epidermal-growth-factor and Gallbladder-Neoplasms

Five gallbladder cancer (GBC) cell lines were examined for morphological changes in collagen gel culture. GBh3 and HUCCT-1 cells formed tubules in response to treatment with epithelial growth factor (EGF) and hepatocyte growth factor (HGF), and showed high levels of expression of E-cadherin (ECD), and low levels of SNAIL, vimentin, transforming growth factor (TGF)-β, and nucleostemin (NS). In contrast, the GBd15 and FU-GBC-1 cell lines treated with EGF and HGF showed a scattering phenotype, and expressed low levels of ECD and high levels of SNAIL, vimentin, TGF-β, and NS. All cell lines expressed the EGF receptor, c-Met, EGF, and TGF-α, but not HGF. Transforming growth factor-β was upregulated by EGF. Knockdown of the EGF receptor abrogated both tubule formation and scattering, whereas KD of TGF-β abrogated only scattering. Knockdown of EGF induced nuclear translocation of β-catenin and Wnt-related NS induction in the scattering cell lines, but not in the tubule-forming cell lines, whereas KD of glycogen synthase kinase-3β in the tubule-forming cell lines resulted in the nuclear translocation of β-catenin and Wnt-related NS induction in response to EGF treatment. These results suggest that EGF enhances epithelial-mesenchymal transformation and acquisition of stemness in GBC cells with a scattering phenotype through the activity of β-catenin. Repression of ECD in scattering GBC cells induced the release of β-catenin from the cell adhesion complexes along the plasma membrane and its translocation to the nucleus to activate Wnt signaling, which upregulated NS.

Topics: Apoptosis; beta Catenin; Cadherins; Cell Line, Tumor; Cell Proliferation; Epidermal Growth Factor; Epithelial-Mesenchymal Transition; ErbB Receptors; Gallbladder Neoplasms; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; GTP-Binding Proteins; Hepatocyte Growth Factor; Humans; Nuclear Proteins; Proto-Oncogene Proteins c-met; Recombinant Proteins; RNA Interference; RNA, Small Interfering; Snail Family Transcription Factors; Transcription Factors; Transforming Growth Factor alpha; Transforming Growth Factor beta; Vimentin; Wnt Signaling Pathway

Epidermal growth factor (EGF) and transforming growth factor beta1 (TGFbeta1) play important roles in tumor biology. Single nucleotide polymorphisms in EGF and TGFB1 genes alter the expression of these growth factors and influence the tumorigenesis process. The aim of our present study was to determine the association of EGF+61A>G (rs4444903) and TGFB1-509C>T (rs1800469) gene polymorphism with susceptibility to gallbladder cancer (GBC). The present case-control association study was carried out in 126 confirmed GBC patients and 190 healthy subjects. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism methods. The GG genotype of EGF+61A>G was significantly associated with GBC [p=0.012, odds ratio (OR)=2.22, 95% confidence interval (CI)=1.19-4.15] in comparison to healthy subjects. Analysis based on gender indicated risk due to GG genotype was limited to female GBC patients (p=0.003, OR=3.45, 95% CI=1.52-7.82). Upon stratification of GBC patients on the basis of the presence or absence of gallstones, the risk due to EGF polymorphism was not modulated by the status of gallstones. The TGFB1-509C>T polymorphism was not associated with GBC. Also, we did not find any association of this polymorphism when GBC patients were subdivided on the basis of gender. However, after stratification of GBC patients on the status of gallstones, we determined that the CT genotype of TGFB1 was associated with increased risk of GBC without gallstones (p value=0.030, OR=2.90, 95% CI=1.26-6.69). Furthermore, the combination of the GG genotype of EGF and the CT genotype of TGFB1 demonstrated synergistic increase in risk of GBC. In conclusion, the higher producing +61G allele of EGF and -509 CT genotype of TGFB1 synergistically increase the susceptibility of gallbladder cancer (p value=0.003). Further study in large samples size is required to confirm our findings.

