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Background: Within the tumor microenvironment, survival pressures are prevalent with potent drivers of tumor progression, angiogenesis, and therapeutic resistance. N6-methyladenosine (m 6 A) methylation has been recognized as a critical post-transcriptional mechanism regulating various aspects of mRNA metabolism. Understanding the intricate interplay between survival pressures and m 6 A modification provides new insights into the molecular mechanisms underlying hepatocellular carcinoma (HCC) progression and highlights the potential for targeting the survival pressures-m 6 A axis in HCC diagnosis and treatment., Data Sources: A literature search was conducted in PubMed, MEDLINE, and Web of Science for relevant articles published up to April 2024. The keywords used for the search included hepatocellular carcinoma, cellular survival, survival pressure, N6-methyladenosine, tumor microenvironment, stress response, and hypoxia., Results: This review delves into the multifaceted roles of survival pressures and m 6 A RNA methylation in HCC, highlighting how survival pressures modulate the m 6 A landscape, the impact of m 6 A modification on survival pressure-responsive gene expression, and the consequent effects on HCC cell survival, proliferation, metastasis, and resistance to treatment. Furthermore, we explored the therapeutic potential of targeting this crosstalk, proposing strategies that leverage the understanding of survival pressures and m 6 A RNA methylation mechanisms to develop novel, and more effective treatments for HCC., Conclusions: The interplay between survival pressures and m 6 A RNA methylation emerges as a complex regulatory network that influences HCC pathogenesis and progression., (Copyright © 2024 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background: Radiofrequency ablation (RFA) is an efficient treatment with unlimited potential for liver cancer that can effectively reduce patient mortality. Understanding the biological process related with RFA treatment is important for improving treatment strategy. This study aimed to identify the critical targets for regulating the efficacy of RFA., Methods: The RFA treatment in hepatocellular carcinoma (HCC) tumor models in vivo, was analyzed by RNA sequencing technology. The heat treatment in vitro for HCC tumor cells was also constructed to explore the mechanism after RFA treatment in tumor cells. Nanoparticles with high affinity to tumor cells were applied as a new therapy to interfere with the expression of maternal embryonic leucine zipper kinase (MELK)., Results: It was found that RFA treatment upregulated MELK expression, and MELK inhibition promoted RFA efficacy by immunogenic cell death and the antitumor response, including anti-tumoral macrophage polarization and increased CD8 + T cell cytotoxicity in HCC. Mechanically, MELK binds to fatty acid-binding protein 5 (FABP5), and affects its ubiquitination through the K48R pathway to increase its stability, thereby activating protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling axis to weaken the RFA-mediated antitumor effect. In addition, the synthesis of arginylglycylaspartic acid (RGD)-lipid nanoparticles (LNPs) targeting tumor cell-intrinsic MELK enhanced RFA efficacy in HCC., Conclusion: MELK is a therapeutic target by regulating RFA efficacy in HCC, and targeting MELK via RGD-LNPs provides new insight into improving RFA efficacy in HCC clinical treatment and combating the malignant progression of liver cancer., Competing Interests: Declarations. Ethical approval and consent to participate: All animal experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee of Wenzhou Medical University (wydw2023-0452). The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Lishui Central Hospital [(2024) No. 177]. The study is retrospective and has been granted an exemption from informed consent. Consent for publication: Not applicable. Competing interests: All authors disclosed no relevant relationships., (© 2025. The Author(s).)

