Effect of Modified Da Chaihutang on FXR/FGF15/FGFR4 Signaling Pathway in Mice with Cholesterol Gallstone Differentiated into Damp-Heat Syndrome / 中国实验方剂学杂志

ObjectiveTo observe the effect of modified Da Chaihutang on cholesterol gallstone （CS） in mice due to damp-heat based on the farnesoid X receptor （FXR）/fibroblast growth factor 15 （FGF15）/fibroblast growth factor receptor 4 （FGFR4） pathway and explore the molecular biological mechanisms of CS differentiated into damp-heat syndrome from the perspective of correspondence between prescription and syndrome. MethodForty-eight six-week-old mice were randomly divided into the blank group， model group， modified Da Chaihutang （23.4 g·kg-1） group， and ursodeoxycholic acid （0.12 g·kg-1） group， with 12 mice in each group. The ones in the latter three groups were exposed to "internal dampness + external dampness + high-cholesterol diet" for 12 weeks for inducing CS due to damp-heat. Mice in the modified Da Chaihutang group and ursodeoxycholic acid group were gavaged with the corresponding drugs， while those in the model and blank groups with the same amount of normal saline for a total of four weeks. Before and after modeling， mice in each group were subjected to open field tests for determining their activities and mental states. Such general conditions as body mass， food intake， fur， and urine and stool of mice in each group were observed and recorded weekly for judging the damp-heat syndrome. After the intervention， the sampled liver and gallbladder tissues of mice in each group were stained with hematoxylin-eosin （HE） staining， and the serum γ-glutamyltransferase （GGT）， alkaline phosphatase （ALP）， and total bilirubin （TBIL） were determined. The total cholesterol （TC） and total bile acid （TBA） contents in bile were measured by enzyme-linked immunosorbent assay （ELISA）. The mRNA and protein expression levels of FXR， FGF15， FGFR4， and cholesterol 7α-hydroxylase gene （CYP7A1） were assayed by real-time fluorescence quantitative polynucleotide chain reaction （Real-time PCR） and Western blot. ResultCompared with the blank group， the model group exhibited enlarged gallbladder， brown turbid bile with flocculent precipitation visible to the naked eye， obvious damp-heat syndrome， lipoid degeneration in the liver tissue， rough and thickened gallbladder wall， elevated ALP， GGT， and TBIL in serum （P<0.01） and TC in bile （P<0.01）， reduced TBA （P<0.01）， up-regulated FXR， FGF15， and FGFR4 mRNA and protein expression in ileum （P<0.05， P<0.01）， and down-regulated CYP7A1 mRNA and protein expression （P<0.01）. Compared with the model group， the two medication groups displayed improved bile turbidity， and the bile in the modified Da Chaihutang group became clearer. After intervention， the damp-heat syndrome of mice in the modified Da Chaihutang group was significantly alleviated. The liver and gallbladder lesions of mice in the two medication groups were significantly relieved， manifested as reduced serum ALP， GGT， and TBIL （P<0.01）. The reduction in ALP and TBIL of the modified Da Chaihutang group was more significant （P<0.01）. The TC contents in the bile of mice from the two medication groups were significantly lowered， whereas the TBA contents were elevated （P<0.01）， with more significant changes present in the modified Da Chaihutang group （P<0.01）. The mRNA and protein expression levels of FXR， FGF15， and FGFR4 in the modified Da Chaihutang group were down-regulated （P<0.05， P<0.01）， while the mRNA and protein expression levels of CYP7A1 rose （P<0.05）， except that the elevation in FGF15 and FGFR4 protein expression and reduction in CYP7A1 protein expression were not significant. The mRNA and protein expression levels of FXR， FGF15， and FGFR4 in the ursodeoxycholic acid group all decreased， among which the reduction in FXR was remarkable （P<0.05）， and the mRNA and protein expression levels of CYP7A1 were significantly up-regulated （P<0.05）. ConclusionModified Da Chaihutang significantly improves the stone， liver function， bile composition， abnormal cholesterol-bile acid metabolism， and damp-heat syndrome in the model mice of CS differentiated into damp-heat syndrome， which may be related to its regulation of key factors FXR， FGF15， FGFR4， and CYP7A1 mRNA and protein expression in the cholesterol-bile acid metabolism pathway.

Association between FGFR4 gene polymorphism and high-risk HPV infection cervical cancer

OBJECTIVES@#To discuss the association between FGFR4 gene polymorphism rs351855 (Glu388Aly) and the susceptibility and chemotherapeutic effect of cervical cancer infected by high-risk type HPV.@*METHODS@#A total of 162 patients with high-risk HPV cervical cancer and 162 healthy women were collected and the genotypes of the FGFR4 rs351855 locus were detected. The genotype distributions in the two groups were compared. The cervical cancer patients were divided into four groups which namely good therapeutic effect group and bad therapeutic effect, recurrence or metastasis and no recurrence or metastasis group respectively, and the risks of different genotype on the curative effect and prognosis were analyzed by Logistic regression. The survival time of patients with different genotypes was compared.@*RESULTS@#There was no statistic difference in FGFR4 rs351855 genotype distribution between the patients group and control group (P > 0.05), among which the risk of chemotherapy failure on GA + AA patients was 3.257 times as much as that of the GG patients, and the risk of recurrence or metastasis of GA + AA patients was 2.783 times as much as that of the GG patients. For AA patients, the risk of chemotherapy failure and the risk of relapse and metastasis are 3.833 and 3.406 times, respectively, as much as that of the GG patients. The overall survival of GA and AA patients was shorter than that of the GG patients, and significant difference was found (χ = 7.098, P = 0.029). The difference in overall survival between GA + AA patients and GG patients was almost statistically significant (χ = 3.634, P = 0.057).@*CONCLUSIONS@#The FGFR4 rs351855 polymorphism is not associated with the susceptibility of high-risk HPV cervical cancer, but patients with gene A was at higher risk of unfavorable chemotherapy prognosis compared with patients with GG.

