2920

CXCL2

chemokine (C-X-C motif) ligand 2;CXCL2;chemokine (C-X-C motif) ligand 2

C-X-C motif chemokine 2|GRO2 oncogene|MGSA beta|MIP2-alpha|gro-beta|growth-regulated protein beta|macrophage inflammatory protein 2-alpha|melanoma growth stimulatory activity beta

4q21

protein-coding

The dietary antioxidant Curcumin has been proposed for cancer chemoprevention since it induces apoptosis and inhibits the formation of breast cancer metastases. Curcumin acts through the inhibition of phosphorylation of the inhibitor of kappa B (IkappaB), which in turn reduces the nuclear translocation of nuclear factor kappa B (NFkappaB), an inflammation- and cell survival-related transcription factor. However, it is not clear whether the strong antimetastatic effect can exclusively be explained by inhibition of NFkappaB. Here, we addressed the effects of Curcumin (IC(50) = 17 muM) in MDA-MB-231 breast cancer cells using microarray gene expression analyses. Among the 62 genes whose expression was significantly altered, we found the two inflammatory cytokines CXCL1 and -2 (Groalpha and -beta) that were downregulated. Further validation of the microarray results by quantitative real-time reverse transcription-polymerase chain reaction, western blots and enzyme-linked immunosorbent assay revealed that Curcumin impairs transcription of CXCL1 and -2 >24 h and reduces the corresponding proteins. Using small interfering RNA techniques, we elucidated the underlying molecular mechanism revealing that reduction of CXCL1 and -2 messenger RNA levels is NFkappaB dependent and requires intact IkappaBalpha expression. Moreover, CXCL1 and -2 silencing leads to downregulation of several metastasis-promoting genes among which we found the cytokine receptor CXCR4. We therefore suggest that the decrease of CXCL1 and -2 mediated by Curcumin is involved in the inhibition of metastasis.

metastasis and chemoresistance in cancer are linked phenomena, but the molecular basis for this link is unknown. We uncovered a network of paracrine signals between carcinoma, myeloid, and endothelial cells that drives both processes in breast cancer. cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attract CD11b(+)Gr1(+) myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival. Although chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-alpha production by endothelial and other stromal cells. TNF-alpha via NF-kB heightens the CXCL1/2 expression in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis. This network of endothelial-carcinoma-myeloid signaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunities for intervention.

AIM: To determine the association between serum levels of growth-related gene product beta (GRObeta) and clinical parameters in esophageal squamous cell carcinoma (ESCC). METHODS: Using enzyme-linked immunosorbent assay, serum GRObeta levels were measured in ESCC patients (n = 72) and healthy volunteers (n = 83). The association between serum levels of GRObeta and clinical parameters of ESCC was analyzed statistically. RESULTS: The serum GRObeta levels were much higher in ESCC patients than in healthy controls (median: 645 ng/L vs 269 ng/L, P < 0.05). Serum GRObeta levels were correlated positively with tumor size, lymph node metastasis, and tumor-node-metastasis (TNM) staging, but not with gender or the histological grade of tumors in ESCC patients. The sensitivity and specificity of the assay for serum GRObeta were 73.61% and 56.63%, respectively. CONCLUSION: GRObeta may function as an oncogene product and contribute to tumorigenesis and metastasis of ESCC.

The purpose of this study was to investigate the expression of CXCL12 and its receptor CXCR4 in gastric cancer and to determine their relationship with lymph node metastasis. Fifty patients with pathologically confirmed gastric cancer were analyzed from September 2004 to December 2004. The expression levels of CXCL12 and CXCR4 were examined by immunohistochemical staining in the primary gastric tumor tissues, adjacent normal mucosa tissues, and metastatic lymph nodes and were analyzed along with clinicopathological risk factors, to determine their correlation with the prognosis. Positive staining for CXCL12 and CXCR4 was identified in 90.0 and 80.0% of the primary gastric tumor tissues, respectively, with significantly higher expression intensities observed in the primary gastric tumor tissues than in the adjacent normal mucosa tissues (P < 0.01 and P = 0.01, respectively). Positive staining for CXCL12 and CXCR4 was identified in 94.4 and 91.7% of metastatic lymph nodes, respectively, with significantly higher expression intensities in the metastatic lymph nodes than in the adjacent normal mucosa tissues (P < 0.01 and P = 0.01, respectively). expression of CXCL12 in the primary gastric tumor tissues was not significantly associated with the clinicopathological characteristics of the tumor or the disease prognosis. However, the intensity of CXCR4 staining in primary tumor tissues was positively related with lymph node metastasis, TNM staging, and disease prognosis (P = 0.04, 0.03, 0.03, respectively). CXCL12 and CXCR4 are related to formation of gastric tumors and lymph node metastasis. Furthermore, the expression of CXCR4 could be used as a biomarker to predict malignant features of gastric cancer.