OBJECTIVE: Angiogenesis is a critical target for hepatocellular carcinoma (HCC) treatment. The previous studies indicated that Jiedu Fang (JDF) could inhibit hypoxia-induced angiogenesis through interleukin-8 (IL-8). Therefore, the present study further explores the mechanisms behind JDF's inhibition of HCC angiogenesis. METHODS: Angiogenesis was assessed with the capillary-like tube formation assay in vitro and the matrigel plug angiogenesis assay in vivo. A liver cancer-related gene set and genes associated with angiogenesis and the hypoxic microenvironment were analyzed using a bioinformatics platform. Real-time reverse transcription-polymerase chain reaction and Western blotting assays were used to assess the targeted mRNA and protein levels, respectively. The Transwell assay was used to assess the migration and invasion potential of EA.hy 926 cells. The orthotopic tumor xenograft model was established, and immunohistochemistry and immunofluorescence assays were used to detect cluster of differentiation 31 and angiopoietin 2 expression, while an enzyme-linked immunosorbent assay was used to detect vascular endothelial growth factor and IL-8 protein levels. RESULTS: In vitro and in vivo assays showed that IL-8 promoted angiogenesis, and JDF could antagonize this effect. Bioinformatics analysis indicated that aurora kinase A (Aurora A) was an important candidate, which can promote IL-8 expression through activation of signal transducer and activator of transcription 3 (STAT3). The overexpression of Aurora A increased IL-8 secretion and promoted HCC migration, invasion, and angiogenesis, which was partly inhibited by JDF. Such effects were validated by in vivo assays. Further validation using the STAT3 inhibitor S3I-201 demonstrated that STAT3 was regulated by Aurora A. CONCLUSION JDF exhibits efficacy in reducing hypoxia-induced angiogenesis in HCC through a mechanism involving the Aurora A/STAT3/IL-8 signaling pathway. Therefore, JDF holds promise as a potential therapeutic approach for targeting HCC angiogenesis. Please cite this article as: Zhong MF, Luo YJ, Guo YY, Xiang S, Lin WF. Jiedu Fang inhibits hypoxia-induced angiogenesis in hepatocellular carcinoma by targeting Aurora A/STAT3/IL-8 signaling pathway. J Integr Med. 2025; 23(6):683-693.
Carcinoma, Hepatocellular/blood supply* ; Humans ; STAT3 Transcription Factor/metabolism* ; Interleukin-8/metabolism* ; Liver Neoplasms/blood supply* ; Aurora Kinase A/metabolism* ; Neovascularization, Pathologic/drug therapy* ; Animals ; Signal Transduction/drug effects* ; Mice ; Drugs, Chinese Herbal/therapeutic use* ; Cell Line, Tumor ; Mice, Inbred BALB C ; Mice, Nude ; Angiogenesis

OBJECTIVETo study the characteristics of blood flow in common hepatic tumors by 256-slice spiral CT whole-liver perfusion imaging.

METHODSSeventy-one patients with hepatic tumors were examined retrospectively by 256-slice spiral CT whole-liver perfusion. Among them, twenty-seven cases were of primary hepatic cancer, twenty-four cases of hepatic hemangioma, and twenty cases of hepatic metastases.Regions of interest (ROIs) were placed in the tumor parenchyma (Area A), peritumoral hepatic parenchyma (Area B), and normal hepatic parenchyma (Area C), respectively. The time density curves (TDC) were drawn, and perfusion parameters including hepatic arterial perfusion(HAP), portal venous perfusion(PVP), total liver perfusion(TLP) and hepatic erfusion index(HPI) were obtained. The values of ROIs were measured, and the perfusion parameters in the areas A, B, C of different hepatic tumors were statistically analyzed.

