[show abstract][hide abstract] ABSTRACT: Liver metastasis is a major cause of mortality in colorectal cancer (CRC). The current study was to investigate the ability of ulinastatin (UTI) and curcumin (CUR) to inhibit CRC liver metastases via modulating matrix metalloproteinase-9 (MMP-9) and E-cadherin expression. Human CRC HCT-116 cells were treated with compounds individually and in combination in order to understand the effect on cell migration and invasion. The HCT-116 cell line was established to stably express luciferase and green fluorescent protein (GFP) by lentiviral transduction (HCT-116-Luc-GFP). We identified an anti-metastasis effect of UTI and CUR on a CRC liver metastasis mouse model. Tumor development and therapeutic responses were dynamically tracked by bioluminescence imaging. Expression of MMP-9 and E-cadherin in metastatic tumors was detected by immunohistochemical assay. Results of wound healing and cell invasion assays suggest that treatment with UTI, CUR, and UTI plus CUR, respectively, significantly inhibit HCT-116 cell migration and invasion. Furthermore, results of CRC hepatic metastasis on a nude mouse model showed that treatment with UTI, CUR alone, and a combination notably inhibited hepatic metastases from CRC and prolonged survival of tumor-bearing mice, especially in the UTI plus CUR group. These results suggest that the combination of UTI and CUR together may offer greater inhibition against metastasis of CRC.
OncoTargets and Therapy 01/2014; 7:305-14. · 2.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: The pathogenesis of hepatic fibrosis is to be further investigated. Protease-activated receptor-2 (PAR2) plays a role in hepatic fibrosis. This study aims to elucidate the role of activation of PAR2 in the regulation of hepatic stellate cell activities. In this study, the expression of PAR2, Fas and caveolin-1 in human hepatic stellate cell line, HHStec cell (HHStecs) was assessed by real time RT-PCR and Western blot. The levels of collagen were determined by enzyme-linked immunosorbent assay. The PAR2 gene was silenced in HHStecs using RNA interference. Apoptosis of HHStecs was assessed by flow cytometry. The results showed that HHStecs expressed PAR2, which was up regulated by activation with phorbol myristate acetate (PMA). Activation of PAR2 increased the release of collagen from HHStecs. Exposure to PMA induced HHStec apoptosis, which was significantly inhibited by activation of PAR2. The PAR2 activation also suppressed the expression of caveolin-1 and Fas in HHStecs. Over expression of caveolin-1 in HHStecs blocked PAR2-reduced apoptosis. We conclude that HHStecs express PAR2. Activation of PAR2 increases HHStecs to release collagen and reduces the activation-induced HHStec apoptosis, which can be inhibited by the over expression of caveolin-1.
Archives of Biochemistry and Biophysics 01/2014; · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: High recurrence of colon cancer liver metastasis is observed in patients after hepatic surgery, and the cause is believed to be mostly due to the growth of residual microscopic metastatic lesions within the residual liver. Therefore, triggering the progression of occult metastatic foci may be a novel strategy for improving survival from colon cancer liver metastases. In the present study, we identified an anti-recurrence effect of ulinastatin on colon cancer liver metastasis in mice after hepatectomy. Transwell cell invasion assays demonstrated that ulinastatin significantly inhibited the in vitro invasive ability of colon cancer HCT116 cells. Moreover, gelatin zymography and ELISA analysis showed that MMP-9 activity and plasmin activity of colon cancer HCT116 cells were inhibited by ulinastatin, respectively. Furthermore, in vivo BALB/C nu/nu mice model indicated that ulinastatin effectively reduced recurrence after resection of hepatic metastases from colon cancer. The optimum timing for ulinastatin administration was one week after hepatectomy. Taken together, our findings point to the potential of ulinastatin as an effective approach in controlling recurrence of hepatic metastases from colon cancer after hepatectomy via its anti-plasmin activity.
BioMed research international. 01/2013; 2013:437950.
