PEG10

Gene Summary

Gene:PEG10; paternally expressed 10
Aliases: EDR, HB-1, Mar2, MEF3L, Mart2, RGAG3
Location:7q21.3
Summary:This is a paternally expressed imprinted gene that is thought to have been derived from the Ty3/Gypsy family of retrotransposons. It contains two overlapping open reading frames, RF1 and RF2, and expresses two proteins: a shorter, gag-like protein (with a CCHC-type zinc finger domain) from RF1; and a longer, gag/pol-like fusion protein (with an additional aspartic protease motif) from RF1/RF2 by -1 translational frameshifting (-1 FS). While -1 FS has been observed in RNA viruses and transposons in both prokaryotes and eukaryotes, this gene represents the first example of -1 FS in a eukaryotic cellular gene. This gene is highly conserved across mammalian species and retains the heptanucleotide (GGGAAAC) and pseudoknot elements required for -1 FS. It is expressed in adult and embryonic tissues (most notably in placenta) and reported to have a role in cell proliferation, differentiation and apoptosis. Overexpression of this gene has been associated with several malignancies, such as hepatocellular carcinoma and B-cell lymphocytic leukemia. Knockout mice lacking this gene showed early embryonic lethality with placental defects, indicating the importance of this gene in embryonic development. Additional isoforms resulting from alternatively spliced transcript variants, and use of upstream non-AUG (CUG) start codon have been reported for this gene. [provided by RefSeq, Oct 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:retrotransposon-derived protein PEG10
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Liver Cancer
  • Nuclear Proteins
  • Serpins
  • Genomic Imprinting
  • Long Noncoding RNA
  • Apoptosis
  • Hep G2 Cells
  • Paclitaxel
  • Disease Progression
  • Chromosome 7
  • Biomarkers, Tumor
  • Young Adult
  • siRNA
  • Transcription Factors
  • Cell Proliferation
  • Glypicans
  • Gene Dosage
  • Drug Resistance
  • Staging
  • Ubiquitin-Protein Ligases
  • DNA Methylation
  • Hepatocellular Carcinoma
  • Lymphatic Metastasis
  • Survival Rate
  • Oligonucleotide Array Sequence Analysis
  • Immunohistochemistry
  • Gene Expression Profiling
  • Cell Cycle
  • Carrier Proteins
  • Receptors, Progesterone
  • Nerve Growth Factors
  • Vinblastine
  • Uterine Cancer
  • Genomics
  • Cancer Gene Expression Regulation
  • Wilms Tumour
  • Messenger RNA
  • alpha-Fetoproteins
  • Proteins
  • Neoplasm Invasiveness
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PEG10 (cancer-related)

Agosto-Arroyo E, Isayeva T, Wei S, et al.
Differential Gene Expression in Ductal Carcinoma In Situ of the Breast Based on ERBB2 Status.
Cancer Control. 2017; 24(1):102-110 [PubMed] Related Publications
BACKGROUND: The molecular signature of ductal carcinoma in situ (DCIS) in the breast is not well understood. Erb-b2 receptor tyrosine kinase 2 (ERBB2 [formerly known as HER2/neu]) positivity in DCIS is predictive of coexistent early invasive breast carcinoma. The aim of this study is to identify the gene-expression signature profiles of estrogen receptor (ER)/progesterone receptor (PR)-positive, ERBB2, and triple-negative subtypes of DCIS.
METHODS: Based on ER, PR, and ERBB2 status, a total of 18 high nuclear grade DCIS cases with no evidence of invasive breast carcinoma were selected along with 6 non-neoplastic controls. The 3 study groups were defined as ER/PR-positive, ERBB2, and triple-negative subtypes.
RESULTS: A total of 49 genes were differentially expressed in the ERBB2 subtype compared with the ER/PR-positive and triple-negative groups. PROM1 was overexpressed in the ERBB2 subtype compared with ER/PR-positive and triple-negative subtypes. Other genes differentially expressed included TAOK1, AREG, AGR3, PEG10, and MMP9.
CONCLUSIONS: Our study identified unique gene signatures in ERBB2-positive DCIS, which may be associated with the development of invasive breast carcinoma. The results may enhance our understanding of the progression of breast cancer and become the basis for developing new predictive biomarkers and therapeutic targets for DCIS.

