Heme-Inducing Endothelial Pyroptosis Plays a Key Role in Radiofrequency Ablation of Hepatic Hemangioma Leading to Systemic Inflammatory Response Syndrome.

Purpose: Systemic inflammatory response syndrome (SIRS) is a common complication of radiofrequency ablation (RFA) for hepatic hemangiomas. RFA can cause hemolytic reactions during hepatic hemangioma ablation. However, the mechanisms underlying RFA-induced SIRS remain unclear. Methods: We established an orthotopic liver hemangioma model and performed radiofrequency ablation. The levels of interleukin (IL)-1ß and IL-18 and the production of ROS were measured. The wet-to-dry lung ratio, inflammation score, and in vivo endothelial cell permeability were examined. GSDMD-/- mice were used to investigate the effect of heme-inducing SIRS. RNA sequencing (RNA-seq) was performed to identify the main pathways underlying heme-induced SIRS. Western blotting and immunoprecipitation were used to determine the changes and interactions of associated proteins. Results: The levels of heme, IL-1ß, and IL-18 were significantly increased after RFA. The wet-to-dry lung ratio increased in hepatic hemangiomas after RFA, indicating that SIRS occurred. Heme induced increased levels of IL-1ß and IL-18, cell death, wet-to-dry lung radio, and inflammation score in vitro and in vivo, indicating that heme induced SIRS and pyroptosis. Furthermore, GSDMD participates in heme-induced SIRS in mice, and GSDMD deletion in mice reverses the effect of heme. Heme regulates NLRP3 activation through the NOX4/ROS/TXNIP-TRX pathway, and an N-acetyl-L-cysteine (NAC) or NOX4 inhibitor (GLX351322) reverses heme-induced SIRS. Conclusion: Our findings suggest that heme induces endothelial cell pyroptosis and SIRS in mice and decreasing heme levels and ROS scavengers may prevent SIRS in hepatic hemangioma after RFA.

Metformin promotes the normalization of abnormal blood vessels after radiofrequency ablation deficiency in hepatocellular carcinoma by microRNA-302b-3p targeting thioredoxin-interacting protein.

Metformin has shown great promise in the treatment of HCC. Radiofrequency ablation (RFA) deficiency results in recurrence and metastasis of remaining HCC tumors. Here, we aimed to investigate the role and mechanism of metformin in HCC after RFA deficiency. HCC cell line Hep-G2 was selected to simulate RFA deficiency and named HepG2-H cells. After treating cells with different concentrations of metformin (2.5, 5, 10 µM) or transfecting related plasmids, cell proliferation, migration, invasion, apoptosis and angiogenesis were detected, in vitro permeability test was performed, and an angiogenesis-related protein VEGFA was analyzed. The residual HCC model after RFA deficiency was established in mice. Metformin was administered by gavage to detect changes in tumor volume and weight, and CD31 staining was used to observe microvessels. The targeting relationship between miR-302b-3p and TXNIP was demonstrated by the bioinformatics website, dual-luciferase reporter assay, and RNA pull-down assay. The results found that metformin inhibited RFA deficiency-induced growth and angiogenesis of HCC cells in vitro. miR-302b-3p counteracted the therapeutic effect of metformin on RFA deficiency. miR-302b-3p targeted regulation of TXNIP. The up-regulation of TXNIP reversed the effects of overexpression of miR-302b-3p on RFA-deficient HCC cells. Metformin inhibited RFA-deficiency-induced HCC growth and tumor vascular abnormalities in vivo. Overall, metformin promotes the normalization of abnormal blood vessels after RFA deficiency in HCC by miR-302b-3p targeting TXNIP, which can be used to prevent the progression of HCC after RFA.

Thermal ablation of hepatic hemangioma: A multi-center experience with long-term outcomes.

