative incidence of side effects of grade Ⅲ and above in observation and control groups was 16.95% and 33.33%， respectively（χ2=4.261，P<0.05）. ConclusionConsolidation treatment of HCC after MWA surgery with Jiawei Xiaochaihutang relieved symptoms and side effects，improved PS and liver function，regulated tumor microenvironment，inhibited tumor markers and prolonged survival time. The clinical effect was better than that of Biejia decoction pill， and thus it was worthy of clinical use.