Hua Y, Ma X, Liu X, et al.
Identification of the potential biomarkers for the metastasis of rectal adenocarcinoma.
APMIS. 2017; 125(2):93-100 [PubMed] Related Publications
Rectal cancer is a common malignant tumor of the digestive tract, with a high incidence and high mortality. This study aimed to identify the potential biomarkers and therapeutic targets for rectal adenocarcinoma (RAC) metastasis. The expression profiling of RAC patients with metastasis and RAC patients without metastasis was downloaded from The Cancer Genome Atlas (TCGA) database. The datasets were used to identify the genes associated with RAC metastasis. Fifty up-regulated genes and seventeen down-regulated genes were identified in the primary tumor loci of RAC metastasis compared with non-metastasis. Sixty-seven dysregulated gens were conducted to construct the protein-protein network, and CCND3 was the hub protein. The dysregulated genes were significantly enriched in pancreatic secretion, cell adhesion molecules pathways, response to vitamin D of biological process, and retinoid binding of molecular function. Quantitative real-time polymerase chain reaction results demonstrated that CCND3, AQP3, PEG10, and RAB27B had the up-regulated tendency in RAC metastasis; ADCY1 had the down-regulated tendency in RAC metastasis. CCND3, AQP3, PEG10, RAB27B, and ADCY1 might play essential roles in the metastasis process of RAC through pancreatic secretion and cell adhesion molecules pathways. The five genes could be potential diagnosis biomarkers or therapeutic targets for RAC metastasis.

Zhang M, Sui C, Dai B, et al.
PEG10 is imperative for TGF-β1-induced epithelial‑mesenchymal transition in hepatocellular carcinoma.
Oncol Rep. 2017; 37(1):510-518 [PubMed] Related Publications
Substantial evidence indicates that transforming growth factor-beta 1 (TGF-β1) plays a vital role in epithelial-mesenchymal transition (EMT). PEG10 has been shown involved in invasion and metastasis of tumors. The present study investigated the role of PEG10 in TGF-β1-triggered EMT in hepatocellular carcinoma (HCC) progression. Immunohistochemistry and real-time PCR were used to measure the expression level of PEG10 in clinical HCC tissues with or without lymph node metastasis, and normal tissues. The results showed that PEG10 expression is higher in HCC tissues and associated with overall survival (OS) and lymph node metastasis. Moreover, PEG10 expression level was remarkably higher in hepatic cancer cells than the normal hepatic cell line L02. In the present study, we constructed an adenovirus vector containing the coding area of PEG10 (Ad-PEG10) and infected HepG2 cells and found that overexpression of PEG10 promoted the cell migration, invasion ability and EMT of HepG2 cells. TGF-β1 acted on HepG2 cells by enhancing cell migration, invasion, EMT and upregulating PEG10 expression level. However, cells pretreated with adenovirus vector of PEG10 shRNAs (Ad-shRNA1 and Ad-shRNA2) did not occur EMT prior to TGF-β1 stimulation. Moreover, TGF-β1 did not increase the migration and invasion of cells with PEG10 knockdown and overexpression of PEG10 confers chemoresistance to HepG2 cells. Accordingly, sufficient PEG10 expression level is essential for TGF-β1 induced EMT and associated with the chemoresistance in HepG2 cells.

