Targeted silencing of CXCL1 by siRNA inhibits tumor growth and apoptosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive malignancy and a major cause of cancer-related mortality worldwide. Our previous study shows that chemokine (C-X-C motif) ligand 1 (CXCL1) was upregulated and CXCR1 was downregulated in tumor tissues as compared to peritumor tissues by chemotaxis assay. As the status of CXCL subgroups and their receptors affect progression of HCC, we evaluated potential mechanisms of CXCL1 associated with anticancer effects in HCC based on our previous study. The effects of targeting CXCL1 by RNA interference (RNAi) on the proliferation and apoptosis of CBRH-7919 cells were observed in vitro and in vivo. Additionally, whether CXCL1 knockdown significantly reduce the activity of STAT3, NF-κB and HIF-1 or not were also estimated. RNAi of CXCL1 in the CBRH-7919 cells decreased the growth of tumors in nude mice by inhibited cells proliferation and induced apoptosis. In conclusion, these findings suggest that CXCL1 plays critical roles in the growth and apoptosis of HCC. RNAi of CXCL1 inhibits the growth and apoptosis of tumor cells, which indicates that CXCL1 may be a potential molecular target for use in HCC therapy.

Inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma.

AIM: To study the inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma (HCC) in nude mice. METHODS: CBRH-7919 HCC cells were injected into the subcutaneous region of nude mice. Beginning two weeks after the challenge, tumor growth was measured every week for six weeks. The stromal microenvironment and inflammatory cell infiltration was assessed by immunohistochemistry in paired tumor and adjacent peritumoral samples, and macrophage phenotype was assessed using double-stain immunohistochemistry incorporating expression of an intracellular enzyme. A chemokine PCR array, comprised of 98 genes, was used to screen differential gene expressions, which were validated by Western blotting. Additionally, expression of identified chemokines was knocked-down by RNA interference, and the effect on tumor growth was assessed. RESULTS: Inflammatory cell infiltrates are a key feature of adjacent peritumoral tissues with increased macrophage, neutrophil, and T cell (specifically helper and activated subsets) infiltration. Macrophages within adjacent peritumoral tissues express inducible nitric oxide synthase, suggestive of a proinflammatory phenotype. Fifty-one genes were identified in tumor tissues during the progression period, including 50 that were overexpressed (including CXCL1, CXCL2 and CXCL3) and three that were underexpressed (CXCR1, Ifg and Actb). RNA interference of CXCL1 in the CBRH-7919 cells decreased the growth of tumors in nude mice and inhibited expression of CXCL2, CXCL3 and interleukin-1ß protein. CONCLUSION: These findings suggest that CXCL1 plays a critical role in tumor growth and may serve as a potential molecular target for use in HCC therapy.