Fibroblast Growth Factor 4(FGF4) Expression in Malignant Skin Cancers

PURPOSE: FGF4(fibroblast growth factor 4) is a newly characterized gene which was found to be a transforming gene in several cancerous cells. FGF4 expression and amplification has been subsequently observed in several human cancers including stomach cancer, breast cancer, head and neck squamous cell carcinoma, lung cancer and bladder cancer. This study was designed to measure the protein expression of FGF4 in malignant skin cancers. METHODS: We examined 8 normal skin tissues and 24 malignant skin tumor tissues which were 8 malignant melanomas, 8 squamous cell carcinomas and 8 basal cell carcinomas. The specimens were analyzed for the protein expression of FGF4 using immunohistochemical staining. To evaluate the amount of expression of FGF4, the histochemical score(HSCORE) was used. RESULTS: FGF4 was expressed more intensely in malignant melanoma, followed by SCC and BCC in immunohistochemistry. The average HSCORE was 0.01 for normal skin, 2.02 for malignant melanoma, 1.28 for squamous cell carcinoma , and 0.27 for basal cell carcinoma, respectively. The expression of FGF4 in malignant melanoma and squamous cell carcinoma was increased in comparison with normal tissues and basal cell cancer, and the difference was statistically significant(p<0.05). The difference between malignant melanoma and squamous cell carcinoma was not statistically significant. CONCLUSION: These findings provide evidences that the expression of FGF4 plays an important role in malignant melanoma and squamous cell carcinoma progressions. This article demonstrates expression of FGF4 in human skin malignant tumors, and suggests that FGF4 is more expressed in highly aggressive skin tumors.

Immunohistochemical Study on Early Odontogenesis in Hsp70 Knock-out Mice Fetuses Exposed by Maternal Hyperthermia / 대한해부학회지

To investigate the effects of maternal hyperthermia on early odontogenesis,pregnant Hsp70 knock-out and wild type mice at embryonic day (ED)8.5 were immersed in a 43 degrees C water bath until their core body temperature reached that temperature,and then given a further 5 min of hyperthermia.Untreated Hsp70 WT mice fetuses were used as the control group.Fetuses were collected at EDs 13.5,15.5 and 17.5.Developing teeth in the mandible were processed for histological and immunohistochemical studies.Tissue sections were immunostained for FGF-8 and FGF -4 and observed using light microscopy.In the controls, FGF-8 immunolocalization was observed in cells within the dental lamina and in apically located dental epithelium at ED 13.5.However,a few cells were immunopositive in the heat shocked (HS)group.At EDs 15.5 and 17.5 of the control group,the basal lamina adjacent to the dental pulp showed positive immunostaining.In contrast,most of the dental epithelium was immunopositive at ED 15.5 in the HS group and inner and outer dental epithelial cells were continuously immunopositive by ED 17.5.FGF-4 immunolocalization was found in apical dental epithelium at ED 13.3 in the control group,but no such positive reaction was observed in the HS group.At ED 15.5 in the controls,basal lamina and dental epithelium near the cervical loop were immunopositive.In contrast,early cap-stage teeth had cells near the mouth of the dental bud and cervical loop that were immunopositive to FGF-4 in the HS group.In controls at ED 17.5,cells near the future secondary enamel knot were immunopositive,whereas most of the dental epithelium except for cells in the mouth of the dental lamina was negative in the HS group.Thus,maternal hyperthermia may inhibit normal odontogenesis through sustained production of FGF-8 and downregulation of FGF-4.

Roles of FGF-4 on the Differentiation of Trophoblast Stem (TS) Cells / 대한해부학회지

Fibroblast growth factor-4 (FGF-4) has various functions, affecting many signaling pathways, and leading to cellular proliferation and differentiation and to the regulation of cell migration, invasion, and angiogenesis. However, there are few reports of the relationship between TS cells and FGF-4 even if FGF-4 is located in inner cell mass of embryo and Fibroblast growth factor receptor (FGFR) is located in TS cells. Therefore the physiologic effects of FGF-4 on TS cells were investigated for identifying the effects of FGF-4 on TS ell differentiation. FGF-4 was involved in early stage development of the trophoblast via upregulation of eomesodermin mRNA expression. In addition, FGF-4 suppressed the differentiation of TS cells through activation of extracellular-signal regulated kinase (Erk) and suppression of focal adhesion kinase (FAK) activation, which in TS cells is an important indicator of early trophoblast cell differentiation, migration and invasion. FGF-4 was involved in angiogenesis in the trophoblast through the activation of p38 and the induction of Dlx-3 mRNA expression in TS cells. In addition, TS cells cultured with FGF-4 for 4 days in a thrombinfibrinogen gel culture system, a specific culture system for endothelial cells, showed a healthy appearance, while TS cells cultured without FGF-4 were severely damaged. Taken together, these data suggest that FGF-4 is closely involved in differentiation of TS cells for development of placenta.

The Protective Effects of FGF-4 on Hypoxia-mediated Apoptosis of Trophoblast Stem Cells / 체질인류학회지

Preeclampsia and fetal growth restriction are conditions associated with placental hypoperfusion and villous hypoxia. The villous response to this environment includes elevated apoptosis. Recently, trophoblast stem (TS) cells had been successfully derived. FGF-4 locates in the inner cell mass (ICM) of blastocyst and TS cells have fibroblast growth factor receptor-2 (FGFR-2). To identify whether FGF-4 protects hypoxia-induced apoptosis in TS cells, this study was carried out. TS cells were cultured up to 48 h in standard (PO2 = 20%) or hypoxic (PO2 = 3%) conditions. TS cells were very vulnerable against exposure to hypoxia for 48 h but embryonic stem (ES) cells were very resistant to hypoxiamediated apoptosis. Death of TS cells bears the typical hallmarks of apoptosis as determined by DNA laddering. FGF- 4 and epidermal growth factor (EGF) protected the hypoxia-mediated cell death of trophoblast but granulocyte-macrophage colony stimulating factor (GMSF) and transforming growth factor-beta (TGF-beta) did not protect. In conclusion, we speculate that the effects of FGF-4 on apoptosis in trophoblasts may play an important role in protecting the placenta from hypoxic injury in pregnancy related with placental hypoperfusion.