Impact of intracellular alpha fetoprotein on retinoic acid receptors‐mediated expression of GADD153 in human hepatoma cell lines

Li, Chaoying; Wang, Shanshan; Jiang, Wei; Li, Hui; Liu, Zhongmin; Zhang, Chao; McNutt, Michael A.; Li, Gang

doi:10.1002/ijc.26025

Cited by 35 publications

(27 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Afp may function as a signal molecule by binding with nuclear receptors including retinoic acid receptors, transcription factors, and other proteins (28,29). Thus, the high levels observed in our implantation sites might be interfering with the retinoic acid action in fetal tissues.…”

Section: Discussionmentioning

confidence: 94%

Cystathionine β-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites

Nuño-Ayala

Guillén

Arnal

et al. 2012

Physiological Genomics

View full text Add to dashboard Cite

mocysteinemia has been reported in human reproduction as a risk factor for early pregnancy loss, preeclampsia, and congenital birth defects like spina bifida. Female infertility was also observed in cystathionine beta synthase-deficient mice (Cbs-KO) as an animal model for severe hyperhomocysteinemia. The aim for the present research was to elucidate the time-point of pregnancy loss and to pinpoint gene and cellular changes involved in the underlying pathological mechanism. By mating 90-dayold wild-type and Cbs-KO female mice with their homologous male partners, we found that pregnancy loss in Cbs-KO occurred between the 8th and 12th gestation day during placenta formation. DNA microarrays were carried out on uterus from implantation and interimplantation samples obtained on day 8. The results allowed us to select genes potentially involved in embryo death; these were individually confirmed by RT-qPCR, and their expressions were also followed throughout pregnancy. We found that changes in expression of Calb1, Ttr, Expi, Inmt, Spink3, Rpgrip1, Krt15, Gzmc, Gzmb, Tdo2, and Afp were important for pregnancy success, since a different regulation in Cbs-KO mice was found. Also, differences in relationships among selected genes were observed, indicating a dysregulation of these genes in Cbs-KO females. In conclusion, our data provide more information on the gene expression cascade and its timely regulated process required for a successful pregnancy. In addition, we unveil new potential avenues to explore further investigations in pregnancy loss.reproduction; hyperhomocysteinemia; uterus IN EPIDEMIOLOGICAL AND META-ANALYSIS studies, hyperhomocysteinemia (Hhcy) has been found to be a risk factor for placentally mediated diseases, such as preeclampsia, spontaneous abortion, and placental abruption (50). In case-control studies, it has been also reported that homocysteine (Hcy) levels are frequently elevated in complicated pregnancies due to preeclampsia or umbilical placental vascular disease over those present in the normal pregnancy group (11,37,54).Hcy is a nonprotein sulfur amino acid and a substrate for cystathionine ␤-synthase (Cbs) in the transsulfuration pathway, which represents its main metabolic fate. Alternatively, Hcy can be converted into methionine through the remethylation pathway. Three metabolic reactions using different methyl donors are known; one uses betaine, and the reaction is catalyzed by betaine-homocysteine methyltransferase, the second one catalyzed by 5-methyltetrahydrofolate-homocysteine methyltransferase uses as donor 5-methyltetrahydrofolate (43), and the third one is catalyzed by S-methylmethionine-homocysteine methyltransferase with methyl donor S-methylmethionine (46). These metabolic pathways are expressed in different tissues during development. Thus, Cbs is expressed in liver, pregnant myometrium, and decidual tissue, whereas methionine synthase is expressed in all embryonic tissues, the liver being the primary site of activity for these enzymes (48,51,58).Cbs-deficient [Cbs knockout...

show abstract

Section: Discussionmentioning

confidence: 94%

Cystathionine β-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites

Nuño-Ayala

Guillén

Arnal

et al. 2012

Physiological Genomics

View full text Add to dashboard Cite

show abstract

“…Once released from the late endosomal vesicle, the receptor is separated and recycled back to the cell membrane or degraded. AFP can either be stored in the perinuclear spaces or be engaged in activating or inhibiting signal transduction pathways in the cytoplasm …”

Section: Discussionmentioning

confidence: 99%

“…Given that AFP may interact with RAR and interfere with RAR signaling, AFP might therefore interfer with function of genes regulated by ATRA/RAR . Included among the apoptosis/growth related genes regulated by ATRA/RAR which stimulated our interest is Growth arrest and DNA damage 45α ( GADD45α ), which is upregulated up to 9.5‐fold after ATRA administration . Moreover, as tumor suppressor gene GADD45α has a potential RAR recognition site in the upstream region, and was therefore chosen as a target gene for further evaluation of the effect of AFP on the RAR signal pathway.…”

mentioning

confidence: 99%

Alpha fetoprotein mediates HBx induced carcinogenesis in the hepatocyte cytoplasm