Hepatocellular carcinoma (HCC) is a common malignancy worldwide with poor prognosis and high mortality. The aberrant expression or alteration of microRNAs (miRNAs) contributes to the development and progression of cancer. Studies have shown that miR-455 plays a regulatory role in the development of HCC. Therefore, in the present study, the role of miR-455 was analyzed in HepG2 cells proliferation and apoptosis using MTT and flow cytometry methods. Binding sites were predicted by bioinformatics and luciferase assay was used to verify the target relationship between miR-455 and RhoC-encoding gene RHOC. After that, the effects of miR-455 on RHOC and its product RhoC, were explored by qPCR and Western blotting. As PTEN is a key tumor suppressor gene in HCC, and Bcl-2 and Caspase 3 are important indication of apoptosis, expression levels of PTEN, Bcl2 and Caspase 3 proteins were determined in cells overexpressing RhoC. We show that miR-455 promotes HepG2 cells apoptosis and inhibits proliferation. Bioinformatics analysis and luciferase assay indicate that specific recognition sites for miR-455 are within the RhoC 3'-UTR. Luciferase activity was significantly lower in the cells co-transfected with miR-455 mimics and RhoC-WT (p < 0.01) as compared to that in control cells, pointing that RHOC gene is, indeed, targeted by miR-455. RHOC mRNA was significantly reduced after miR-455 transfection in HepG2 cells. In addition, we show that RhoC could activate the HCC cells proliferation ability and inhibit apoptosis rate (p < 0.01), and decrease expression of PTEN and Caspase 3 (p < 0.01), while upregulating levels of Bcl2. In conclusion, our study indicates that miR-455 plays a suppressive role in HCC development by targeting RhoC-encoding mRNA.

Objective: To analyze the clinical efficacy and safety of (125)I radioactive seed implantation in the treatment of sub-capsular hepatocellular carcinoma (sub-HCC) with sequential radiofrequency ablation and transcatheter arterial chemoembolization (TACE). Methods: The clinical data of 76 cases with advanced HCC with sub-capsular nodules including 68 males and 8 females, with an average age of (58±9) years, ranging from 33 to 78 years, enrolled in Lishui Central Hospital from January 2010 to December 2016 were collected.The average maximum diameter of tumor is (5.7±2.3) cm, ranging from 3.1 cm to 12.0 cm.The patients were divided into TACE+ RFA group and (125)I + TACE+ RFA group with 38 cases in each group.The overall survival (OS) and progression free survival(PFS) were calculated.The clinical efficiency and adverse events were evaluated. Results: The disease control rate were 84.2%(32/38) in (125)I + TACE+ RFA group and 63.2% (24/38) in TACE+ RFA group, χ(2)=4.34, P = 0.04.The median PFS were 18 months in (125)I + TACE+ RFA group and 11 months in TACE+ RFA group, χ(2)=4.84, P =0.03.The FPS cumulative rate in (125)I + TACE+ RFA group were higher than that in TACE+ RFA group at 6 months (94.7%±3.6% vs 81.3%±6.4%, Z =24.1>2.58, P =0.00), 1 year (89.2%±5.1% vs 40.7%±8.3%, Z =13.3>2.58, P =0.00) and 2 year (55.9%±8.6% vs 29.6%±8.2%, Z =7.2>2.58, P =0.00). The median OS were 42 months in (125)I + TACE+ RFA group and 30 months in TACE+ RFA group, χ(2)=4.76, P =0.029.The survival cumulative rate in (125)I+ TACE+ RFA group were higher than that in TACE+ RFA group at 1 year (92.1%±4.4% vs 83.8%±6.1%, Z =23.5>2.58, P =0.00), 2 year (75.8%±7.0% vs 59.8%±8.4%, Z =12.43>2.58, P =0.00), 3 year (59.0%±8.2% vs 41.7%±8.9%, Z =8.3>2.58, P =0.00), 5 year (34.2%±8.2% vs 18.2%±8.1%, Z =5.5>2.58, P =0.00). In addition, there was no statistical difference in liver function and complications between TACE+ RFA group and (125)I+ TACE+ RFA group. Conclusion: (125)I radioactive seed implantation plus TACE combined with RFA treatment is an effective and safe treatment for sub-capsular hepatocellular carcinoma.