RESULTSThe values of HAP, PVP, HPI in the tumor parenchyma of primary hepatic carcinoma were (20.00 ± 11.41)ml · min(-1) · 100 ml(-1,) (32.31 ± 21.06)ml · min(-1) · 100 ml(-1,) (52.31 ± 30.55)ml · min(-1) · 100 ml(-1,) and (39.67 ± 11.19)%, showing significant difference as compared with those in peritumoral hepatic parenchyma and in normal hepatic parenchyma(P<0.05). The values of HAP, TLP, and HPI in the tumor parenchyma of hepatic hemangioma were (40.39 ± 29.23)ml · min(-1) · 100 ml(-1,) (132.72 ± 132.65) ml · min(-1) · 100 ml(-1,) and (35.51 ± 15.12)%, were significantly different as compared with those in the peritumoral hepatic parenchyma and in normal hepatic parenchyma(P<0.05). The values of HAP, PVP, HPI in the tumor parenchyma of hepatic metastases were (17.43 ± 12.27)ml · min(-1) · 100 ml(-1,) (36.19 ± 34.99) ml · min(-1) · 100 ml(-1,) and (37.86 ± 14.49)%, significantly different as compared normal hepatic parenchyma (P<0.05). The HAP, PVP, and TLP of tumor tissue and the PVP and HPI of peritumoral tissue in different hepatic tumors were statistically significantly different (P<0.05).

CONCLUSIONSThe multi-slice spiral CT whole-liver perfusion has certain value in the diagnosis of common hepatic tumors. Perfusion parameters in different areas of common hepatic tumors have their own hemodynamic characteristics.

Carcinoma, Hepatocellular ; blood supply ; diagnostic imaging ; Hemangioma ; blood supply ; diagnostic imaging ; Hepatic Artery ; diagnostic imaging ; physiology ; Humans ; Liver ; blood supply ; Liver Neoplasms ; blood supply ; diagnostic imaging ; secondary ; Perfusion Imaging ; Portal Vein ; diagnostic imaging ; physiology ; Regional Blood Flow ; Retrospective Studies ; Tomography, Spiral Computed

OBJECTIVETo explore the surgical risk, perioperative outcome and the response of patients with hepatocellular carcinoma (HCC) after preoperative transcatheter arterial chemoembolization (TACE).

METHODSA retrospective case-matched study was conducted to compare the characteristics and corresponding measures of patients in the preoperative TACE group and the control group without TACE. A total of 105 patients (82 patients with selective and dynamic region-specific vascular occlusion to perform hepatectomy for patients with complex hepatocellular carcinoma) was included in this study, in which 35 patients underwent TACE therapy, and a 1:2 matched control group of 70 subjects.

RESULTSThe patients of preoperative TACE therapy group had a higher level of γ-glutamyl transpeptidase before operation (119.52±98.83) U/L vs. (67.39±61.25) U/L (P=0.040). The operation time was longer in the TACE group than that in the control group but with a non-significant difference (232.60±95.43) min vs. (218.70±75.13) min (P=0.052). The postoperative recovery of liver function and severe complications in the preoperative TACE group were similar to that in the control group (P>0.05). There were no massive hemorrhage, biliary fistula and 30-d death neither in the treatment group and matched control group.

CONCLUSIONSPreoperative TACE therapy has certain negative effect on liver function. It is preferable to use selective and dynamic region-specific vascular occlusion technique during hepatectomy and combine with reasonable perioperative treatment for this group of patients, that can ensure safety of patients and promote their rapid recovery.

Carcinoma, Hepatocellular ; blood supply ; therapy ; Case-Control Studies ; Chemoembolization, Therapeutic ; adverse effects ; methods ; Hepatectomy ; methods ; Humans ; Liver ; physiopathology ; Liver Neoplasms ; blood supply ; therapy ; Operative Time ; Preoperative Period ; Recovery of Function ; Retrospective Studies ; gamma-Glutamyltransferase ; analysis

OBJEVTIVETo explore the feasibility and reliability of ultrasonic monitoring of portal vein (PV) and hepatic vein (HV) blood flow volume changes in the process of induced carcinogenesis of hepatocellular carcinoma and the correlation of PV/HV blood flow volume ratio (Qpv/Qhv) with the severity of liver cirrhosis.

METHODSSD rats with diethylnitrosamine-induced liver carcinogenesis underwent regular liver ultrasound examinations including color flow imaging and pulsed Doppler examination. The main PV and HV blood flow parameters were measured to calculate Qpv/Qhv until successful induction of liver cancer.