Li X, Xiao R, Tembo K, et al.
PEG10 promotes human breast cancer cell proliferation, migration and invasion.
Int J Oncol. 2016; 48(5):1933-42 [PubMed] Related Publications
Paternally expressed imprinted gene 10 (PEG10), derived from the Ty3/Gypsy family of retrotransposons, has been implicated as a genetic imprinted gene. Accumulating evidence suggests that PEG10 plays an important role in tumor growth in various cancers, including hepatocellular carcinoma, lung cancer and prostate cancer. However, the correlation between PEG10 and breast cancer remains unclear. In the present study, we evaluated and characterized the role of PEG10 in human breast cancer proliferation, cell cycle, clone formation, migration and invasion. The expression level of PEG10 was significantly elevated in breast cancer tissues and associated with distant metastasis and poor clinical outcome. Gene set enrichment analysis indicated that high expression of PEG10 could enrich cell cycle-related processes in breast cancer tissues. Ectopic overexpression of PEG10 in breast cancer cells enhanced cell proliferation, cell cycle, clone formation along with migration and invasion. Cell-to-cell junction molecule E-cadherin was downregulated and matrix degradation proteases MMP-1, MMP-2, MMP-9 were up-regulated after PEG10 overexpression. Our results demonstrated that PEG10 is a crucial oncogene and has prognostic value for breast cancer, which could be applied in breast cancer diagnosis and targeting therapy in future.

Nalluri S, Ghoshal-Gupta S, Kutiyanawalla A, et al.
TIMP-1 Inhibits Apoptosis in Lung Adenocarcinoma Cells via Interaction with Bcl-2.
PLoS One. 2015; 10(9):e0137673 [PubMed] Free Access to Full Article Related Publications
Tissue inhibitors of metalloproteinases (TIMPs) are multifaceted molecules that exhibit properties beyond their classical proteinase inhibitory function. Although TIMP-1 is a known inhibitor of apoptosis in mammalian cells, the mechanisms by which it exerts its effects are not well-established. Our earlier studies using H2009 lung adenocarcinoma cells, implanted in the CNS, showed that TIMP-1 overexpressing H2009 cells (HB-1), resulted in more aggressive tumor kinetics and increased vasculature. The present study was undertaken to elucidate the role of TIMP-1 in the context of apoptosis, using the same lung cancer cell lines. Overexpressing TIMP-1 in a lung adenocarcinoma cell line H2009 resulted in an approximately 3-fold increased expression of Bcl-2, with a marked reduction in apoptosis upon staurosporine treatment. This was an MMP-independent function as a clone expressing TIMP-1 mutant T2G, lacking MMP inhibition activity, inhibited apoptosis as strongly as TIMP1 overexpressing clones, as determined by inhibition of PARP cleavage. Immunoprecipitation of Bcl-2 from cell lysates also co-immunoprecipitated TIMP-1, indicative of an interaction between these two proteins. This interaction was specific for TIMP-1 as TIMP-2 was not present in the Bcl-2 pull-down. Additionally, we show a co-dependency of TIMP-1 and Bcl-2 RNA and protein levels, such that abrogating Bcl-2 causes a downregulation of TIMP-1 but not TIMP-2. Finally, we demonstrate that TIMP-1 dependent inhibition of apoptosis occurs through p90RSK, with phosphorylation of the pro-apoptotic protein BAD at serine 112, ultimately reducing Bax levels and increasing mitochondrial permeability. Together, these studies define TIMP-1 as an important cancer biomarker and demonstrate the potential TIMP-1 as a crucial therapeutic target.

Akamatsu S, Wyatt AW, Lin D, et al.
The Placental Gene PEG10 Promotes Progression of Neuroendocrine Prostate Cancer.
Cell Rep. 2015; 12(6):922-36 [PubMed] Related Publications
More potent targeting of the androgen receptor (AR) in advanced prostate cancer is driving an increased incidence of neuroendocrine prostate cancer (NEPC), an aggressive and treatment-resistant AR-negative variant. Its molecular pathogenesis remains poorly understood but appears to require TP53 and RB1 aberration. We modeled the development of NEPC from conventional prostatic adenocarcinoma using a patient-derived xenograft and found that the placental gene PEG10 is de-repressed during the adaptive response to AR interference and subsequently highly upregulated in clinical NEPC. We found that the AR and the E2F/RB pathway dynamically regulate distinct post-transcriptional and post-translational isoforms of PEG10 at distinct stages of NEPC development. In vitro, PEG10 promoted cell-cycle progression from G0/G1 in the context of TP53 loss and regulated Snail expression via TGF-β signaling to promote invasion. Taken together, these findings show the mechanistic relevance of RB1 and TP53 loss in NEPC and suggest PEG10 as a NEPC-specific target.