Zhang

Chen

Liu

et al. 2015

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Although tumor-associated fetal protein AFP has demonstrated utility as a clinical tumor marker, the significance of intracellular AFP is still unclear. The aim of this study was to explore the role of cytoplasmic AFP during HBx induced carcinogenesis, which had not previously been recognized; 614 HCC patients were analyzed for correlation of HBV infection with AFP level, and much higher AFP levels were found in HBsAg positive patients. Tumor tissue specimens from 20 HCC patients were used for analysis of AFP and GADD45a. Analysis of HCC specimens showed that upregulation of cytoplasmic AFP is associated with down-regulation of GADD45a in neoplastic tissue. Transfected HBx promotes transcription of AFP by acting on the elements in the AFP gene regulatory region. HBx itself did not directly impact transcription of GADD45a. However, the obstruction of RAR signaling by HBx induced elevation of AFP, which led to down-regulation of GADD45a. Cytoplasmic AFP was able to interact with RAR, disrupting its entrance into the nucleus and binding to the elements in the regulatory region of the GADD45a gene. Knockdown of AFP in siRNA-transfected AFP positive cell lines was synchronously associated with an incremental increase of RAR binding to DNA, as well as upregulation of GADD45a and it was contrary in AFP gene-transfected AFP negative cell lines. These results indicate cytoplasmic AFP is not only a histochemical tumor biomarker for human hepatoma but is also an intracellular signal molecule and potential participant in HBx induced hepatocarcinogenesis.Over the last decade, a multitude of studies have established circulating alpha fetoprotein (AFP) as a growth regulator during ontogenic growth and tumor progression.1-6 While this is a still developing field replete with unanswered questions, compelling progress which has been made in determining the biological role of cytoplasmic AFP as a signal molecule has attracted considerable interest, as aberrantly elevated AFP disturbs the normal signaling network and results in hepatocyte proliferation. As shown in previous studies, regulation of cytoplasmic AFP in development and growth of malignant hepatic tumor cells is achieved through binding to signal molecules involved in growth or apoptosis. These findings have shown cytoplasmic AFP may interfere with the proliferative and apoptotic signaling of the caspase-3 cascade and PI3K signaling, and this leads to aberrant growth of hepatocellular carcinoma (HCC) cells. 7,8 Findings in this study revealed a hitherto undiscovered role for cytoplasmic AFP in carcinogenesis and drug resistance. The regulatory attributes and clinical significance of AFP have been recently summarized and discussed.9 However, to date findings have been insufficient for complete clarification of the intrinsic mechanism underlying the impact of cytoplasmic AFP, and in particular have been insufficient to clarify its clinical relationship to virus induced carcinogenesis.HCC is the fifth most frequent neoplasm worldwide, and accounts for 5.6% of all human canc...

show abstract

“…In our previous research, intracellular AFP was shown to be a signal molecule. Recently, a number of proteins, including nuclear receptors and other intracellular signal molecules involved in cell growth or apoptosis, have been reported to bind to cytoplasmic AFP [4, 5, 7, 30]. These results indicated that the poor prognosis associated with high APF is caused by high cell proliferation, high angiogenesis and low apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Icaritin inhibits the expression of alpha-fetoprotein in hepatitis B virus-infected hepatoma cell lines through post-transcriptional regulation

Zhang

et al. 2016

Oncotarget

Self Cite

View full text Add to dashboard Cite

Although it has showed that icaritin can apparently suppress growth of HCC by reducing the level of AFP, the intrinsic mechanism remains unclear. In this study, we explored the possible mechanism of miRNAs on post-transcriptional regulation of AFP gene, as well as the effects of HBV infection and icaritin in hepatoma cells. The results showed that miR-620, miR-1236 and miR-1270 could bind target sites in the range of 9–18 nt and 131–151 nt downstream of the stop codon in the AFP mRNA 3′-UTR to suppress the expression of AFP. Mutation of these target sites could reverse the effects of these miRNAs. Icaritin (10 μM) might reduce the stability and translational activity of AFP mRNA by increasing the expression levels of these mentioned miRNAs. HBV infection resulted in apparent decreases of these miRNAs and, consequently, increased AFP expression. The results indicated that miR-620, miR-1236 and miR-1270 are critical factors in the post-transcriptional regulation of AFP. Icaritin can counteract the effect of HBV. These findings will contribute to full understanding of the regulatory mechanism of AFP expression in hepatoma cells. And also it revealed a synergistic mechanism of HBV infection and elevation of AFP in the pathogenesis of HCC, as well as the potential clinical significance of icaritin on the therapy of HCC induced by HBV.

show abstract

Impact of intracellular alpha fetoprotein on retinoic acid receptors‐mediated expression of GADD153 in human hepatoma cell lines

Cited by 35 publications

References 32 publications

Cystathionine β-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites

Cystathionine β-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites

Alpha fetoprotein mediates HBx induced carcinogenesis in the hepatocyte cytoplasm

Icaritin inhibits the expression of alpha-fetoprotein in hepatitis B virus-infected hepatoma cell lines through post-transcriptional regulation

Contact Info

Product

Resources

About