| Objective:The purpose of the present study was to determine whether lamivudine in combination with transarterial chemoembolization (TACE) could reduce HBV activation and improve the survival of patients with hepatocellular carcinoma (HCC).Methods:From July 2008 to October 2011, a total of 181 consecutive HBV-related HCC patients undergoing TACE were randomized to two groups (92:lamivudine,89: control). Follow-up was every 3 months. Primary and secondary endpoints were time to progression (TTP) and overall survival (OS), respectively, both of which were evaluated by the Kaplan-Meier technique and summarized by the hazard ratio (HR).Results:The level of HBV DNA became undetectable in 42 (45.6%) patients in the lamivudine group, compared with 10 (11.2%) in the control group (P<0.001). The median time to progression (TTP) was 8.2 months in lamivudine group and 4.3 months in control group (P=0.005), and lamivudine therapy was an independent protective factor related to TTP (P=0.006). Moreover,1-,2-,3-year survival rates were 83%,69%,58% in lamivudine group and 60%,48%,48% in control group respectively (P=0.002). With multivariate Cox regression model, lamivudine therapy (P=0.002) and AFP level (P=0.003) were two independent predictors for overall survival.Conclusion:Lamivudine therapy could reduce HBV activation and improve survival of HCC patients treated with TACE. Lamivudine therapy and AFP level are two independent factors affecting overall survival.Background and Aim:Hepatocellular carcinoma (HCC) is one of the most common malignancies in China, about 230000 people die of liver cancer every year, accounting for about 55% of global death toll of HCC, most of which are male. Despite advances in the early detection of HCC and the development of various combination treatments including surgery, radiotherapy and chemotherapy, the prognosis of patients with HCC remains poor. Because most patients are in an advanced stage of disease at the time of diagnosis, only approximately 20% of patients have the opportunity of receiving radical treatment. However, the overall 5-year survival rate is low because of the high incidence of recurrence and metastasis after hepatic resection.The occurrence and development of tumor is a complex process that involved multiple genes, links and stages. TME Refers to the tumor microenvironment in which the tumor occurs in the course of its environment. The TME is composed of many different kinds of cells such as endothelial cells, fibroblasts, lymphocytes and macrophages. It also consists of numerous soluble molecules such as growth factors, cytokines, chemokines, antibodies, proteases, various types of enzymes, and metabolites as well as an extracellular matrix. The intensive relationship that exists between tumor cells and the TME plays a major role in tumor initiation, growth and metastasis.Hypoxia is one of the characters of solid tumors. Many researches has found that and it is a negative prognostic factor owing to its contributions to epithelial-mesenchymal transition (EMT), vasculogenesis, invasiveness, metastasis and poor prognosis. Hypoxia-inducible factor is the most important endogenous transcription factor in hypoxia, and is the key factor that mediates physiologic and pathologic hypoxic reaction. Previous research have proved that there were dozens of HIF-1α target genes played the crucial roles in tissue and microenvironment. And there are always new target genes were found. CXCL6 (granulocyte chemotactic protein-2, GCP2) is a member of the ELR+ CXC chemokine family, which is characterized by the presence of four conserved cysteine residues near the amino terminus forming the Cys-X-Cys or "CXC" motif. And they have neutrophil chemotaxis, pro-angiogenic, anti-bacterial and regulation of immune function. In small cell lung cancer, CXCL6 expression is induced in response to hypoxia and a HIF binding site was identified in the HRE (hypoxia response element) within the promoter of CXCL6.This research aimed to discover HIF-la related to liver cancer metastasis, to identify the effect of the key transcriptional factor HIF-1α on migration and invasion of liver cancer cells, and to further explore its underlying molecular mechanisms, providing new clues for the diagnosis and treatment of liver cancer.Methods and methods:HIF-la mRNA and protein expression levels were assessed by qRT-PCR and Western blot in human HCC cell lines with the same genetic background but high and low metastatic potential (MHCC97H and MHCC97L, respectively) and in the low metastatic potential cell lines HepG2 and Huh7 in comparison to the control liver cell line Chang Liver; The expression of HIF-la was assessed by immunohistochemistry in HCC tissue microarrays from 129 patients, and their prognostic values and other clinicopathological data of HCC patents were retrospectively analyzed; Using shRNA to silence HIF-la gene expression and detected the level of CXCL6 expression in HCC cell lines, using wound healing assays,Transwell and BD Matrigel to observe cellular mobility and invasion ability. Overexpressing HIF-1α,and then repeat the above experiment; To further examine the regulation of CXCL6 expression by HIF-la, the sequence of the CXCLC6 promoter was screened and promoter-luciferase constructs were generated based on the location of the putative; To confirm the binding of HIF-1α to the promoter of CXCL6, ChIP-qRT-PCR was performed using sonicated chromatins immunoprecipitated from HCC cell lines using an anti-HIF-1α antibody or an IgG control;The human liver cancer model in nude mice were established with MHCC97H and MHCC97H/HIF-1α (-) cell lines. Tumor growth were observed. The tumors were pathologically examined by microscope; The expression of CXCL6 was assessed by immunohistochemistry in HCC tissue from 129 patients, and their prognostic values and other clinicopathological data of HCC patients were retrospectively analyzed.Results:(1) The mRNA expression and protein level of HIF-la and CXCL6 were significantly higher in HCC cell lines than that of control group; when HCC cells lines were subjected to hypoxia,the mRNA levels of HIF-la and CXCL6 started to increase after 4h hypoxia in a time-dependent manner. Overexpression of HIF-1α in HCC tissues was correlated with microvascular invasion andTNM classification.(2) HIF-1α regulates the expression of CXCL6 at the transcriptional level, thus increasing the invasion, migration of HCC cell lines.(3) HIF-1α gene knockout significantly inhibited tumor growth in nude mice.high levels of CXCL6 were associated withdecreased overall survival and an increased probability of recurrenceConclusion:The present study showed that HIF-1α is upregulated in HCC and it modulates the expression of the pro-angiogenic chemokine CXCL6 via direct interaction with an HRE in its promoter; Furthermore, HIF-1α stabilization promoted HCC migration and invasion in vitro in a CXCL6 dependent manner, and CXCL6 expression was correlated with poor prognosis, suggesting that it could serve as a potential therapeutic target for the treatment of HCC. |
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