Peng W, Fan H, Wu G, et al.
Upregulation of long noncoding RNA PEG10 associates with poor prognosis in diffuse large B cell lymphoma with facilitating tumorigenicity.
Clin Exp Med. 2016; 16(2):177-82 [PubMed] Related Publications
Diffuse large B cell lymphoma (DLBCL) is one of the most common malignancies worldwide. To date, there has been little progress in improving the overall survival of DLBCL patients. Emerging evidences have implicated that long noncoding RNAs (lncRNAs) have important regulatory roles in fundamental biological processes, and some of them are involved in cancer initiation, development and progression. This study was to investigate the expression of lncRNA PEG10 in a cohort of DLBCL patients to assess its clinical value and biological function in DLBCL. We first found that the expression of PEG10 was upregulated in DLBCL tumorous tissues and that cell lines compared with the normal. Moreover, we illustrated that PEG10 was significantly correlated with B symptoms, IPI score, CHOP-like treatment and rituximab. In addition, ROC(AUC) of PEG10 was up to 0.8228, implicating that PEG10 could be a diagnostic marker for distinguishing DLBCL from normal. Importantly, we verified that PEG10 was a key independent predictive factor for DLBCL prognosis from sizable samples through the longtime follow-ups. Furthermore, we revealed that knockdown of PEG10 expression by siRNA could lead to growth arrest and cell apoptosis in vitro. Our results suggested that PEG10 could represent a novel indicator of poor prognosis and might be served as a potential target for the diagnosis and gene therapy of DLBCL.

Rojiani MV, Ghoshal-Gupta S, Kutiyanawalla A, et al.
TIMP-1 overexpression in lung carcinoma enhances tumor kinetics and angiogenesis in brain metastasis.
J Neuropathol Exp Neurol. 2015; 74(4):293-304 [PubMed] Related Publications
Tissue inhibitors of matrix metalloproteinase (TIMP) orchestrate many biologic activities, including inhibition of matrix metalloproteinase activity, activation of pro-matrix metalloproteinases, and regulation of cell proliferation, angiogenesis, and apoptosis induction. Tissue inhibitors of matrix metalloproteinase can play a protective role during tumor invasion and metastasis, but elevated TIMP messenger RNA levels have also been associated with aggressive cancers and poor clinical outcome. We examined the potential roles of TIMP-1 in H2009 lung adenocarcinoma cells and in cells transfected with a human TIMP-1-overexpressing vector (HB-6 and HB-1). Tumors resulting from the implantation of parental cell lines and transfected HB-1 cells into the brains of nude mice had a typical carcinoma profile, but human TIMP-1-overexpressing tumors showed enhanced tumor kinetics and focally more infiltrative features; vessel density assessed with anti-CD31 immunohistochemistry was also greater within HB-1 tumor implants. Similar effects on HB-6 and HB-1 cells versus parental cell lines and empty vector clones were observed in endothelial cell assays. Anchorage-independent growth and invasion through Matrigel were also increased in TIMP-1-overexpressing cells. Together, these results indicate tumor-promoting functions of TIMP-1 through alterations in angiogenesis, increased tumorigenicity, and invasive behavior. Although matrix metalloproteinase inhibition has been the traditionally identified function of TIMP-1, matrix metalloproteinase-independent interactions may contribute to the growth of metastatic carcinomas in the brain.

