• Animals
• Mice
• Carcinoma, Hepatocellular/pathology
• Endothelial Cells/metabolism
• Liver Neoplasms/pathology
• Matrix Metalloproteinase 2
• Proteomics
• Vascular Endothelial Growth Factor A/metabolism

• Anti-inflammation
• Fuzheng Xiaozheng prescription
• HCC
• Lipid related metabolism
• mRNA
• miRNA

• Animals
• Male
• Rats
• Antineoplastic Agents/therapeutic use
• Carcinoma, Hepatocellular/chemically induced
• Carcinoma, Hepatocellular/drug therapy
• Diethylnitrosamine/toxicity
• Drugs, Chinese Herbal/therapeutic use
• Gene Expression Regulation, Neoplastic/drug effects
• Liver/drug effects
• Liver/pathology
• Liver Neoplasms/chemically induced
• Liver Neoplasms/drug therapy
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasms, Experimental/drug therapy
• Phytotherapy
• Random Allocation
• Rats, Sprague-Dawley
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Transcriptome

Objective: We had previously proved that insufficient radiofrequency ablation (RFA) could enhance invasiveness and metastasis of hepatocellular carcinoma (HCC) through epithelial-mesenchymal transition (EMT), which is mediated by activating β-catenin signaling. Thus, the aim of the present study was to demonstrate whether the combined treatment of interferon-α (IFN-α) and “Songyou Yin” (SYY) minimizes the pro-metastatic effects of insufficient RFA, as well as to explore its underlying mechanism. Methods: Insufficient RFA was performed in an orthotopic nude mice model of HCCLM3 with high metastatic potential. The effects of IFN-α, SYY, and combined IFN-α and SYY were observed in the animal model. Tumor sizes, lung metastasis, and survival time were assessed. Immunochemistry staining, real-time polymerase chain reaction, and Western blot were used to examine gene expression related to metastasis and angiogenesis in residual cancer after insufficient RFA. Results: For up to 8 weeks of treatment, the combined therapy significantly decreased the residual cancer sizes, minimized the lung metastasis rate, and prolonged the survival time of nude mice, which might be due to suppression of the EMT via β-catenin signal blockade, in addition to attenuating angiogenesis in residual cancer after insufficient RFA. Conclusion: IFN-α combined with SYY significantly weakened the enhanced metastatic potential of residual cancer after insufficient RFA by attenuating EMT, which is mediated through inhibiting activation of β-catenin. In addition, decreasing angiogenesis of residual cancer might also play a certain role.

• EMT
• IFN-α
• Songyou Yin
• angiogenesis
• radiofrequency ablation
• β-catenin

• Salvia miltiorrhiza extract
• activator protein 1
• breast cancer MCF-7 cell line
• human matrix metalloproteinase-9
• invasion

It was previously reported that treatment with the herbal formula Songyou Yin (SYY) may serve a role in attenuating epithelial-mesenchymal transition (EMT). In the present study, the effect of treatment with SYY on transforming growth factor-β1 (TGF-β1)-induced EMT was investigated and the potential underlying molecular mechanisms were evaluated. MHCC97H cells were pretreated with SYY for 4 weeks and subsequently named MHCC97HSYY cells. Simultaneously, MHCC97H cells were cultured for 4 weeks without SYY and used as a negative control. Western blot analysis and enzyme-linked immunosorbent assays demonstrated that treatment with SYY inhibited EMT-associated changes and TGF-β1 expression in MHCC97H cells. MHCC97H and MHCC97HSYY cells were treated with 10 ng/ml TGF-β1 to induce EMT. The results of the present study demonstrated that pretreatment with SYY markedly inhibited TGF-β1-induced morphological changes, and reversed the expression of the EMT markers E-cadherin and N-cadherin. In addition, expression levels of the TGF-β1 downstream proteins, phosphorylated mothers against decapentaplegic homologs (p-SMAD)2 and 3, were reduced. Transwell assays indicated that pretreatment with SYY inhibited TGF-β1-induced cancer cell invasion and migration. The results of the present study indicate that SYY inhibited EMT through attenuation of TGF-β1 expression, and downregulation of p-SMAD2 and 3.

