Taken together, our findings strongly suggest that phosphorylated HSP20 inhibits TGF-α-induced HCC cell migration and invasion via suppression of the JNK signaling pathway.
The results indicate that targeting HIF-2α-mediated activation of the TGF-α/EGFR pathway warrants further investigation as a potential strategy to enhance the efficacy of sorafenib for treating HCC.
Here, we applied functional genomics approach to study step-by-step development of hepatocellular carcinoma (HCC) in the c-Myc/Tgfα transgenic mouse model of aggressive human liver cancer.
In addition, Cox relative hazards model also revealed that TGFA+88344G>A was associated with onset age of HCC occurrence in subjects (RH = 1.46, P(corr) = 0.04).
Thus, TGF-beta signaling inactivation appears to cooperate with TGF-alpha in vivo to promote the formation of liver cancer that recapitulates molecular features of human HCC.
Upregulation of iNos cross-talk with IKK/NF-kappaB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-alpha transgenic mice. iNOS, IKK/NF-kappaB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis.
We found progressive iNos induction in rat and mouse liver lesions, always at higher levels in the most aggressive models represented by HCC of rats genetically susceptible to hepatocarcinogenesis and c-Myc-TGF-alpha transgenic mice. iNOS, inhibitor of kB kinase/NF-kB and RAS/ERK upregulation was significantly higher in HCC with poorer prognosis (as defined by patients' survival length) and positively correlated with tumor proliferation, genomic instability and microvascularization and negatively with apoptosis.
We investigated the correlation between GI and DNA methylation, and influence of methionine metabolism deregulation on these parameters and hepatocarcinogenesis in c-Myc and c-Myc/Tgf-alpha transgenic mice and human HCCs.
Both MYC and transforming growth factor alpha (TGFalpha) are commonly over-expressed in hepatocellular carcinomas, and transgenic mice expressing these genes rapidly develop tumors via the suppression of MYC-induced apoptosis by the growth factor.
The TGF-alpha positive expressing rate in well differentiated HCC was significantly higher than that in moderately and poorly differentiated HCC (P<0.05).
The levels of TGFalpha mRNA were overexpressed in the underlying livers of patients with HCC compared with patients with CVH, although they were lower than those found in HCC tissues.
We here show that preS1, a part of the HBV large surface protein, carries a transcriptional transactivation domain and activates the transcription of the TGF-alpha gene by 2-fold in human HCC HuH6 cells.
TGF-alpha was overexpressed in 17%, equally expressed in 21%, and down-regulated in 62% of the hepatocellular carcinomas when compared to the surrounding hepatic tissue.
The immunohistochemical expression of transforming growth factor-alpha increased during the stepwise development from glycogen-storing liver acini to hepatocellular carcinomas.
Molecular biological analyses of the induced lesions revealed point mutations in the p53 gene in 60.9% of HCCs, and elevated expression of mRNAs for p53, c-myc, c-fos, TGF-alpha, TGF-beta1, alpha-fetoprotein, GST-P, and GGT, and decreased mRNA expression of EGF and EGFR in HCCs when compared to controls.
In contrast, transforming growth factor alpha (TGF alpha) is a factor which stimulates hepatocyte growth and causes hepatocellular carcinoma in an autocrine fashion.
Transforming growth factor alpha (TGF alpha) overexpression is associated with human hepatocellular carcinoma and with transformation of rat liver epithelial cell lines.