Bang H, Ha SY, Hwang SH, Park CK
Expression of PEG10 Is Associated with Poor Survival and Tumor Recurrence in Hepatocellular Carcinoma.
Cancer Res Treat. 2015; 47(4):844-52 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Paternally expressed gene 10 (PEG10), first identified as an imprinted gene, is paternally expressed and maternally silenced. In hepatocellular carcinoma (HCC), PEG10 has been identified as a potential target gene located within the amplified 7q21 locus. The purpose of this study was to investigate the expression of PEG10 protein in HCC and evaluate its prognostic significance.
MATERIALS AND METHODS: PEG10 protein expression was examined by immunohistochemistry in tumor tissues from 218 HCC patients undergoing curative resection. Furthermore, the relationships between PEG10 expression and clinicopathologic features or postoperative survival of HCC patients were evaluated. The median follow-up period was 119.8 months for survivors.
RESULTS: PEG10 expression was observed in 148 of the 218 HCCs (67.9%) and was significantly correlated with younger age, female, higher Edmondson grade, microvascular invasion, intrahepatic metastasis, higher American Joint Committee on Cancer T-stage, and higher α-fetoprotein level. PEG10 expression was an independent predictor of early recurrence (p=0.013), and it showed an unfavorable influence on recurrence-free survival (p < 0.001). A subgroup analysis showed that among patients with α-fetoprotein ≤ 20 ng/mL (80 patients), the PEG10-positive group also showed an unfavorable influence on recurrence-free survival (p=0.002). Moreover, a multivariate survival analysis identified PEG10 as an independent predictor of shorter recurrence-free survival (p=0.005). PEG10 expression showed an unfavorable influence on overall survival (p=0.007) but was not an independent predictor of shorter overall survival (p=0.128).
CONCLUSION: PEG10 protein could be a potential biomarker predicting early recurrence and recurrence-free survival in HCC patients after curative resection, even in those with normal serum α-fetoprotein levels.

Zang W, Wang T, Huang J, et al.
Long noncoding RNA PEG10 regulates proliferation and invasion of esophageal cancer cells.
Cancer Gene Ther. 2015; 22(3):138-44 [PubMed] Related Publications
Long chain noncoding RNAs (LncRNAs), a class of noncoding RNA nucleotides longer than 200 bp, have important roles in a variety of biological processes. Accumulating evidence has confirmed the involvement of LncRNAs in cancer initiation, development and progression. We investigated the expression of LncRNA PEG10 in a cohort of esophageal carcinomas to assess its impact on esophageal cancer cell proliferation, apoptosis and invasion. Quantitaive reverse transcription polymerase chain reaction assays were used to quantify LncRNA PEG10 expression levels in 43 paired EC samples and adjacent non-neoplastic tissues. Cell growth, apoptosis and Transwell invasion assays were used to evaluate the effects of LncRNA PEG10 on esophageal cancer cells. LncRNA PEG10 was expressed at higher levels in esophageal cancer tissues than in adjacent non-neoplastic tissues (P<0.05). This relatively high expression was significantly associated with the occurrence of lymph node metastases (P<0.05). Apoptosis and migration rates were significantly decreased in two esophageal cancer cell lines (EC9706 and KYSE150) transfected with si-LncRNA PEG10 (P<0.05). Downregulation of LncRNA PEG10 decreased the expression of PEG10 (P<0.05). Our results indicated that LncRNA PEG10 is upregulated in esophageal cancer tissues, and its downregulation inhibits proliferation and invasion, and promotes apoptosis in esophageal cancer cells. LncRNA PEG10 may serve as a therapeutic agent in esophageal cancer.

Deng X, Hu Y, Ding Q, et al.
PEG10 plays a crucial role in human lung cancer proliferation, progression, prognosis and metastasis.
Oncol Rep. 2014; 32(5):2159-67 [PubMed] Related Publications
Paternally expressed gene 10 (PEG10) has been identified as a genetic imprinted gene, which is important for apoptosis resistance in cancer cells. Mounting evidence suggests that PEG10 is expressed in the majority of hepatocellular carcinoma (HCC) cells with growth-promoting activity. In the present study, we evaluated the correlation between PEG10 expression and the clinicopathological features of lung, breast and HCC tumors, and predicted the relationship between survival and expression levels of PEG10 in lung cancer patients. Furthermore, we chose non-small cell lung cancer cell line A549 as a model to analyze the function of PEG10 in proliferation and metastasis in vitro. Our results revealed that expression of PEG10 was closely correlated with clinical TNM grade and patient prognosis in lung cancer. PEG10 enhanced cell proliferation and promoted tumor cell migration and invasion by upregulating the expression of β-catenin, MMP-2 and MMP-9, and decreased the expression of E-cadherin in the A549 cells. Our findings provide significant insight into the molecular mechanisms of lung cancer and offer novel ideas for designing new therapeutic targets for lung carcinoma.