• Songyou Yin
• epithelial-mesenchymal transition
• hepatocellular carcinoma
• transforming growth factor-β1

Chronic fibrosis is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathological progression of hepatic fibrosis has been linked to cellular processes that promote tumor growth and metastasis. Several recent studies have highlighted the cross-talk between tumor cells and activated hepatic stellate cells (aHSCs) in HCC. The herbal compound Songyou Yin (SYY) is known to attenuate hepatoma cell invasion and metastasis via down-regulation of cytokine secretion by aHSCs. However the underlying mechanism of SYY treatment in reversal of hepatic fibrosis and metastasis of liver cancers is not known. In the current study, a nude mouse model with liver fibrosis bearing orthotopic xenograft was established and we found that SYY could reduce associated fibrosis, inhibit tumor growth and improve survival. In the subcutaneous tumor model with fibrosis, we found that SYY could inhibit liver cancer. In vitro, hepatoma cells incubated with conditioned media (CM) from SYY treated aHSCs showed reduced proliferation, decrease in colony formation and invasive potential. SYY treated group showed altered gene expression, with 1205 genes up-regulated and 1323 genes down-regulated. Gene cluster analysis indicated that phosphatidylinositol-3-kinase (PI3K) was one of the key genes altered in the expression profiles. PI3K related markers were all significantly down-regulated. ELISA also indicated decreased secretion of cytokines which were regulated by PI3K/AKT signaling after SYY treatment in the hepatic stellate cell line, LX2. These data clearly demonstrate that SYY therapy inhibits HCC invasive and metastatic potential and improves survival in nude mice models with chronic fibrosis background via inhibition of cytokine secretion by activated hepatic stellate cells.

• Songyou Yin
• activated hepatic stellate cells
• chronic fibrosis
• hepatocellular carcinoma

The invasion and metastasis of hepatocellular carcinoma, as well as their speed and extent, are the important factors affecting curative effects in many patients with hepatocellular carcinoma, and they are also effective indicators for evaluating the prognosis and survival time of patients. Therefore, how to inhibit the metastasis of hepatocellular carcinoma cells is one of the hot research topics in the treatment of liver cancer. Chinese medicine is a group of effective agents for liver cancer treatment by inhibiting invasion and metastasis. They can, directly or indirectly, inhibit the growth of tumor microvessels and regulate the activities of matrix metalloproteinases, the expression of adhesion molecules and tumor microenvironment by modulating signaling pathways associated with the invasion and metastasis of hepatocellular carcinoma. This article will review the current progress in understanding the mechanisms for traditional Chinese medicine to inhibit the invasion and metastasis of hepatocellular carcinoma from the perspective of signal transduction pathways.

• Chinese medicine
• Hepatocellular carcinoma
• Invasion and metastasis
• Mechanisms
• Progress

Hepatectomy generally offers the best chance of long-term survival for patients with hepatocellular carcinoma (HCC). Many studies have shown that hepatectomy accelerates tumor metastasis, but the mechanism remains unclear.

An orthotopic nude mice model with palliative HCC hepatectomy was performed in this study. Metastasis-related genes in tumor following resection were screened; HCC invasion, metastasis, and some molecular alterations were examined in vivo and in vitro. Clinical significance of key gene mRNA expression was also analyzed.

Metastasis suppressor 1 (MTSS1) located in the central position of gene function net of residual HCC. MTSS1 was up-regulated in residual tumor after palliative resection. In hepatitis B-related HCC patients undergone palliative hepatectomy, those with higher MTSS1 mRNA expression accompanied by activation of matrix metalloproteinase 2 (MMP2) in residual HCC, had earlier residual HCC detection after hepatectomy and poorer survival when compared to those with lower MTSS1. In different cell lines, the levels of MTSS1 mRNA increased in parallel with metastatic potential. MTSS1 down regulation via siRNA decreased MMP2 activity, reduced invasive potentials of HCC by 28.9 % in vitro, and averted the deteriorated lung metastatic extent in vivo.

The poor prognosis of hepatitis B-related HCC patients following palliative hepatectomy associates with elevated MTSS1 mRNA expression; therefore, MTSS1 may provide a new research field for HCC diagnosis and treatment.

The online version of this article (doi:10.1186/s13046-016-0361-8) contains supplementary material, which is available to authorized users.