BACKGROUND: Thermal ablation, currently used extensively for liver tumors, also has been applied. successfully to hepatic hemangioma; however, it is still considered experimental because previous studies have comprised small sample sizes with short follow-up periods. PURPOSE: We aimed to investigate the effectiveness, safety, and long-term outcomes of thermal ablation for hepatic hemangioma. MATERIALS AND METHODS: From October 2011 to February 2021, the data of 357 patients with 378 hepatic hemangiomas treated by thermal ablation at six hospitals were analyzed in this retrospective study. The technical success, safety, and long-term follow-up results were analyzed. RESULTS: A total of 252 patients (mean age, 49.2 ± 10.5 years) with 273 subcapsular hemangiomas underwent laparoscopic thermal ablation, whereas 105 patients with 105 hemangiomas located in the liver parenchyma underwent CT-guided percutaneous ablation. Of the 378 hepatic hemangiomas (5.0-21.2 cm), 369 lesions were subjected to one session of ablation, while 9 lesions were subjected to two sessions of ablation. Technical success was achieved in 100.0% of cases. Complete ablation was achieved in 361 of 378 hemangiomas (95.5%), while 17 hemangiomas (4.5%) were incompletely ablated, showing subtle enhancement at the peripheral rim. The major complication rate was 2.0% (7/357). The median follow-up period was 67 months (range, 12-124 months). Of the 224 patients with hemangioma-related symptoms, 216 demonstrated complete disappearance of symptoms (96.4%), while 8 were ameliorated (3.6%). Ablated lesion shrinkage was progressive, and 11.4% of hemangiomas almost completely disappeared over time (P < 0.01). CONCLUSION: With a reasonable ablation strategy and comprehensive treatment measurements, thermal ablation could be a safe, feasible, and effective treatment option for hepatic hemangioma.

Angiogenesis in hepatocellular carcinoma: mechanisms and anti-angiogenic therapies.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Angiogenesis, the process of formation of new blood vessels, is required for cancer cells to obtain nutrients and oxygen. HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth, progression, invasion, and metastasis. Current anti-angiogenic therapies target mainly tyrosine kinases, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), and are considered effective strategies for HCC, particularly advanced HCC. However, because the survival benefits conferred by these anti-angiogenic therapies are modest, new anti-angiogenic targets must be identified. Several recent studies have determined the underlying molecular mechanisms, including pro-angiogenic factors secreted by HCC cells, the tumor microenvironment, and cancer stem cells. In this review, we summarize the roles of pro-angiogenic factors; the involvement of endothelial cells, hepatic stellate cells, tumor-associated macrophages, and tumor-associated neutrophils present in the tumor microenvironment; and the regulatory influence of cancer stem cells on angiogenesis in HCC. Furthermore, we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC. A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.

Progression of hepatocellular carcinoma after radiofrequency ablation: Current status of research.

Hepatocellular carcinoma (HCC) remains an important disease for health care systems in view of its high morbidity, mortality, and increasing incidence worldwide. Radiofrequency ablation (RFA) is preferred to surgery as a local treatment for HCC because it is safer, less traumatic, less painful, better tolerated, causes fewer adverse reactions, and allows more rapid postoperative recovery. The biggest shortcoming of RFA when used to treat HCC is the high incidence of residual tumor, which is often attributed to the vascular thermal deposition effect, the wide infiltration zone of peripheral venules, and the distance between satellite foci and the main focus of the cancer. Recurrence and progression of the residual tumor is the most important determinant of the prognosis. Therefore, it is important to be aware of the risk of recurrence and to improve the efficacy of RFA. This review summarizes the relevant literature and the possible mechanisms involved in progression of HCC after RFA. Current studies have demonstrated that multimodal treatments which RFA combined with other anti-cancer approaches can prevent progression of HCC after RFA.

Pan-Cancer analysis shows that ACO2 is a potential prognostic and immunotherapeutic biomarker for multiple cancer types including hepatocellular carcinoma.