[show abstract][hide abstract] ABSTRACT: To investigate the effect of osteopontin (OPN) on the invasion and metastasis of human hapatocellular carcinoma (HCC).
HCC cell lines (HCC-LM3) were transfected with the chemically synthesized small interfering RNA (siRNA). Real-time PCR and Western blot were used to quantify the mRNA and OPN protein levels. The malignant phenotypes including cellular growth, colony formation and invasion capability of the HCC cells were analyzed.
The OPN mRNA and proteins levels were decreased by 75% and 80% in OPN siRNA treated cells. Colony formation and migratory capability were reduced in OPN siRNA treated cells (P < 0.05).
The specific siRNA is able to reduce the OPN expression at both the mRNA and protein levels and significantly inhibits the invasiveness of HCC cells.
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 07/2009; 17(6):422-5.
[show abstract][hide abstract] ABSTRACT: To investigate the stimulated effect of liver regeneration on colon cancer cells in remnant liver in rats.
Rat models with liver metastases or retro-peritoneal metastases of colon cancer were established: animals underwent 37% or 70% liver resection and were compared with a sham laparotomy (15, 25, 15 cases, respectively). Metastases were performed two weeks before resection. Rats were killed 3 weeks after the resection. Total body weight, liver and tumor weights were recorded. The human colon adenocarcinoma cell line Lovo was cultured in the presence of portal serum withdrawn 24 hours and 14 days after partial hepatectomy (PH). DNA synthesis was assessed by flow cytometry analysis for 5-Bromodeoxyuridine (5-BrdU) incorporation.
The tumor growth was accelerated in the remnant liver in 70% PH group, but the tumors in 37% PH group and retro-peritoneal site were not influenced by PH. Compared with the control group, after cultured 72 hours with portal serum withdrawn 24 h after PH, a higher 5-BrdU incorporation was found in the Lovo cell lines (P < 0.05), and it reached the peak after 120 hours of culture (P < 0.05). No difference was found between the groups when cultured with the portal serum withdrawn 14 d after PH (P > 0.05).
PH may accelerate the growth of residual microscopic tumor in the liver which contributes to local recurrence. It has no systemic effect and effects on the cancer cell lines in extrahepatic sites. The excision extension is related to the stimulating effects on the cancer cell line, and subtotal hepatectomy is presumably a major determinant.
Zhonghua wai ke za zhi [Chinese journal of surgery] 03/2009; 47(5):369-72.
[show abstract][hide abstract] ABSTRACT: To study the relationship between the dynamic changes of caveolin-1 with the degrees of liver fibrosis and portal venous pressure (PVP) in the process of rat liver cirrhosis formation induced by dimethylnitrosamine (DMN); also to investigate the mechanisms of caveolin-1 in the regulation of endothelial nitric oxide synthase (eNOS).
Liver cirrhosis was induced in rats by DMN. The degrees of liver fibrosis and PVP were measured. NOS activity was assessed by citrulline generation. Protein expressions of caveolin-1, eNOS and caveolin-1-eNOS interactions were examined by Western blot and immunoprecipitation, respectively.
Four weeks after DMN administration, liver fibrosis was at its peak and then decreased gradually. Immunoprecipitation and Western blot demonstrated that there was enhanced binding of caveolin-1 with eNOS in the process of rat liver cirrhosis. An increase in caveolin-1 expression was detected but the expression of eNOS was lower in cirrhotic tissues than in normal liver tissues. Caveolin-1 protein levels were positively correlated with the degrees of liver fibrosis and the levels of PVP (r=0.967, P < 0.01; r=0.922, P < 0.01, respectively), while NOS catalytic activity was negatively correlated with the degrees of liver fibrosis and levels of PVP (r= 0.973, P < 0.01; r=-0.947, P < 0.01) respectively.
Caveolin-1 upregulation is associated with the development of portal hypertension in liver cirrhosis. Over-expression of caveolin-1 in perisinusoidal cells may promote caveolin-1-eNOS binding and reduce the activity of eNOS.
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 03/2008; 16(3):184-7.