• Hepatocellular carcinoma
• Invasion
• Metastasis
• Metastasis suppressor 1

The present study aimed to investigate the effect of Buyang Huanwu decoction (BYHWD) on tumor growth, metastasis and angiogenesis in nude mice bearing human hepatocellular carcinoma (HCC) HCCLM3 xenografts. A total of 96 nude mice bearing HCCLM3 xenografts were randomly divided into four groups: BYHWD group (LB), Yi-qi decoction group (LY), Huo-xue decoction group (LH) and model group (LM). Each of these groups was divided into three subgroups (n=8), which were observed on days 21, 25, 38 following treatment, respectively. The tumor weights, volumes and pulmonary metastases were recorded. The expression of CD105 and the microvessel density (MVD) were assessed, and the expression levels of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), and regulator of G protein signaling 5 (RGS-5) were analyzed using immunohistochemical staining. Compared with the LM group, no significant decrease in tumor weight or volume were observed in the herbal medicine treatment groups, the number of the metastases in the lungs decreased, whereas the expression levels of RGS-5 and HIF-1α decreased in the LB group on day 35. However, the expression levels of VEGF increased in the LB group on days 28 and 35 post-treatment. The results of the present study suggested that BYHWD may inhibit angiogenesis and metastasis by affecting the expression levels of VEGF, RGS-5 and HIF-1α, and suggested that BYHWD may contribute to the tumor microenvironment and vasculature normalization in HCC.

Objective. Both the Chinese herbal compound Songyou Yin (SYY) and swimming exercise have been shown to have protective effects against liver cancer in animal models. In this study, we investigated whether SYY and moderate swimming (MS) have enhanced effect on suppressing progression of liver cancer by immunomodulation. Methods. C57BL/6 mice were transplanted with Hepa1-6 murine liver cancer cell lines and received treatment with SYY alone or SYY combined with MS. The green fluorescent protein (GFP)-positive metastatic foci in lungs were imaged with a stereoscopic fluorescence microscope. Flow cytometry was used to test the proportion of CD4 +, CD8 + T cells in peripheral blood and the proportions of CD4 + CD25 + Foxp3 + Treg cells in peripheral blood, spleen, and tumor tissues. Cytokine transforming growth factor (TGF)-β1 level in serum was detected by ELISA. Results. SYY plus MS significantly suppressed the growth and lung metastasis of liver cancer and prolonged survival in tumor-burdened mice. SYY plus MS markedly raised the CD4 to CD8 ratio in peripheral blood and lowered the serum TGF-β1 level and the proportions of Treg cells in peripheral blood, spleen, and tumor tissue. The effects of the combined intervention were significantly superior to SYY or MS alone. Conclusion. The combined application of SYY and MS exerted an enhanced effect on suppressing growth and metastasis of liver cancer by strengthening immunity.

• herbal medicine
• immunity
• liver cancer
• metastasis
• swimming

Traditional Chinese medicine (TCM) has played a positive role in the management of hepatocarcinoma. Hepatocarcinoma patients may present Qi-stagnation, damp-heat, blood stasis, Qi-deficiency, Yin-deficiency and other TCM syndromes (Zheng). Modern treatments such as surgery, transarterial chemoembolization (TACE) and high intensity focus ultrasound treatment would influence the manifestation of TCM syndromes. Herbs with traditional efficacy of tonifying Qi, blood and Yin, soothing liver-Qi stagnation, clearing heat and detoxifying and dissolving stasis, have been demonstrated to be potent to prevent hepatocarcinogenesis. TCM has been widely used in all aspects of integrative therapy in hepatocarcinoma, including surgical resection, liver transplantation, TACE, local ablative therapies and even as monotherapy for middle-advanced stage hepatocarcinoma. Clinical practices have confirmed that TCM is effective to alleviate clinical symptoms, improve quality of life and immune function, prevent recurrence and metastasis, delay tumor progression, and prolong survival time in hepatocarcinoma patients. The effective mechanism of TCM against hepatocarcinoma is related to inducing apoptosis, autophagy, anoikis and cell senescence, arresting cell cycle, regulating immune function, inhibiting metastasis and angiogenesis, reversing drug resistance and enhancing effects of chemotherapy. Along with the progress of research in this field, TCM will contribute more to the prevention and treatment of hepatocarcinoma.

• Hepatocarcinoma
• Traditional Chinese medicine
• Prevention
• Treatment
• Traditional Chinese medicine syndrome (Zheng)
• Therapeutic principle
• Chinese herbal formula
• Chinese herb

Anti-inflammation via inhibition of NF-κB pathways in hepatic stellate cells (HSCs) is one therapeutic approach to hepatic fibrosis. Tanshinone IIA (C₁₉H₁₈O₃, Tan IIA) is a lipophilic diterpene isolated from Salvia miltiorrhiza Bunge, with reported anti-inflammatory activity. We tested whether Tan IIA could inhibit HSC activation.