RESULTSThe PV diameter increased significantly with the severity of liver cirrhosis in the rats (P<0.05), and the PV blood flow velocity reduced but the blood flow volume increased significantly in liver cancer and cirrhosis stages (P<0.05). Normal hepatic vein blood flow was significantly greater than that measured in liver cirrhosis and hepatocellular carcinoma stages. The Qpv/Qhv measured in normal rats was significantly lower than that in liver cirrhosis and liver cancer stages, but the ratios were comparable between the latter two stages.

CONCLUSIONUltrasonography is reliable to monitor the change of liver hemodynamics in rats with induced liver carcinogenesis, in which the changes of Qpv/Qhv are correlated with the severity of liver cirrhosis.

Animals ; Blood Flow Velocity ; Blood Volume ; Carcinoma, Hepatocellular ; blood supply ; diagnostic imaging ; Hemodynamics ; Hepatic Veins ; Liver Cirrhosis ; diagnostic imaging ; Liver Neoplasms ; blood supply ; diagnostic imaging ; Portal Vein ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Ultrasonography

OBJECTIVEThe efficiency network is a complicated network for revealing the efficient mechanism of traditional Chinese medicines (TCMs) and relations among efficiencies. The efficiency-property relations were used to establish a warm-pungent-liver efficiency network to explain the principle of treating hepatoma with medicines invigorating blood circulation and eliminating blood stasis. Safflower, a warm-pungent medicine distributing along the live meridian, was taken for example to discuss the efficiency network' s application in the identification of active ingredients of TCMs and the combination.

METHODIn the early stage of this study, combined warm-pungent-liver medicines distributed along the liver meridian and invigorating blood circulation and eliminating blood stasis were taken as the study objects to collect the pharmacological effect data of warm-pungent-liver medicines and obtain the pharmacological effect combinations with the highest blood circulation-invigorating association by the association rules and the chi-square test. The pharmacological target data recorded in the DrugBank database is used to establish the warm-pungent-liver efficiency network according to the principle line of "efficiency-property-pharmacology-target-protein interaction" under the background of the protein interaction network.

RESULTThe blood circulation-invigorating medicines could directly treat hepatoma by impacting protooncogene, cancer suppressor gene, cell apoptosis and anti-inflammation, and indirectly treat hepatoma by resisting coagulation and adhesion, regulating local blood circulation, preventing cancer cell metastasis and enhancing the tissues' sensitivity to the anticancer drugs. Among the active ingredients of safflower screened based on the blood circulation-invigorating network targets, carthamin yellow, quercetin and luteolin have been proved to have the anti-hepatoma effect in literatures, which indicated the reliability of this study's results and the purpose of the efficiency network.

CONCLUSIONThe efficiency network is an effective method for revealing the TCM's mechanism, and lays a foundation for discovering key active ingredients of TCMs for treating specific diseases.

Antineoplastic Agents, Phytogenic ; chemistry ; therapeutic use ; Blood Circulation ; drug effects ; Carcinoma, Hepatocellular ; drug therapy ; genetics ; metabolism ; physiopathology ; Drugs, Chinese Herbal ; chemistry ; therapeutic use ; Gene Regulatory Networks ; drug effects ; Humans ; Liver ; blood supply ; drug effects ; Liver Neoplasms ; drug therapy ; genetics ; metabolism ; physiopathology

OBJECTIVETo detect the expression of Nodal in hepatocellular carcinoma (HCC), and explore its relationship with angiogenesis and epithelial-mesenchymal transition (EMT).

METHODSFrom September 2006 to June 2010, the 16 self-paired frozen HCC specimens were collected and the expression of Nodal was detected by qPCR and Western blot. The 10 normal liver tissues and 96 cases of HCC tumor and paracarcinomatous tissues were collected. The expression of Nodal and relationship among Nodal, clinicopathological characteristics of HCC and patients' prognosis were detected and analyzed using immunohistochemistry. The expressions of Nodal, Vimentin and CD34 in 96 HCC tumor tissues were detected by immunohistochemistry, and then judgment relationship between the expression of Nodal, EMT and angiogenesis.