Association between FGFR4 gene polymorphism and high-risk HPV infection cervical cancer

Objectives To discuss the association between FGFR4 gene polymorphism rs351855 (Glu388Aly) and the susceptibility and chemotherapeutic effect of cervical cancer infected by high-risk type HPV. Methods A total of 162 patients with high-risk HPV cervical cancer and 162 healthy women were collected and the genotypes of the FGFR4 rs351855 locus were detected. The genotype distributions in the two groups were compared. The cervical cancer patients were divided into four groups which namely good therapeutic effect group and bad therapeutic effect, recurrence or metastasis and no recurrence or metastasis group respectively, and the risks of different genotype on the curative effect and prognosis were analyzed by Logistic regression. The survival time of patients with different genotypes was compared. Results There was no statistic difference in FGFR4 rs351855 genotype distribution between the patients group and control group (P > 0.05), among which the risk of chemotherapy failure on GA + AA patients was 3.257 times as much as that of the GG patients, and the risk of recurrence or metastasis of GA + AA patients was 2.783 times as much as that of the GG patients. For AA patients, the risk of chemotherapy failure and the risk of relapse and metastasis are 3.833 and 3.406 times, respectively, as much as that of the GG patients. The overall survival of GA and AA patients was shorter than that of the GG patients, and significant difference was found (χ

FGFR4 Arg388 Is Correlated with Poor Survival in Resected Colon Cancer Promoting Epithelial to Mesenchymal Transition / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cancer progression during tumor proliferation, invasion, and metastasis. This study evaluated the prognostic role of FGFR4 polymorphism in patients with resected colon cancer, including the underlying mechanism. MATERIALS AND METHODS: FGFR4 polymorphism was characterized in patientswho received curative resection for stage III colon cancer. FGFR4-dependent signal pathways involving cell proliferation, invasion, and migration according to genotypes were also evaluated in transfected colon cancer cell lines. RESULTS: Among a total of 273 patients, the GG of FGFR4 showed significantly better overall survival than the AG or AA, regardless of adjuvant treatment. In the group of AG or AA, combination of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) resulted in better survival than fluorouracil/leucovorin or no adjuvant chemotherapy. However, in GG, there was no difference among treatment regimens. Using multivariate analyses, the Arg388 carriers, together with age, N stage, poor differentiation, absence of a lymphocyte response, and no adjuvant chemotherapy, had a significantly worse OS than patients with the Gly388 allele. In transfected colon cancer cells, overexpression of Arg388 significantly increased cell proliferation and changes in epithelial to mesenchymal transition markers compared with cells overexpressing the Gly388 allele. CONCLUSION: The Arg388 allele of FGFR4 may be a biomarker and a candidate target for adjuvant treatment of patients with resected colon cancer.

FGFR4 Arg388 Is Correlated with Poor Survival in Resected Colon Cancer Promoting Epithelial to Mesenchymal Transition / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cancer progression during tumor proliferation, invasion, and metastasis. This study evaluated the prognostic role of FGFR4 polymorphism in patients with resected colon cancer, including the underlying mechanism. MATERIALS AND METHODS: FGFR4 polymorphism was characterized in patientswho received curative resection for stage III colon cancer. FGFR4-dependent signal pathways involving cell proliferation, invasion, and migration according to genotypes were also evaluated in transfected colon cancer cell lines. RESULTS: Among a total of 273 patients, the GG of FGFR4 showed significantly better overall survival than the AG or AA, regardless of adjuvant treatment. In the group of AG or AA, combination of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) resulted in better survival than fluorouracil/leucovorin or no adjuvant chemotherapy. However, in GG, there was no difference among treatment regimens. Using multivariate analyses, the Arg388 carriers, together with age, N stage, poor differentiation, absence of a lymphocyte response, and no adjuvant chemotherapy, had a significantly worse OS than patients with the Gly388 allele. In transfected colon cancer cells, overexpression of Arg388 significantly increased cell proliferation and changes in epithelial to mesenchymal transition markers compared with cells overexpressing the Gly388 allele. CONCLUSION: The Arg388 allele of FGFR4 may be a biomarker and a candidate target for adjuvant treatment of patients with resected colon cancer.

Significance of FGFR4 expression in prognosis in lung adenocarcinoma / 实用医学杂志

Objective To investigate the expression of FGFR4 in lung adenocarcinoma tissue and its association with the prognosis of lung adenocarcinoma. Methods The expression FGFR4 in 128 lung adenocarcinoma tissue and the normal lung tissue was detected by the immunohistochemistry SP method.The relationship between the expression of FGFR4 in lung adenocarcinoma and the prognosis of lung adenocarcinoma was analyzed. Results The expression of FGFR4 protein in lung adenocarcinoma was significantly lower than that in the tumor-adjacent normal lung tissue (P 0.05), but was significantly and positively correlated with the degree of tumor differentiation and T stage, N stage and the clinical TNM stage of lung adenocarcinoma (P < 0.05).Kaplan-Meier survival test showed that the postoperative survival time in the high expression group of FGFR4 was significantly longer than that in the low FGFR4 expression group (P < 0.05). Conclusion The expression of FGFR4 protein in lung adenocarcinoma was significantly lower than that in the tumor-adjacent normal lung tissue. Postoperative survival time in the high FGFR4expression group was significantly longer than that in the low FGFR4 expression group.