Background: Recent evidence increasingly suggests key roles for the tricarboxylic acid cycle and fatty acid metabolism in tumor progression and metastasis. Aconitase 2 (ACO2) is a component of the tricarboxylic acid cycle and represents a key cellular metabolic hub that promotes de novo fatty acid biosynthesis. However, there have been few reports on the role of ACO2 in tumorigenesis and cancer progression. Methods: Through the comprehensive use of datasets from The Cancer Genome Atlas, Genotype-Tissue Expression Project, cBioPortal, Human Protein Atlas, UALCAN, Gene Expression Profiling Interactive Analysis, DNA Methylation Interactive Visualization Database, and TIMER2, we adopted bioinformatics methods to uncover the potential carcinogenic roles of ACO2, including by analysing ACO2 expression and correlations between prognosis, genetic mutations, immune cell infiltration, DNA methylation, tumor mutational burden, and microsatellite instability in different tumors. Additionally, the expression level and tumor-promoting effect of ACO2 were verified in hepatocellular carcinoma (HCC) cells. To explore the underlying mechanisms of ACO2 in human cancer, ACO2-related gene enrichment analysis and lipid metabolomics were performed using LM3 cells with or without ACO2 knockdown. Results: The results indicated that ACO2 was highly expressed in most cancers, showing early diagnostic value in six tumor types, and was positively or negatively associated with prognosis in different tumors. Moreover, ACO2 expression was associated with immune cell infiltration, such as CD8+ T cells and tumor-associated neutrophils, in some cancers. For most cancer types, there was a significant association between immune checkpoint-associated genes and ACO2 expression. Compared with normal hepatocytes, ACO2 was upregulated in HCC cells, which promoted their proliferation and migration. Furthermore, to explore the underlying molecular mechanism, we performed KEGG pathway enrichment analysis of ACO2-associated genes and lipidomics using LM3 cells with or without ACO2 knockdown, which screened 19 significantly altered metabolites, including 17 with reduced levels and 2 with increased levels. Conclusion: Through pan-cancer analysis, we discovered for the first time and verified that ACO2 could be a useful diagnostic biomarker for cancer detection. Additionally, ACO2 could be used as an auxiliary prognostic marker or as a marker for immunotherapy in some tumor types.

Circular BANP knockdown inhibits the malignant progression of residual hepatocellular carcinoma after insufficient radiofrequency ablation.

BACKGROUND: Circular RNAs (circRNAs) are endogenous non-coding RNAs, some of which have pathological roles. The current study aimed to explore the role of circRNA BTG3-associated nuclear protein (circ-BANP) binding with let-7f-5p and its regulation of the toll-like receptor 4 (TLR4)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in residual hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA). METHODS: Circ-BANP, let-7f-5p, and TLR4 expressions in HCC samples were assessed using reverse transcription- quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Bioinformatics prediction, RNA pull-down assay, and dual luciferase reporter gene assay were used to analyze the relationships among circ-BANP, let-7f-5p, and TLR4. Huh7 cells were used to generate an in vitro model of residual HCC, defined as Huh7-H cells, which were transfected with either a plasmid or the sequence of circ-BANP, let-7f-5p, or TLR4. Expression of circ-BANP, let-7f-5p, and TLR4 mRNA was determined by RT-qPCR. TLR4, STAT3, p-STAT3, vascular endothelial growth factor A, vascular endothelial growth factor receptor-2, and epithelial-mesenchymal transformation (EMT)-related factors proteins were determined by Western blotting. Cell proliferation was determined by cell counting kit-8 and 5-Ethynyl-2'-deoxyuridine (EdU) assay and cell migration and invasion by Transwell assay. Animal studies were performed by inducing xenograft tumors in nude mice. RESULTS: Circ-BANP and TLR4 mRNAs were upregulated in HCC tissues (the fold change for circ-BANP was 1.958 and that for TLR4 was 1.736 relative to para-tumors) and expression further increased following insufficient RFA (fold change for circ- BANP was 2.407 and that of TLR4 was 2.224 relative to para-tumors). Expression of let-7f-5p showed an opposite tendency (fold change for let-7f-5p in HCC tissues was 0.491 and that in tumors after insufficient RFA was 0.300 relative to para-tumors). Competitive binding of circ-BANP to let-7f-5p was demonstrated and TLR4 was identified as a target of let-7f-5p (P < 0.01). Knockdown of circ-BANP or elevation of let-7f-5p expression inhibited the TLR4/STAT3 signaling pathway, proliferation, invasion, migration, angiogenesis, and EMT in Huh7 and Huh7-H cells (P < 0.01). The effects induced by circ-BANP knockdown were reversed by let-7f-5p inhibition. Overexpression of TLR4 reversed the impact of let-7f-5p upregulation on the cells (P < 0.01). Silencing of circ-BANP inhibited the in vivo growth of residual HCC cells after insufficient RFA (P < 0.01). CONCLUSIONS: Knockdown of circ-BANP upregulated let-7f-5p to inhibit proliferation, migration, and EMT formation in residual HCC remaining after insufficient RFA. Effects occur via regulation of the TLR4/STAT3 signaling pathway.

Arsenic trioxide inhibits angiogenesis of hepatocellular carcinoma after insufficient radiofrequency ablation via blocking paracrine angiopoietin-1 and angiopoietin-2.

