Published online Apr 28, 2015. doi: 10.3748/wjg.v21.i16.4864
Peer-review started: October 11, 2014
First decision: October 29, 2014
Revised: November 24, 2014
Accepted: December 14, 2014
Article in press: December 16, 2014
Published online: April 28, 2015
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-1β 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.
Core tip: An orthotopic transplantation tumor model of hepatocellular carcinoma (HCC) with CBRH-7919 cells was established. Inflammatory cell infiltration and macrophage phenotype were assessed by immunohistochemistry. A chemokine PCR array was used to identify differentially expressed genes, and tumor growth was assessed after knockdown with RNA interference. This study describes the inflammatory microenvironment and differential expression of chemokines in hepatocellular carcinoma. The data suggest that CXCL1 plays a critical role in tumor growth and may serve as a potential molecular target for use in HCC therapy.