RESULTSImmunohistochemistry showed that Nodal mainly expressed in the cytoplasm. The high expression rate of Nodal in HCC tumor tissues was 72.9% (70/96), which was remarkably higher than that in paracarcinomatous tissues (8.3%) and normal liver tissues (0) (χ(2) = 83.001 and 24.470, both P < 0.001). qPCR and Western blot analysis showed that the expression level of Nodal in HCC was significantly higher than that in paracarcinomatous and normal tissues (P < 0.05). The high expression of Nodal in HCC was correlated with tumor size (χ(2) = 15.318, P = 0.000), alpha-fetoprotein (χ(2) = 3.850, P = 0.049), indocyanine green retention rate at 15 minutes (χ(2) = 6.590, P = 0.010), and invasion and metastasis (χ(2) = 17.824, P = 0.000). High expression of Nodal was positively correlated with high microvascular density in HCC (t = 3.070, P = 0.006), but not with Vimentin (r = 0.198, P = 0.053). Survival analysis showed that accumulated survival rate of patients with high expression of Nodal was significantly less than that the low expression (χ(2) = 487.053, P < 0.001). The Cox multivariate analysis demonstrated that high expression of Nodal was independent risk factors for cumulative survival in patients with hepatocellular carcinoma after a curative resection (RR = 2.757, 95%CI: 1.450-5.240, P = 0.002).

CONCLUSIONSNodal does not participate in EMT of HCC, but can promote angiogenesis, and it could be used as a predictor of poor prognosis.

Adult ; Aged ; Carcinoma, Hepatocellular ; blood supply ; metabolism ; Epithelial-Mesenchymal Transition ; Female ; Humans ; Liver Neoplasms ; blood supply ; metabolism ; Male ; Middle Aged ; Neovascularization, Pathologic ; Nodal Protein ; metabolism ; Prognosis ; Vimentin ; metabolism

Carcinoma, Hepatocellular ; blood supply ; diagnostic imaging ; Humans ; Liver Neoplasms ; blood supply ; diagnostic imaging ; Microvessels ; diagnostic imaging ; Neovascularization, Pathologic ; diagnostic imaging ; Tomography, X-Ray Computed ; methods

OBJECTIVETo observe the inhibition effects of polypeptide extract from scorpion venom (PESV) combined 5-fluorouracil (5-Fu) on vasculogenic mimicry (VM) of H2 hepatoma carcinoma cells in mice and its possible mechanisms.

METHODSThe H22 carcinoma cell suspension was subcutaneously inoculated into 60 Kunming mice. Then tumor-bearing mice were randomly divided into three groups, i.e., the control group, the 5-Fu group, and the combination group (PESV +5-Fu), 20 in each group. The tumor volume was measured once every other day after 14 successive days of intervention. Then the tumor volume growth curve was drawn, and the tumor inhibitory rate was calculated. The morphological changes of the tumor tissue were observed by HE staining. The VM density of each tumor tissue were detected by immunohistochemical assay and periodic acid-schiff stain (PAS). The protein expression levels of hypoxia inducible factor-la (HIF-la) and matrix metalloproteinase-2 (MMP-2) were detected using immunohistochemical assay. The gray value was semi-quantitatively analyzed using LeicaQwinV3 Image Analysis Software.

RESULTSThe growth of H22 hepatoma transplantation tumor was inhibited more obviously in the combination group and the 5-Fu group than in the control group (P <0.05). There was statistical difference in the tumor weight and the tumor volume between the combination group and the 5-Fu group (P <0.05). Immunohistochemical assay and PAS showed that the VM density was obviously lower in the combination group than in the control group and the 5-Fu group (P <0.01). Compared with the control group, the protein expressions of HIF-la and MMP-2 significantly decreased in the combination group (P <0.01).

CONCLUSIONSPESV combined 5-Fu could inhibit the generation of VM of H22 hepatoma transplantation tumor in mice. Its mechanisms might be associated with inhibiting the expressions of HIF-lalpha and MMP-2 in the microenvironment of tumors.

Animals ; Carcinoma, Hepatocellular ; blood supply ; Cell Line, Tumor ; Charybdotoxin ; pharmacology ; Fluorouracil ; pharmacology ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Liver Neoplasms ; blood supply ; Male ; Matrix Metalloproteinase 2 ; metabolism ; Mice ; Mice, Inbred Strains

OBJECTIVETo evaluate the incidence of extrahepatic collateral arteries involved in the blood supply to hepatocellular carcinoma (HCC) and to assess the technical success rates and complications of transcatheter arterial chemoembolization (TACE) through the collaterals.

