2353

FOS

FBJ murine osteosarcoma viral oncogene homolog;FOS;FBJ murine osteosarcoma viral oncogene homolog

FBJ murine osteosarcoma viral (v-fos) oncogene homolog (oncogene FOS)|G0/G1 switch regulatory protein 7|activator protein 1|cellular oncogene c-fos|proto-oncogene c-Fos

14q24.3

protein-coding

c-fos was first identified as a viral oncoprotein, and has been studied in terms of its oncogenic function in tumorigenesis. Many experimental and clinical data indicated that c-fos expression plays a role in the progression of several types of carcinomas. However, some recent studies challenge this view as they indicate that c-fos has tumor suppressor activity. In the present study, we assessed c-fos protein expression in 625 consecutive gastric cancers immunohistochemically, and analyzed its relationship with clinicopathologic factors and survival. We found that a loss of c-fos expression is correlated with a more advanced stage, lymph node metastasis, lymphatic invasion and shorter survival, indicating that c-fos expression in gastric cancer cells is lost during progression and that this loss is associated with a poor prognosis. The above findings suggest that loss of c-fos expression has tumor suppressor activity in gastric cancer and we suspect that this suppressor activity might be related to the pro-apoptotic function of c-fos.

BACKGROUND: Interleukin-1beta (IL-1beta) has been implicated in the progression of gastric adenocarcinoma (GA); however, the molecular mechanisms of action of IL-1beta in GA are poorly characterized. P38 and JNK are the major MAPK family members that regulate IL-1beta signaling pathways. Here, we investigated the role of both p38 and JNK in IL-1beta-induced GA cell migration, invasion and metastatic potential. METHODS: The effects of IL-1beta-induced p38 and JNK activation in GA cells were determined using in vitro Transwell migration and invasion assays of MKN-45 and AGS cells, or an in vivo metastasis assay in nude mice. The IL-1beta-induced p38 signaling pathway was further characterized in GA cells. Activation of the IL-1beta/p38 signaling pathway was also assessed in human primary GA tissues by immunohistochemistry. RESULTS: IL-1beta-induced activation of p38 increased GA cell migration and invasion in vitro and promoted the metastatic potential of GA cells in vivo; these effects were attenuated by p38 siRNA or the p38 inhibitor SB202190. MMP2 or MMP9 siRNAs and the MMP2/9 inhibitor BiPS also inhibited IL-1beta-induced GA cell migration and invasion in vitro. IL-1beta-induced p38 activation significantly increased MMP2 and MMP9 mRNA and protein expression and activity. Luciferase reporter assays demonstrated that the activator protein-1 (AP-1) and the AP-1 binding sites of the MMP9 promoter (-670/MMP9) were activated by IL-1beta-induced p38 activation. Phospho-p38 was significantly upregulated in human GA tissues (compared to matched non-neoplastic tissues), and significantly associated with lymph node metastasis, and invasion beyond the serosa. expression of phospho-p38 significantly correlated with IL-1beta, MMP2, MMP9, and c-fos expression in both human GA tissues and GA cell metastases in the lungs of nude mice. IL-1beta was also capable of activating JNK in GA cells, but activation of JNK was not associated with GA cell migration and invasion. Therefore, IL-1beta-induced the migration and invasion in GA cells were regulated by p38, but not by JNK. CONCLUSIONS: IL-1beta-induced p38 activation and the IL-1beta/p38/AP-1(c-fos)/MMP2 & MMP9 pathway play an important role in metastasis in GA; this pathway may provide a novel therapeutic target for GA.

This study investigates whether the anti-metastasis effect of microRNA-139 (miR-139) on hepatocellular carcinoma (HCC) is mediated through regulating c-fos expression. The expression levels of miR-139 and c-fos in human HCC cell sublines with high (MHCC97H) and low (MHCC97L) spontaneous metastatic potentials were quantified using QPCR or Western blot. miR-139 mimics was transfected into MHCC97H cells to overexpress miR-139, and miR-139 inhibitor was transfected into MHCC97L cells to down-express miR-139. The effect of overexpression or down-expression of miR-139 on c-fos expression of MHCC97H and MHCC97L cells was evaluated using QPCR and Western blot. The 3' untranslated region segments of FOS containing the miR-139 binding sites were amplified by PCR, and the luciferase activity in the transfected cells was assayed. In comparison with the expression level of miR-139 in MHCC97L cells, the expression level in MHCC97H cells was significantly decreased, whereas c-Fos was significantly up-regulated in MHCC97H. The overexpression of miR-139 significantly inhibited the expression of c-fos in MHCC97H cells, and the down-expression of miR-139 significantly promoted the expression of c-fos in MHCC97L cells. miR-139 suppressed the luciferase activity of the pGL-FOS by approximately 40% compared with the negative control. In vitro cell migration analysis demonstrated that depletion of c-fos or overexpression of miR-139 in MHCC97H cells reduced cell migration, whereas overexpression of c-fos or depletion of miR-139 in MHCC97L cells increased cell migration. Thus, we got the conclusion that miR-139 expression is down-regulated in human HCC cell sublines with high spontaneous metastatic potentials (MHCC97H). Derepression of c-Fos caused by miR-139 down-regulation contributes to the metastasis of HCC.

Osteosarcoma is a rare but aggressive bone neoplasm in humans, which is commonly treated with surgery, classical chemotherapy and radiation. Sorafenib, an inhibitor of a number of kinases targeting the Raf/MEK/ERK pathway, is a promising new chemotherapeutic agent in human medicine that has been approved since 2006 for the therapy of renal cell carcinoma and since 2007 for the treatment of hepatocellular carcinoma. Here, we studied the antimetastatic potential of 4 microM of this multikinase inhibitor in a human osteosarcoma cell line. DNA microarray-based gene expression profiling detected 297 and 232 genes upregulated or downregulated at a threshold of >2-fold expression alteration (P<0.05) in the sorafenib-treated cells. Three genes (CXCR4, FOS and S100A4) that are involved in tumor progression were chosen for validation by quantitative PCR (qPCR) and protein expression analysis. The decrease in RNA expression detected by microarray profiling was confirmed by qPCR for all three genes (P<0.01). On the protein level, sorafenib-induced reduction of S100A4 was verified both by western blotting and immunohistochemistry. For CXCR4 and c-Fos, a reduced protein expression was shown by immunohistochemistry, for c-Fos also by immunoblotting. We conclude that sorafenib could serve as a potent chemotherapeutical agent by which to inhibit the metastatic progression of osteosarcomas.