To investigate the effects of lentiviral vector-mediated shRNA suppressing CXCR7 on tumour invasion and metastasis in hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). HCCLM3 cell lines were cultured and assigned into the CXCR7-shRNA, negative control (NC) and blank groups. The qRT-PCR and Western blotting were applied to detect the mRNA and protein expressions of CXCR7, CXCR4 and MMP-2 in HCCLM3 cells. Cell proliferation and invasion were evaluated by MTT and Transwell assays. A Buffalo rat model of HCC was established. Fifty model rats were divided into the CXCR7-shRNA + TACE, CXCR7-shRNA, TACE, NC and control groups. Immunohistochemistry was performed to detect the expressions of CXCR7, MMP-2, vascular endothelial growth factor (VEGF) and intratumoral CD31-positive vessel count in tumour tissues of mice. Compared with the blank and NC groups, the mRNA and protein expressions of CXCR7 and MMP-2 were decreased in the CXCR7-shRNA group. The cell proliferation and invasion rates of the CXCR7-shRNA group were lower than the blank and NC groups. At the 4th week after TACE, tumour weight of the CXCR7-shRNA + TACE group increased continuously. The CXCR7-shRNA + TACE group showed longer survival time and smaller tumour sizes than other groups. Compared with other groups, the CXCR7-shRNA + TACE and CXCR7-shRNA groups had less number of lung metastatic nodules and lower expressions of CXCR7, MMP-2, VEGF and CD31-positive vessel count. CXCR7-shRNA inhibits tumour invasion and metastasis to improve the efficacy of TACE in HCC by reducing the expressions of CXCR7, MMP-2 and VEGF., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objective: To investigate the effect of transcatheter arterial chemoembolization(TACE)combined with thymosin alpha1(Tα1)on the autophagy of immune cells from advanced hepatocellular carcinoma. Methods: A total of 30 patients with advanced liver cancer enrolled in Lishui Central Hospital from September 2015 to June 2016 were collected in this study. The average age of patients was 16-75(56±12) years. All patients were treated with TACE after enrolled in hospital in a week. Patients were divided into TACE group and TACE+ Tα1 treatment group(15 cases in each group). Patients in TACE group received a conventional treatment, without any immunotherapy, while the TACE+ Tα1 treatment group accepted TACE following a subcutaneously injection of 1.6 mg Tα1 twice a week for 4 weeks. Flow cytometry was used to detect the T cell subsets in two groups both before and after TACE treatment for 1, 4 weeks and at 3 months follow-up. Peripheral blood mononuclear cells (PBMC) were isolated by density gradient centrifugation. The expression of Beclin-1, LC3 protein and mRNA were detected by Western blot (WB) and PCR respectively. Results: There was no statistical difference of the percentage of CD3(+) , CD4(+) , CD8(+) T cell subsets and Beclin-1, LC3 protein and mRNA expression between the two groups before TACE treatment ( P >0.05). The percentage of CD3(+) , CD4(+) , CD8(+) T cell subsets in TACE+ Tα1 group at 1 week post-TACE treatment (58.45%±16.34%, 38.33%±15.16%, 27.31%±12.54%), at 4 weeks post-TACE treatment (62.38%±18.62%, 43.19%±13.86%, 29.54%±10.33%) and 3 months follow-up (64.15%±13.76%, 41.28%±14.65%, 29.38%±15.65%) were statistically higher than those in TACE group at 1 week post-TACE treatment (53.71%±11.17%, 32.12%±10.53%, 24.45%±13.72%) at 4 weeks post-TACE treatment (52.12%±14.26%, 31.16%±15.43%, 23.39%±15.33%) and 3 months follow-up (54.28%±13.15%, 32.17%±14.98%, 24.34%±14.12%) ( P <0.05). The Beclin-1, LC3 protein and mRNA expression in TACE+ Tα1 group at 1 week post-TACE treatment (protein: 0.57±0.08, 2.26±0.36, mRNA: 0.62±0.11, 2.69±0.27), at 4 weeks post-TACE treatment (protein: 0.66±0.09, 3.11±0.45, mRNA: 0.78±0.13, 3.43±0.61) were higher than those in TACE group at 1 week post-TACE treatment (protein: 0.45±0.16, 1.43±0.30, mRNA: 0.52±0.15, 1.15±0.37), at 4 weeks post-TACE treatment (protein: 0.51±0.13, 1.81±0.35, mRNA: 0.56±0.10, 1.98±0.41) ( P <0.05). But there was no statistically significant difference in the expression of Beclin-1 and LC3 in two groups at 3 months follow-up ( P >0.05). Conclusions: TACE combined with Tα1 significantly increase the level of autophagy in the immune cells of patients with advanced primary hepatocellular carcinoma.