METHODS1356 TACE procedures were performed in 874 consecutive patients through extrahepatic collateral pathways to HCC between August 2006 and August 2010 in our department. The extrahepatic collateral pathways to HCC revealed on angiography were retrospectively evaluated. TACE through extrahepatic collaterals using iodized oil and gelatin sponge particles was performed when a catheter was advanced into the feeding branch to avoid nontarget embolization.

RESULTSIncidences of collateral source to HCC were 76.3% from the right inferior phrenic artery (RIPA), 2.4% from the left inferior phrenic artery (LIPA), 6.9% from the right and 0.4% from the left internal mammary arteries (RIMA, LIMA), 2.9% from the right intercostal artery (RICA), 2.0% from the omental artery, 0.8% from the right or middle colic artery, 2.3% from the cystic artery, 1.3% from the left and 1.1% from the right gastric arteries (LGA, RGA), 3.5% from the right renal capsular artery (RRCA), right middle adrenal artery (RMAA) and right inferior adrenal artery (IAA). Technical success rates of TACE were 95.9% in the RIPA, 93.8% in the LIPA, 100.0% in the RIMA and LIMA, 55.0% in the RICA, 77.8% in the omental artery, 63.6% in the colic artery, 67.7% in the cystic artery, 76.5% in the LGA, 73.3% in the RGA and 95.8% in the RRCA, RMAA, and RIAA. Complications included skin erythema and necrosis after TACE through the RIMA, skin erythema after TACE through the RICA, cholecystitis after TACE through the cystic artery (n = 1), and pleural effusion, basal atelectasis and hiccup after TACE through the IPA.

CONCLUSIONTACE through extrahepatic collaterals is safe and feasible, and with a high success rate in the treatment of hepatocellular carcinoma.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents ; administration & dosage ; Arteries ; Carcinoma, Hepatocellular ; blood supply ; diagnostic imaging ; pathology ; therapy ; Chemoembolization, Therapeutic ; adverse effects ; methods ; Collateral Circulation ; Erythema ; etiology ; Female ; Humans ; Iodized Oil ; administration & dosage ; Liver Neoplasms ; blood supply ; diagnostic imaging ; pathology ; therapy ; Male ; Middle Aged ; Pleural Effusion ; etiology ; Retrospective Studies ; Tomography, X-Ray Computed ; Young Adult

OBJECTIVETo investigate the potential utility of microangiography with synchrotron radiation to detect murine hepatocellular carcinoma (HCC) angiogenesis using an ex vivo model system.

METHODSAn HCC xenograft model was established by implanting HCCLM3 cells into male mice livers (n = 6). Twenty-eight days later, three of the mice were randomly selected for barium sulfate infusion into the liver and tumor via the inferior vena cava followed by ligation of the arteries, veins and common bile duct; the remaining three mice were left untreated and served as controls. All mice were sacrificed to collect livers for analysis using the BL13W beamline X-ray imager (Shanghai Synchrotron Radiation Facility, China). In addition, the tumor vasculature was evaluated by immunostaining of formalin-fixed tissues for CD31, CD34, and F8.

RESULTSHigh resolution images of tumor angiogenesis were acquired and image analysis indicated that the normal blood vessels had been displaced by the fast growing tumors. Abundant and tortuous tumor angiogenesis in the tumor periphery area and sparse angiogenesis inside the tumor were also visualized clearly. These features were similar to the immunohistological results. The smallest tumor vessels visualized were approximately 20 mum in diameter.

CONCLUSIONMicroangiography with synchrotron radiation using barium sulfate as contrast agent is a viable imaging strategy for tumor angiogenesis.

Angiography ; methods ; Animals ; Carcinoma, Hepatocellular ; blood supply ; diagnostic imaging ; Cell Line, Tumor ; Humans ; Liver Neoplasms ; blood supply ; diagnostic imaging ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neovascularization, Pathologic ; diagnostic imaging ; Tomography, X-Ray ; Xenograft Model Antitumor Assays