Qin J, Liu M, Ding Q, et al.
The direct effect of estrogen on cell viability and apoptosis in human gastric cancer cells.
Mol Cell Biochem. 2014; 395(1-2):99-107 [PubMed] Related Publications
Epidemiology researches indicated that gastric cancer is a male-predominant disease; both expression level of estrogen and expression pattern of estrogen receptors (ERs) influence its carcinogenesis. But the direct effect of estrogen on gastric cancer cells is still unclear. This study aimed to explore the direct effect of β-estradiol (E2) on gastric cancer cells. SGC7901 and BGC823 were treated with a serial of concentrations of E2. The survival rates of both the cell lines were significantly reduced, and the reduction of viability was due to apoptosis triggered by E2 treatment. Caspase 3 was activated in response to the increasing E2 concentration in both SGC7901 and BGC823. Cleaved Caspase 3 fragments were detected, and the expression levels of Bcl-2 and Bcl-xL were reduced. Apoptosis was further confirmed by flow cytometry. The expression level of PEG10, an androgen receptor target gene, was reduced during E2 treatment. Both ERα and ERβ were expressed in these cell lines, and the result of bioinformatics analysis of gastric cancer from GEO datasets indicated that the expression levels of both ERα and ERβ were significantly higher in noncancerous gastric tissues than in gastric cancer tissues. Our research indicated that estrogen can reduce cell viability and promote apoptosis in gastric cancer cells directly; ERs expression level is associated with gastric cancer. Our research will help to understand the mechanism of gender disparity in gastric cancer.

Saad Y, El-Serafy M, Eldin MS, et al.
New genetic markers for diagnosis of hepatitis C related hepatocellular carcinoma in Egyptian patients.
J Gastrointestin Liver Dis. 2013; 22(4):419-25 [PubMed] Related Publications
BACKGROUND AND AIM: Early detection of hepatocellular carcinoma (HCC) enhances effective and curative management. New genetic markers with distinct diagnostic ability are required.
AIM: determine the expression of GPC3, PEG10, SERPINI1, MK and QP-C in the peripheral blood of HCC patients.
METHODS: 74 HCV patients were recruited and divided into three groups; chronic hepatitis (I), liver cirrhosis (II) and HCC (III). Demographics, laboratory and imaging data were collected. Child score and metastatic work up were completed. The expression of the five candidate genes in the peripheral blood was performed by qRT-PCR assay.
RESULTS: Groups were gender matched, age in group I was significantly lower than in groups II and III (37.7 vs 50.4 and 55.6, p value <0.005). CHILD score; group II and III A/B/C = (7/5/6) and (20/6/3). AFP was significantly higher in group III than I and II (204 vs 3.9 and 6.9, p < 0.01). In HCC group 69% of the lesions were < 5 cm, and had 1-2 nodules; 14% had metastases. GPC3, PEG10, SERPINI1 and MK mRNA were significantly higher in the HCC group compared to the other groups while QP-C mRNA was higher in chronic hepatitis C group compared to other groups. The gene expression values in HCC patients were independent of the tumor size, AFP levels or extrahepatic metastasis. Combined measurement of the five gene markers showed 100% sensitivity and 33% specificity, 48% PPV and 100% NPV.
CONCLUSION: GPC3, PEG10, SERPINI1 and MK are genetic markers that can represent a useful tool for detection of HCC.