This study evaluated if iodine-125 brachytherapy prophylaxis after radiofrequency ablation (RFA) prolongs time to recurrence (TTR) and overall survival (OS) of patients in high risk of locoregional hepatocellular carcinoma (HCC) recurrence. 116 patients with total tumor necrosis after RFA were divided into iodine-125 brachytherapy prophylaxis treatment group and control group. The primary endpoint was TTR, and secondary endpoints were OS and treatment-related adverse events. There were no significant differences among the baseline characteristics of two subgroups patients. The mean iodine-125 particles were 29.8 (26.59 ± 12.51 mCi) per patient. The mean follow-up was 25 months, and mean TTR of treatment and control groups were 21.7 and 15.9 months (P = 0.733); mean OS of two subgroups were 41.7 and 40.9 months (P = 0.316). There were no significant differences of 1-, 2-, 3-, 4-and 5-years TTR and OS and patients' immunity pre- and 1 month post-treatment. Extrahepatic metastasis was found to have a statistically significant influence on TTR, and AFP, extrahepatic metastasis were found to have a statistically significant influence on OS by multivariate analysis. There was no major complications and procedure related death. Iodine-125 brachytherapy prophylaxis after RFA can't improve TTR and OS of HCC patients who were in high risk of locoregional tumor recurrence.

Our study aims to evaluate the efficacy of transcatheter arterial chemoembolization in the treatment of patients with liver metastasis using integrated 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. A total of 97 liver metastasis patients treated by transcatheter arterial chemoembolization were enrolled in this study. The 18 F-fluorodeoxyglucose positron emission tomography/computed tomography images of liver metastasis patients were collected before and after transcatheter arterial chemoembolization treatment. The efficacy of transcatheter arterial chemoembolization for the treatment of liver metastasis was evaluated according to the revised Response Evaluation Criteria in Solid Tumors guidelines. The receiver operating characteristic curve analysis was used to determine cut-off values of 18 F-fluorodeoxyglucose positron emission tomography parameters (Tsuvmax, Tsuvmax/Lsuvmax, and Tsuvmax/Lsuvmean) for predicting the efficacy of transcatheter arterial chemoembolization. Progression-free survival and the incidence of postoperative complications were compared. Correlation of Tsuvmax, Tsuvmax/Lsuvmax, and Tsuvmax/Lsuvmean with blood supply and lipiodol deposition in the lesion was analyzed. Among three 18 F-fluorodeoxyglucose positron emission tomography parameters, the receiver operating characteristic analysis showed that Tsuvmax/Lsuvmax with a cut-off value of 3.56 was the best predictor of transcatheter arterial chemoembolization efficacy. According to the cut-off value of Tsuvmax/Lsuvmax, liver metastasis patients were divided into the Tsuvmax/Lsuvmax ≤ 3.56 and Tsuvmax/Lsuvmax > 3.56 groups. Compared with the Tsuvmax/Lsuvmax > 3.56 group, the Tsuvmax/Lsuvmax ≤ 3.56 group showed a longer progression-free survival and a lower incidence of postoperative complications. The Tsuvmax, Tsuvmax/Lsuvmax, and Tsuvmax/Lsuvmean in the lesion with abundant blood supply were significantly lower than those in peripheral liver parenchyma, while the Tsuvmax, Tsuvmax/Lsuvmax, and Tsuvmax/Lsuvmean in the lesion with lack of blood supply were significantly higher than those in peripheral liver parenchyma. Spearman correlation analysis indicated that lipiodol deposition in the lesion was positively correlated with the Tsuvmax, Tsuvmax/Lsuvmax, and Tsuvmax/Lsuvmean. The Tsuvmax/Lsuvmax of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography may be a good tool for predicting the blood supply and efficacy of transcatheter arterial chemoembolization for patients with liver metastasis.