The cell line of rat hepatic stellate cells (HSC-T6) was stimulated with lipopolysaccharide (LPS) (100 ng/ml). Cytotoxicity was assessed by MTT assay. HSC-T6 cells were pretreated with Tan IIA (1, 3 and 10 µM), then induced by LPS (100 ng/ml). NF-κB activity was evaluated by the luciferase reporter gene assay. Western blotting analysis was performed to measure NF-κB-p65, and phosphorylations of MAPKs (ERK, JNK, p38). Cell chemotaxis was assessed by both wound-healing assay and trans-well invasion assay. Quantitative real-time PCR was used to detect gene expression in HSC-T6 cells.

All concentrations of drugs showed no cytotoxicity against HSC-T6 cells. LPS stimulated NF-κB luciferase activities, nuclear translocation of NF-κB-p65, and phosphorylations of ERK, JNK and p38, all of which were suppressed by Tan IIA. In addition, Tan IIA significantly inhibited LPS-induced HSCs chemotaxis, in both wound-healing and trans-well invasion assays. Moreover, Tan IIA attenuated LPS-induced mRNA expressions of CCL2, CCL3, CCL5, IL-1β, TNF-α, IL-6, ICAM-1, iNOS, and α-SMA in HSC-T6 cells.

Our results demonstrated that Tan IIA decreased LPS-induced HSC activation.

• Abietanes/pharmacology
• Actins/metabolism
• Animals
• Anti-Inflammatory Agents, Non-Steroidal/pharmacology
• Cell Line, Transformed
• Chemotaxis/drug effects
• Enzyme Activation/drug effects
• Hepatic Stellate Cells/drug effects
• Hepatic Stellate Cells/metabolism
• Lipopolysaccharides/pharmacology
• MAP Kinase Signaling System/drug effects
• Mitogen-Activated Protein Kinases/metabolism
• NF-kappa B/metabolism
• Phosphorylation
• Rats

Though gallotannin was known to have anti-oxidant and antitumor activity, the underlying antitumor mechanism of gallotannin still remains unclear. Thus, in the present study, antitumor mechanism of gallotannin was elucidated in hepatocellular carcinoma cells. Gallotannin significantly exerted cytotoxicity against Hep G2 and Chang hepatocellular carcinoma cells with the accumulation of the sub-G1 population and increase of terminal deoxynucleotidyltransferasedUTP nick end labeling (TUNEL) positive cells as an apoptotic feature. Also, gallotannin attenuated the expression of pro-caspase9, pro-caspase3, Bcl2 and integrin β1 and cleaved poly(ADP)-ribose polymerase (PARP) in Hep G2 and Chang cancer cells. Furthermore, gallotannin suppressed cell repair motility by wound healing assay and also inhibited cell adhesion in Hep G2 cells. Of note, gallotannin attenuated the expression of epithelial cadherin (E-cadherin) to form cell-cell adhesion from the early stage, and also beta-catenin at late phase in Hep G2 cells. Consistently, Immunofluorescence assay showed that E-cadherin or β-catenin expression was suppressed in a time dependent manner by gallotannin. Furthermore, silencing of E-cadherin by siRNA transfection method enhanced PAPR cleavage, caspase 3 activation and sub G1 population and attenuated the cell adhesion induced by gallotannin in Hep G2 cells. Overall, our findings demonstrate that the disruption of cell adhesion junction by suppression of E-cadherin mediates gallotannin enhanced apoptosis in Hep G2 liver cancer cells.

• E-cadherin.
• Hep G2 cells
• PARP
• apoptosis
• caspase
• gallotannin

• AMPK
• GSK3β
• HepG2 cells
• apoptosis
• ursolic acid

• AMP-Activated Protein Kinases/metabolism
• Apoptosis/drug effects
• Carcinoma, Hepatocellular/pathology
• Caspase 3/metabolism
• Cell Adhesion Molecules/metabolism
• Glycogen Synthase Kinase 3/metabolism
• Glycogen Synthase Kinase 3 beta
• Hep G2 Cells
• Humans
• Indoles/pharmacology
• Leupeptins/pharmacology
• Liver Neoplasms/pathology
• Maleimides/pharmacology
• Membrane Proteins
• Phosphorylation
• Poly(ADP-ribose) Polymerases/metabolism
• Protein Kinase Inhibitors/pharmacology
• Proto-Oncogene Proteins c-akt/metabolism
• RNA-Binding Proteins
• TOR Serine-Threonine Kinases/metabolism
• Triterpenes/pharmacology
• Ubiquitination
• Ursolic Acid