Fujiki N, Konno H, Kaneko Y, et al.
Estrogen response element-GFP (ERE-GFP) introduced MCF-7 cells demonstrated the coexistence of multiple estrogen-deprivation resistant mechanisms.
J Steroid Biochem Mol Biol. 2014; 139:61-72 [PubMed] Related Publications
The acquisition of estrogen-deprivation resistance and estrogen receptor (ER) signal-independence in ER-positive breast cancer is one of the crucial steps in advancing the aggressiveness of breast cancer; however, this has not yet been elucidated in detail. To address this issue, we established several estrogen-deprivation-resistant (EDR) breast cancer cell lines from our unique MCF-7 cells, which had been stably transfected with an ERE-GFP reporter plasmid. Three cell lines with high ER activity and another 3 cell lines with no ER activity were established from cell cloning by monitoring GFP expression in living cells. The former three ERE-GFP-positive EDR cell lines showed the overexpression of ER and high expression of several ER-target genes. Further analysis of intracellular signaling factors revealed a marked change in the phosphorylation status of ERα on Ser167 and Akt on Thr308 by similar mechanisms reported previously; however, we could not find any changes in MAP-kinase factors. Comprehensive phospho-proteomic analysis also indicated the possible contribution of the Akt pathway to the phosphorylation of ERα. On the other hand, constitutive activation of c-Jun N-terminal kinase (JNK) was observed in ERE-GFP-negative EDR cells, and the growth of these cells was inhibited by a JNK inhibitor. An IGF1R-specific inhibitor diminished the phosphorylation of JNK, which suggested that a novel signaling pathway, IGF1R-JNK, may be important for the proliferation of ER-independent MCF-7 cells. These results indicate that ER-positive breast cancer cells can acquire resistance by more than two mechanisms at a time, which suggests that multiple mechanisms may occur simultaneously. This finding also implies that breast cancers with different resistance mechanisms can concomitantly occur and mingle in an individual patient, and may be a cause of the recurrence of cancer.

Ortega M, Mallo M, Solé F, et al.
5q- syndrome and multiple myeloma diagnosed simultaneously and successful treated with lenalidomide.
Leuk Res. 2013; 37(10):1248-50 [PubMed] Related Publications
A 72-year-old woman was diagnosed with 5q- myelodysplastic syndrome in the course of an indolent multiple myeloma (MM). Bone marrow (BM) cytogenetics disclosed two unrelated clones: 46,XX,del(5)(q13q33), and [47,X,-X,der(1;21)(q10;q10),-4,-4,+5,del(5)(q13q31),+7,der(7)t(1;7)(p34.2;p22),add(8)(p23),-13,+15,der(16) t(1;16)(q23;q12.2),+19,-21,+mar1,+mar2]. The last complex karyotype belonged to malignant plasma cells. FISH and SKY techniques demonstrated different 5q deletions. EGR1 gene (on 5q31) lost in 5q- syndrome remained in 5q- plasma cells. Biclonal evolution was noted: myeloid 5q- cells added a deletion 13q and plasma cells showed monosomy 13. Patient achieved complete cytogenetic response of 5q- syndrome with low-dose of lenalidomide, and a partial remission of MM with high-dose of lenalidomide/dexamethasone combination.

Zhang X, Li W, Li H, et al.
Genomic methylation profiling combined with gene expression microarray reveals the aberrant methylation mechanism involved in nasopharyngeal carcinoma taxol resistance.
Anticancer Drugs. 2012; 23(8):856-64 [PubMed] Related Publications
Taxol is a first-line chemoagent used for treatment of nasopharyngeal carcinoma (NPC). A major obstacle to achieving successful treatment is the development of cellular taxol drug resistance. Aberrant DNA methylation has been recognized to be associated with the transcriptional inactivation of genes related to cancer drug resistance development. To identify the mechanism of DNA methylation involved in NPC taxol resistance, we applied a genome-wide DNA methylation microarray assay to reveal methylation alteration in taxol-resistant NPC cell lines (CNE-1/taxol, 5-8F/taxol, HNE-2/taxol) established previously in our laboratory. Combining with gene expression microarray, we identified drug resistance-associated genes in taxol-resistant cell lines. We also investigated the coeffect of taxol and the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) to confirm the involvement of DNA methylation. The methylation profiling revealed differential patterns between the drug-sensitive and -resistant cell lines. As a result, taxol-resistant cell lines were detected to be globally hypermethylated. Forty-eight differentially methylated genes (30 hypermethylated and 18 hypomethylated) were further identified commonly in the three taxol-resistant cell lines. Six of them (DLC1, CHFR, ABCC5, PEG10, ERBB2, and GSTP1) were independently confirmed to contribute to taxol resistance by both methylation-specific PCR and quantitative real-time PCR. Finally, we conclude that DNA methylation is closely correlated with taxol drug resistance in NPC cells. Combined analysis of DNA methylation and gene expression may enable the discovery of new therapeutic targets and prognostic biomarkers of cancers. Furthermore, DNA methylation inhibitors can reverse chemoresistance and prevent the development of acquired drug resistance.