Objective: To discuss the association between ultrasound screening frequency and total mortality in patients with HCC before diagnosing HCC, and explore the optimal ultrasound screening frequency for HCC high-risk groups. Methods: Retrospectively collected clinical data of 615 cases of liver cirrhosis who developed to HCC from January 1, 2010 to December 31, 2015. Before diagnosing HCC, all patients were divided into five groups according to ultrasound screening frequency: 0-6, 7-12, 13-24, 25-36 months and not screened within 3 years (never screened). The chance to receive curative therapy, 5-year cumulative mortalities and independent factors of mortality in patients with HCC were analyzed. Results: Chances to receive curative therapy among the 0-6, 7-12, 13-24, 25-36 months and never screened groups were 38.2%, 27.2%, 25.4%, 23.8% and 19.7%, respectively ( P <0.05). The 5-year overall mortality rates were 76.4%, 77.7%, 79.3%, 82.5% and 84.6%, respectively. Compared with 0-6 months, the adjusted OR of mortality for the other groups were 1.112, 1.235, 1.305 and 1.451, respectively (all P <0.05). Multivariate analysis showed that ultrasound screening frequency, curative treatment and Child-Pugh (class A/B) were the factors to affect long-term survival in patients with HCC (all P <0.05). Conclusion: For HCC high-risk groups, optimal ultrasound screening frequency is within 6 months, and high-frequency ultrasound screening can increase the chance of receiving curative treatment, reduce total mortality, and improve overall survival.

Objective: To investigate the clinical efficacy of radiofrequency ablation(RFA)combined with (125)I seed in patients with multiple nodular hepatocellular carcinoma(HCC)., Methods: The clinical data of 47 patients with multiple nodular HCC confirmed clinically or pathologically in the Fifth Affiliated Hospital of Wenzhou Medical University between January 2009 and September 2014 were retrospectively analyzed. All patients were divided into two groups depending on treatment: RFA group(n=29); RFA combined with (125)I seed group(n=18). Survival time was estimated with the Kaplan-Meier analysis. The survival curve was compared by Log-rank test., Results: The clinical data and tumor situation of patients between two groups did not show significant differences. The follow-up time ranged from 2 to 55 months. At the end of the study, the median progression-free survival of two groups were 18 months and 11 months, and the differences were statistically significant(P=0.036). The overall survival rates in RFA combined with (125)I seed group at 1, 2, and 3 years (94.4%, 78.0%, 66.8%, respectively) were higher than those in RFA group (88.5%, 68.6%, 57.1%, respectively). However, the differences between the two groups were not statistically significant(P=0.554)., Conclusions: For multiple nodular HCC, RFA combined with (125)I seed can prolong progression-free survival, have an advantage in local control rate, and is better than single RFA at short-term curative effect.However, its long-term outcomes should be further explored by a large-sample, multi-center and randomized trial.

Purpose: The prognostic value of (18)F-deoxyglucose positron emission tomography ((18)F-FDG PET) on hepatocellular carcinoma (HCC) remains inconclusive. This study aims to investigate the prognostic role of pretreatment (18)F-FDG PET on HCC patients by meta-analysis., Methods: PubMed, Embase, Cochrane library, and Wanfang databases were searched until June 2015. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were synthesized by Stata 10.0, and the combined results were used as effective values., Results: Twenty-two studies containing a total of 1721 patients were identified. According to random-effect model, meta-analysis results showed that high Tumor SUV/Liver SUV (Tsuv/Lsuv) ratio was significantly associated with poorer overall survival (OS) (HR = 2.04; 95% CI 1.50-2.79; P = 0.000) and poorer disease-free survival (HR = 7.17; 95% CI 3.58-14.36; P = 0.000); and high Tumor SUV (Tsuv) value was also correlated with poor OS (HR = 1.53; 95% CI 1.26-1.87; P = 0.000). Meanwhile, subgroup analysis results showed that the significant association above was not altered by study sample size, parameter cutoff value, analytic method, and follow-up period, but there was no significant association between Tsuv/Lsuv ratio and OS in patients who underwent resection (HR = 1.71; 95% CI 1.00-2.92; P = 0.052)., Conclusions: Both high Tsuv/Lsuv ratio and high Tsuv value are associated with poor prognosis in HCC patients. Therefore, pretreatment (18)F-FDG PET is a useful tool in predicting the prognosis of HCC patients. More studies with explicit treatment modalities are required to investigate the prognostic value of pretreatment (18)F-FDG PET on HCC patients.