Topics: Adult; Age of Onset; Epidermal Growth Factor; Female; Gallbladder Neoplasms; Genetic Predisposition to Disease; Genotype; Humans; India; Male; Middle Aged; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Sex Factors; Transforming Growth Factor beta1

Epidermal growth factor(EGF) and its receptor(EGFR) play an important role in tumorigenesis. Cholelithiasis and cholecystitis were closely related to gallbladder carcinoma. This study was designed to investigate the relationship between the expression of EGF and EGFR in chronic cholecystitis and gallbladder carcinoma.. SABC immunohistochemistry was used to determine the expression of EGF, EGFR, and proliferating cell nuclear antigen (PCNA) in surgically resected specimens of 41 gallbladder carcinomas, 26 simple hyperplasia tissues, 14 dysplasia tissues,and 10 normal gallbladder tissues.. The positive expression rates of EGF and EGFR were higher in gallbladder carcinomas(63.4%,70.7%) and dysplasia tissues (71.4%,85.7%) than in simple hyperplasia tissues (15.4%,27%) and normal gallbladder tissues (0%,0%)(P< 0.01); PCNA counting score tended to increase with the severity of mucosa change degree(P< 0.01), which were 1.0 in normal tissues, 1.0 in simple hyperplasia tissues, 1.9288+/-0.9972 in dysplasia tissues,and 3.0488+/-0.669 in gallbladder carcinomas. Significantly positive correlation were shown between EGF,EGFR, and PCNA(P< 0.05). There was no correlation between EGF, EFGR, and PCNA expression and tumor TNM stage(P>0.05).. Expression of EGF and EGFR is involved in the gallbladder carcinogenesis, and is related to high activity of cell proliferation.

Topics: Adult; Aged; Aged, 80 and over; Cholecystitis; Epidermal Growth Factor; ErbB Receptors; Female; Gallbladder Neoplasms; Gene Expression; Humans; Immunohistochemistry; Male; Middle Aged; Proliferating Cell Nuclear Antigen

The expression of cripto, a member of the epidermal growth factor (EGF) family, was examined by immunohistochemistry in benign lesions and carcinomas of the gall bladder. Cripto expression was detected in 6 (67 percent) of 9 hyperplasias, 4 (58 percent) of 7 adenomas, and 89 (68 percent) of 132 adenocarcinomas of the gall bladder. The degree of cripto expression was not correlated with depth of tumour invasion, tumour stage or patient prognosis. The incidence of cases with cripto expression was significantly higher in papillary and well-differentiated adenocarcinomas (positive 73 percent; strongly positive 38 percent) than in moderately and poorly differentiated adenocarcinomas (positive 54 percent; strongly positive 17 percent) (P < 0.05). These results suggest that cripto expression may not relate to progression in gall bladder carcinomas, but may be associated with tumour differentiation.

Topics: Adenocarcinoma; Adenoma; Epidermal Growth Factor; Gallbladder; Gallbladder Neoplasms; Gene Amplification; Gene Rearrangement; GPI-Linked Proteins; Humans; Hyperplasia; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Membrane Glycoproteins; Neoplasm Proteins

The expression of oncogene products and growth factors (epidermal growth factor, transforming growth factor-beta, erbB-2, ras p 21, and c-myc) in gallbladder cancer and chronic cholecystitis was measured by immunohistochemical staining on paraffin-embedded serial sections. Expression of these products was graded according to staining intensity in an area of positively stained cells. This study reports the detection of oncogene products and growth factors in cholecystitis as well as in early and late gallbladder cancer. The multiexpression of oncogene products and growth factors was greater for both gallbladder cancer groups as compared with the cholecystitis group. The percentage of epidermal growth factor positivity diminished with increased proportion of interstitial tissue and, conversely, the percentage of transforming growth factor positivity increased with increased proportion of interstitial tissue. The proportion of ras positivity was significantly greater in both early and advanced cholecystic cancer as compared with cholecystitis, but also was considerable even for cholecystitis. These results suggest that various oncogenes may have significant roles in gallbladder cancer and that collagen synthesis is reduced by epidermal growth factor and enhanced by transforming growth factor-beta.

Topics: Cholecystitis; Chronic Disease; Epidermal Growth Factor; Gallbladder Neoplasms; Gene Expression; Growth Substances; Humans; Immunohistochemistry; Oncogene Protein p21(ras); Oncogene Proteins; Oncogene Proteins, Viral; Proto-Oncogene Proteins c-myc; Receptor, ErbB-2; Transforming Growth Factor beta