Although significantly develops in hepatocellular carcinoma (HCC), features of HCC remain an aggressive cancer with a dismal outcome. Traditional Chinese medicine (TCM), specifically Chinese herbal medicine (CHM), is one of the most popular complementary and alternative medicine modalities worldwide. The use of heat-clearing and detoxicating (Chinese named qingre jiedu) CHM has attracted great attention as an alternative antitumor including HCC considering its low toxicity and high activity. Together these reports indicate that CHM is a promising anti-HCC herbal remedy in basic research. For patients with advanced HCC, CHM including formula and single combined with transcatheter arterial chemoembolization or chemotherapy is able to decrease tumor growth and the side effect of toxicity and improve overall survival, quality of life, and immune function. Due to its abundance, low cost, and safety in consumption, CHM remains a species with tremendous potential for further investigation in HCC.

Activated hepatic stellate cells (aHSCs) play an important role in the progression of hepatocellular carcinoma (HCC). Here, we determined if cytokines secreted in response to the herbal compound “Songyou Yin” (SYY) treatment of aHSCs could influence invasiveness and metastatic capabilities of hepatoma cells.

Primary rat hepatic stellate cells (HSCs) were isolated, activated, divided into SYY treated and untreated (nSYY) groups, and conditioned media (CM-SYY and CM-nSYY, respectively) were collected. The hepatoma cell line, McA-RH7777 was cultured for 4 weeks with SYY, CM-SYY, and CM-nSYY, designated McA-SYY, McA-SYYCM and McA-nSYYCM. The invasiveness and metastatic capabilities were evaluated using Matrigel invasion assay in vitro and pulmonary metastasis in vivo. Matrix metalloproteinase-2 (MMP-2), MMP-9, E-cadherin, N-cadherin, and vimentin protein levels in McA-SYYCM and McA-nSYYCM were evaluated by Western blot. Cytokine levels in conditioned media were tested using enzyme-linked immunosorbent assay (ELISA).

Matrigel invasion assay indicated that the number of McA-SYYCM cells passing through the basement membrane was less than in McA-nSYYCM cells (P < 0.01). Similar results were also observed in vivo for lung metastasis. McA-SYYCM cells showed less pulmonary metastasis capabilities than McA-nSYYCM cells (P < 0.001). The reduced expression of MMP-2 and reversed epithelial to mesenchymal transition with E-cadherin upregulation, and N-cadherin and vimentin downregulation were also found in McA-SYYCM compared to McA-nSYYCM. Metastasis-promoting cytokines hepatocyte growth factor, interleukin-6, transforming growth factor-β1, and vascular endothelial growth factor were markedly decreased in CM-SYY compared to CM-nSYY.

SYY attenuates hepatoma cell invasiveness and metastasis capabilities through downregulating cytokines secreted by activated hepatic stellate cells.

• hepatoma
• scutellaria barbata
• invasion
• metastasis
• matrix metalloproteinase

• Antineoplastic Agents, Phytogenic/pharmacology
• Carcinoma, Hepatocellular
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Flavonoids/pharmacology
• Gene Expression/drug effects
• Gene Expression Regulation/drug effects
• Humans
• Inhibitory Concentration 50
• Matrix Metalloproteinase 2/genetics
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 9/genetics
• Matrix Metalloproteinase 9/metabolism
• Plant Extracts/pharmacology
• Scutellaria/chemistry
• Tissue Inhibitor of Metalloproteinase-1/genetics
• Tissue Inhibitor of Metalloproteinase-1/metabolism
• Tissue Inhibitor of Metalloproteinase-2/genetics
• Tissue Inhibitor of Metalloproteinase-2/metabolism

We investigated the effect of Chinese herbal compound Song-you Yin on HCC stemness. MHCC97H and Hep3B cell lines were pretreated with SYY for 4 weeks, and their chemosensitivity to oxaliplatin was evaluated. The expression of CSC-related markers, cell invasion and migration, and colony formation were also examined. SYY-treated orthotopic nude mouse models of human HCC were developed to explore the effect of oxaliplatin on tumor growth, metastasis, and survival. The CSC-related molecular changes in vivo were also evaluated. The result showed that MHCC97H and Hep3B cells pretreated with SYY showed significantly increased chemosensitivity to oxaliplatin and the downregulation of CSC-related markers CD90, CD24, and EPCAM. SYY also attenuated cell motility, invasion, and colony formation in MHCC97H and Hep3B cell lines. The reduced tumorigenicity and pulmonary metastasis were observed in SYY-pretreated cell lines. Combination treatment with oxaliplatin and SYY significantly reduced tumor volume and pulmonary metastasis and prolonged survival compared with oxaliplatin treatment alone. Immunohistochemical analysis showed reduced expression of CD90, ABCG2, ALDH, CD44, EPCAM, vimentin, and MMP-9 and increased the expression of E-cadherin, in HCC cells following combination treatment. These data clearly demonstrate that SYY renders hepatocellular carcinoma sensitive to oxaliplatin through the inhibition of stemness.

