Both ERbeta and wild-type ERalpha were found to be expressed more often in patients with chronic liver disease compared with those with HCC (69% vs. 45% [P = 0.046] and 46% vs. 10% [P = 0.0008], respectively).
Differences in ligand-activation of estrogen receptor alpha (ER(alpha)) were investigated in human HepG2 liver carcinoma and U2 osteogenic sarcoma cells transfected with wild-type ER (ER-wt) and variants expressing only activation function 1 (ERAF1) or AF2 (ER-AF2).
In a previous experiment, we showed that transient overexpressed estrogen receptor-alpha induced early stage HCC cell line Hep 3B cell apoptosis by increasing the hTNF-alpha gene expression in a ligand-independent manner.
In conclusion, (1) the presence of variant liver ER transcripts in the tumor was the strongest negative predictor of survival in inoperable hepatocellular carcinoma; (2) their presence was associated with spontaneous survival significantly worse than in patients with wild-type estrogen receptors; and (3) HBsAg-positive patients with variant receptors were characterized by the worst survival.
In HCV-associated cirrhosis and HCC the decreased expression of estrogen receptor alfa (ERα) in male patients may explain the worse outcome of HCV infection in men than in women.
In order to analyze the associations between estrogen receptor gene alpha polymorphisms and cancers susceptibility, we genotyped six single nucleotide polymorphisms (SNPs) in 163 Caucasian cancer patients--103 breast cancers and 60 other malignancies (colorectal, bladder, hepatocellular carcinoma and acute myeloid leukemia)--and 114 healthy controls using hybridization probes.
In summary, the present study demonstrated that both ERα and β were sufficient to inhibit PPARγ and provide a valuable therapeutic option for the treatment of HCC patients.
In this work we have investigated mRNA expression of wild-type and splice variants of ERα in nontumoral, cirrhotic, and malignant human liver, as well as in HCC cell lines, using an exon-specific reverse transcription polymerase chain reaction (RT-PCR).
Our hypothesis is based on the fact that liver tissue express ER and its different variants exert multiple functions in various stages of liver disease and participate in an extremely complicated signal transduction process, therefore we believe that the presence of one or more SNPs of ESR1 and ESR2 genes may be related with the increase of risk in developing and the severity of HCC, as well as in the response to different treatments.
Our previous study identified that estrogen receptor alpha (ERα) protein is downregulated in 60% of female HCC cases, via a miR-18a elevation mediated suppression of ERα translation.
Polymorphisms in estrogen receptor alpha (ESR1) are reported to be associated with the susceptibility to persistent HBV infection, HBV liver cirrhosis and HBV-related hepatocellular carcinoma (HCC).
Recently, we observed a significant association between the risk for hepatocellular carcinoma and the polymorphisms of the estrogen receptor (ESR) alpha (ESR1) gene, supporting the hypothesis of involvement for the estrogen-ESR axis in the estrogen-induced hepatocarcinogenesis.
Stable transfection of the chimeric Gal4 estrogen receptor and luciferase gene constructs in MCF-7 breast cancer and Hepa.1c1c7 mouse hepatoma cell lines, as well as transfection of a newly constructed luciferase reporter gene pEREtata-Luc in the ECC-1 human endometrial cell line, resulted in constitutive, non-estradiol-inducible clones.
Taken together, our study identified two genetic variants at 6q25.1 newly associated with HCC risk, suggesting ESR1 and estrogen signaling may play a role in mediating susceptibility to HCC in Chinese population.