OBJECTIVES: Angiogenesis occurs during tumor progression of hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA). Arsenic trioxide (ATO) shows promising therapeutic potential in advanced HCC. Whether ATO regulates angiogenesis and can be used to prevent tumor progression in HCC after insufficient RFA is still unknown. METHODS: Insufficient RFA was simulated using a water bath. MTT assay and tube formation assay were used to evaluate the effects of ATO on viability and proangiogenic abilities of SMMC7721 and HepG2 cells after insufficient RFA in vitro. The molecular changes with the treatment of ATO were evaluated through Western blot. An ectopic nude mice model was used to evaluate the effect of ATO on the tumor of SMMC7721 cells in vivo after insufficient RFA. RESULTS: In this study, HepG2 and SMMC7721 cells after insufficient RFA (named HepG2-H and SMMC7721-H, respectively) showed higher proliferation than the untreated cells and promoted tube formation of endothelial cells in a paracrine manner. ATO eliminated the difference in proliferation between untreated and RFA-treated cells and suppressed angiogenesis induced by HCC cells after insufficient RFA through the Ang-1 (angiopoietin-1)/Ang-2 (angiopoietin-2)/Tie2 pathway. Hif-1α overexpression abolished the inhibitory effect of ATO on angiogenesis in HCC after insufficient RFA. ATO inhibited tumor growth and angiogenesis in HCC after insufficient RFA. CONCLUSIONS: Our results demonstrate that ATO blocks the paracrine signaling of Ang-1 and Ang-2 by inhibiting p-Akt/Hif-1α and further suppresses the angiogenesis of HCC after insufficient RFA.

Circular BANP knockdown inhibits the malignant progression of residual hepatocellular carcinoma after insufficient radiofrequency ablation.

BACKGROUND: Circular RNAs (circRNAs) are endogenous non-coding RNAs, some of which have pathological roles. The current study aimed to explore the role of circRNA BTG3-associated nuclear protein (circ-BANP) binding with let-7f-5p and its regulation of the toll-like receptor 4 (TLR4)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in residual hepatocellular carcinoma (HCC) after insufficient radiofrequency ablation (RFA). METHODS: Circ-BANP, let-7f-5p, and TLR4 expressions in HCC samples were assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Bioinformatics prediction, RNA pull-down assay, and dual luciferase reporter gene assay were used to analyze the relationships among circ-BANP, let-7f-5p, and TLR4. Huh7 cells were used to generate an in vitro model of residual HCC, defined as Huh7-H cells, which were transfected with either a plasmid or the sequence of circ-BANP, let-7f-5p, or TLR4. Expression of circ-BANP, let-7f-5p, and TLR4 mRNA was determined by RT-qPCR. TLR4, STAT3, p-STAT3, vascular endothelial growth factor A, vascular endothelial growth factor receptor-2, and epithelial-mesenchymal transformation (EMT)-related factors proteins were determined by Western blotting. Cell proliferation was determined by cell counting kit-8 and 5-Ethynyl-2'-deoxyuridine (EdU) assay and cell migration and invasion by Transwell assay. Animal studies were performed by inducing xenograft tumors in nude mice. RESULTS: Circ-BANP and TLR4 mRNAs were upregulated in HCC tissues (the fold change for circ-BANP was 1.958 and that for TLR4 was 1.736 relative to para-tumors) and expression further increased following insufficient RFA (fold change for circ-BANP was 2.407 and that of TLR4 was 2.224 relative to para-tumors). Expression of let-7f-5p showed an opposite tendency (fold change for let-7f-5p in HCC tissues was 0.491 and that in tumors after insufficient RFA was 0.300 relative to para-tumors). Competitive binding of circ-BANP to let-7f-5p was demonstrated and TLR4 was identified as a target of let-7f-5p (P < 0.01). Knockdown of circ-BANP or elevation of let-7f-5p expression inhibited the TLR4/STAT3 signaling pathway, proliferation, invasion, migration, angiogenesis, and EMT in Huh7 and Huh7-H cells (P < 0.01). The effects induced by circ-BANP knockdown were reversed by let-7f-5p inhibition. Overexpression of TLR4 reversed the impact of let-7f-5p upregulation on the cells (P < 0.01). Silencing of circ-BANP inhibited the in vivo growth of residual HCC cells after insufficient RFA (P < 0.01). CONCLUSIONS: Knockdown of circ-BANP upregulated let-7f-5p to inhibit proliferation, migration, and EMT formation in residual HCC remaining after insufficient RFA. Effects occur via regulation of the TLR4/STAT3 signaling pathway.