• tanshinone iia
• vascular normalization
• palliative resection
• hepatocellular carcinoma
• metastasis

• Abietanes/pharmacology
• Animals
• Antineoplastic Agents, Phytogenic/administration & dosage
• Antineoplastic Agents, Phytogenic/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/surgery
• Cell Growth Processes/drug effects
• Cell Line, Tumor
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/pathology
• Liver Neoplasms/surgery
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Metastasis
• Random Allocation
• Xenograft Model Antitumor Assays

• Acetates/chemistry
• Animals
• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/pharmacology
• Blotting, Western
• Butanols/chemistry
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Chemical Fractionation
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/secondary
• Dose-Response Relationship, Drug
• Drugs, Chinese Herbal/chemistry
• Drugs, Chinese Herbal/pharmacology
• Female
• Gene Expression Regulation, Neoplastic/drug effects
• HT29 Cells
• Humans
• Inhibitory Concentration 50
• Matrix Metalloproteinase 2/genetics
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 7/genetics
• Matrix Metalloproteinase 7/metabolism
• Matrix Metalloproteinase 9/genetics
• Matrix Metalloproteinase 9/metabolism
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Solvents/chemistry
• Time Factors
• Tumor Burden/drug effects
• Vascular Endothelial Growth Factor A/genetics
• Vascular Endothelial Growth Factor A/metabolism
• Water/chemistry
• Xenograft Model Antitumor Assays

• Active ingredients
• Chemoprevention
• Chemosensitization
• Hepatocellular carcinoma
• Herbs
• Molecular targets

Liver resection is a widely accepted treatment for hepatocellular carcinoma (HCC). Our previous clinical study showed that the rate of palliative resection was 34.0% (1958-2008, 2754 of 8107). However, the influence of palliative resection on tumor metastasis remains controversial. The present study was conducted to evaluate the effect of palliative resection on residual HCC and to explore interventional approaches.

Palliative resection was done in an orthotopic nude mice model of HCC (MHCC97H) with high metastatic potential. Tumor growth, invasion, metastasis, lifespan, and some molecular alterations were examined in vivo and in vitro. Mice that underwent palliative resection were treated with the Chinese herbal compound "Songyou Yin," interferon-alfa-1b (IFN-α), or their combination to assess their effects.

In the palliative resection group, the number of lung metastatic nodules increased markedly as compared to the sham operation group (14.3 ± 4.7 versus 8.7 ± 3.6, P < 0.05); tumor matrix metalloproteinase 2 (MMP2) activity was elevated by 1.4-fold, with up-regulation of vascular endothelial growth factor (VEGF) and down-regulation of tissue inhibitor of metalloproteinase 2 (TIMP2). The sera of mice undergoing palliative resection significantly enhanced cell invasiveness by 1.3-fold. After treatment, tumor volume was 1205.2 ± 581.3 mm³, 724.9 ± 337.6 mm³, 507.6 ± 367.0 mm³, and 245.3 ± 181.2 mm³ in the control, "Songyou Yin," IFN-α, and combination groups, respectively. The combined therapy noticeably decreased the MMP2/TIMP2 ratio and prolonged the lifespan by 42.2%. Moreover, a significant (P < 0.001) reduction of microvessel density was found: 43.6 ± 8.5, 34.5 ± 5.9, 23.5 ± 5.6, and 18.2 ± 8.0 in the control and treatment groups, respectively.

Palliative resection-stimulated HCC metastasis may occur, in part, by up-regulation of VEGF and MMP2/TIMP2. "Songyou Yin" reinforced the ability of IFN-α to inhibit the metastasis-enhancing potential induced by palliative resection, which indicated its potential postoperative use in patients with HCC.

• ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
• Abietanes
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Doxorubicin/pharmacology
• Drug Resistance, Neoplasm/drug effects
• Humans
• Models, Biological
• Molecular Structure
• Phenanthrenes/chemistry
• Phenanthrenes/isolation & purification
• Phenanthrenes/pharmacology
• Plants, Medicinal/chemistry
• Salvia miltiorrhiza/chemistry