Safety and efficacy of microwave versus radiofrequency ablation for large hepatic hemangioma: a multicenter retrospective study with propensity score matching.

OBJECTIVES: To compare the safety and efficacy of microwave ablation (MWA) and radiofrequency ablation (RFA) for such hemangiomas (5-9.9 cm in diameter). METHODS: This multicenter retrospective cohort study investigated the differences in technical success, ablation time, complete ablation, complications, hospital stay, and clinical response between MWA and RFA. A total of 452 patients with hepatic hemangiomas were screened. Propensity score matching was performed. Univariable and multivariate regression analyses were used. RESULTS: Among the 452 patients, 394 met the eligibility criteria and completed the follow-up. After the propensity score matching analysis, 72 pairs of patients were created. No technical failures were found. The RFA group had a longer ablation time (48.63 ± 18.11 min versus [vs.] 37.18 ± 15.86 min, p < 0.001), higher morbidity of hemoglobinuria (77.78% vs. 50.00%, p < 0.001), and longer hospital stay (5.01 ± 1.56 days vs. 4.34 ± 1.42 days, p < 0.05) than the MWA group. The treatment methods (p = 0.032, OR = 0.105, 95% CI = 0.013-0.821), size of the hemangioma (p = 0.021, OR = 5.243, 95% CI = 1.285-21.391), and time of ablation (p = 0.031, OR = 1.145, 95% CI = 1.013-1.294) were significant independent risk factors associated with hemoglobinuria. No recurrence or delayed complications were observed. There were no differences in complete ablation, clinical response, and health-related quality of life between the groups. CONCLUSIONS: MWA and RFA appear to be effective treatments for large hepatic hemangiomas. However, MWA had a shorter ablation time than RFA, and MWA was associated with fewer hemolysis-related complications and shorter hospital stays. KEY POINTS: • MWA and RFA appear to be effective treatments for large hepatic hemangiomas. • MWA had a shorter ablation time than RFA. • MWA was associated with fewer hemolysis-related complications and shorter hospital stays.

Complications of Radiofrequency Ablation for Hepatic Hemangioma: A Multicenter Retrospective Analysis on 291 Cases.

PURPOSE: To report the complications of radiofrequency ablation (RFA) for hepatic hemangioma. PATIENTS AND METHODS: Investigators from six centers performed RFA for hepatic hemangioma and used a standardized follow-up protocol. Data were collected from 291 patients, including 253 patients with hepatic hemangioma 5 to 9.9 cm in diameter (group A) and 38 with hepatic hemangioma ≥ 10 cm (group B). Technical success, complete ablation, and complications attributed to the RFA procedure were reported. Analysis of variance was used to determine whether the major complication rate was related to tumor size or clinical experience. RESULTS: A total of 304 lesions were treated in 291 patients. Technical success was achieved without adverse events in all cases. A total of 301 lesions were completely ablated, including 265 of 265 (100%) lesions in group A, and 36 of 39 (92.31%) in group B. The rate of technology-related complications was similar in groups A and B (5.14% (13/253) and 13.16% (5/38), respectively; P = 0.121). Moreover, all technology-related complications occurred during the early learning curve period. The rate of hemolysis-related complications in two groups were 83.40% (211/253) and 100% (38/38) (P =0.007) and the systemic inflammatory response syndrome-related complications in two groups were 33.99% (86/253) and 86.84% (33/38) (P<0.001). There were no delayed complications in either group. CONCLUSION: RFA is minimally invasive, safe, and effective for hepatic hemangiomas 5 to 9.9 cm in diameter. More clinical data are needed to confirm the safety of RFA for hepatic hemangiomas ≥ 10 cm.

ICAM-1 Activates Platelets and Promotes Endothelial Permeability through VE-Cadherin after Insufficient Radiofrequency Ablation.

Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) often leads to aggressive local recurrence and increased metastasis, and vascular integrity and platelets are implicated in tumor metastasis. However, whether interactions between endothelial cells and platelets induce endothelial permeability in HCC after insufficient RFA remains unclear. Here, significantly increased CD62P-positive platelets and sP-selectin in plasma are observed in HCC patients after RFA, and tumor-associated endothelial cells (TAECs) activate platelets and are susceptible to permeability after heat treatment in the presence of platelets in vitro. In addition, tumors exhibit enhanced vascular permeability after insufficient RFA in mice; heat treatment promotes platelets-induced endothelial permeability through vascular endothelial (VE)-cadherin, and ICAM-1 upregulation in TAECs after heat treatment results in platelet activation and increased endothelial permeability in vitro. Moreover, the binding interaction between upregulated ICAM-1 and Ezrin downregulates VE-cadherin expression. Furthermore, platelet depletion or ICAM-1 inhibition suppresses tumor growth and metastasis after insufficient RFA in an orthotopic tumor mouse model, and vascular permeability decreases in ICAM-1-/- mouse tumor after insufficient RFA. The findings suggest that ICAM-1 activates platelets and promotes endothelial permeability in TAECs through VE-cadherin after insufficient RFA, and anti-platelet and anti-ICAM-1 therapy can be used to prevent progression of HCC after insufficient RFA.

Platelet lysates in Hepatocellular Carcinoma patients after radiofrequency ablation facilitate tumor proliferation, invasion and vasculogenic mimicry.

Background: Platelets play important roles in tumorigenesis, angiogenesis and metastatic dissemination of tumor cells. Radiofrequency ablation (RFA) could increase the circulating tumor cells in patients with primary or metastatic lung tumors. Whether platelet lysates in hepatocellular carcinoma (HCC) after RFA promote tumor progression has not been elaborated. Methods: HCC patients within Milan Criteria and without taking anti-platelet drugs were selected in the study. MTT assay, colony formation assay, transwell assay, tube formation and western blot were used to evaluate the effect of platelet lysates on HCC cells in vitro. Lung metastatic assay was performed in vivo. Results: Platelet lysates from patients after RFA promoted cell proliferation, colony formation, migration, invasion and vasculogenic mimicry in Hep3B and HCCLM3 cells compared with those from patients before RFA. Platelet lysates after RFA significantly increased the expression of p-Akt, p-Smad3 and snail, and decreased the expression of E-cadherin compared with those before RFA in Hep3B and HCCLM3 cells. Hep3B-Luc2-tdT cells incubation with platelet lysates from patients after RFA displayed enhanced lung metastasis compared with those before RFA. Conclusions: Platelet lysates from HCC patients after RFA promoted the proliferation, migration, invasion and vasculogenic mimicry of HCC cells, which indicated that RFA in combination with anti-platelet drug may be used to improve the prognosis of HCC.

ATPase Inhibitory Factor 1 Promotes Hepatocellular Carcinoma Progression After Insufficient Radiofrequency Ablation, and Attenuates Cell Sensitivity to Sorafenib Therapy.

Epithelial-mesenchymal transition (EMT) and angiogenesis is involved in tumor progression after radiofrequency ablation (RFA). ATPase inhibitory factor 1 (IF1) is a bad predictor of prognosis. Sorafenib inhibited EMT of hepatocellular carcinoma (HCC) after RFA. Whether IF1 promotes the EMT and angiogenesis of HCC and attenuates the effect of sorafenib after insufficient RFA is investigated. In this study, higher expression of IF1 was found in residual tumor after insufficient RFA. Hep3B or Huh7 cells after insufficient RFA were designated as Hep3B-H or Huh7-H cells in vitro. Hep3B-H or Huh7-H cells exhibited enhanced capacities of colony formation, migration, and increased expression of EMT associated markers and IF1 compared with Hep3B or Huh7 cells. IF1 knockdown in Hep3B-H or Huh7-H cells decreased the colony formation and migratory capacity, and IF1 overexpression in Hep3B or Huh7 cells increased these capacities. IF1 in HCC cells directly and indirectly affected angiogenesis of TAECs after insufficient RFA. IF1 promoted HCC cells growth and metastasis after insufficient RFA. IF1 increased HCC cells resistance after insufficient RFA to sorafenib. Higher IF1 expression indicated poor disease survival in HCC patients after sorafenib therapy. NF-κB activation induced by IF1 attenuated the effect of sorafenib on HCC cells after insufficient RFA. Our results demonstrated that IF1 promotes the EMT and angiogenesis, and attenuates HCC cell sensitivity to sorafenib after insufficient RFA through NF-κB signal pathway.