Xiong J, Qin J, Zheng Y, et al.
PEG10 promotes the migration of human Burkitt's lymphoma cells by up-regulating the expression of matrix metalloproteinase-2 and -9.
Clin Invest Med. 2012; 35(3):E117-25 [PubMed] Related Publications
PURPOSE: Paternally expressed gene 10 (PEG10) is important for apoptosis resistance in cancer cells; however, the effect of PEG10 on tumor cell migration remains poorly understood. In this study, we investigated the effects of PEG10 on proliferation, apoptosis, adhesion and migration in the Burkitt's lymphoma cell line, Raji.
METHODS: Apoptosis was induced by 5-fluorouracil (5-FU) in pcDNA3.0/PEG10 transiently transfected HEK293T cells and PEG10-suppressed Raji cells. siRNAPEG10 was used to inhibit PEG10 expression. Fluorescence-activated cell sorting (FACS) were performed to analyze the effect of PEG10 on apoptosis. CCK-8 were performed to detect cell proliferation and adhesion. Matrigel invasion were performed using PEG10-suppressed Raji cells to investigate cell migration. The expression levels of matrix metalloproteinases -2and -9 (MMP-2 and MMP-9) were analyzed in PEG10-suppressed Raji cells using both real-time RT-PCR and Western blot analysis.
RESULTS: HEK293T cells that overexpressed PEG10 exhibited greater viability 48 h following treatment with 5-FU, relative to control cells. Specific inhibition of PEG10 expression by siRNA resulted in inhibition of growth and apoptosis in Raji cells. Adherence and invasion capabilities were downregulated and expression levels of MMP-2 and MMP-9 were reduced in PEG10-suppressed Raji cells.
CONCLUSIONS: Our findings demonstrated that PEG10 enhances the apoptotic resistance and viability of Raji cells. The migration and adherence invasion capacity of Raji cells could potentially be affected by regulation of the expression of MMP-2 and MMP-9. Our research provides a promising strategy for cancer immunotherapy of lymphoma.

Tysome JR, Macfarlane R, Durie-Gair J, et al.
Surgical management of vestibular schwannomas and hearing rehabilitation in neurofibromatosis type 2.
Otol Neurotol. 2012; 33(3):466-72 [PubMed] Related Publications
OBJECTIVES: To report our approach to the surgical management of vestibular schwannomas (VSs) and hearing rehabilitation in neurofibromatosis Type 2 (NF2).
DESIGN: Retrospective cohort study.
SETTING: Tertiary referral NF2 unit.
PATIENTS: Between 1981 and 2011, seventy-five patients were managed in our NF2 unit, of which, 58 patients are under current review.
MAIN OUTCOME MEASURES: Patients who underwent VS excision were evaluated for tumor size, surgical approach, and outcomes of hearing and facial nerve function. All current patients were evaluated for NF2 mutation, hearing, and auditory implantation outcomes.
RESULTS: Forty-four patients underwent resection of 50 VS in our unit, of which, 14% had facial neuroma excision and reinnervation during the same operation. At 12 months after surgery, facial nerve outcomes were House-Brackmann (HB) 1 in 33%, HB2 in 21%, and HB3 in 30%. Total VS resection was achieved in 78% of patients using a translabyrinthine approach. Seventy-two percent of the current patients have American Association of Otolaryngology-Head and Neck Surgery class A to C hearing (maximum speech discrimination score over 50%) in the better hearing ear, and a further 14% are full-time users of cochlear implants or auditory brainstem implants. The remaining patients have been assessed for auditory implantation.
CONCLUSION: By following a policy of treating VS in NF2 patients where tumor growth is observed, complete tumor resection can be achieved through a translabyrinthine approach while achieving comparable facial nerve outcomes to published series. We advocate proactive hearing rehabilitation in all patients with timely assessment for auditory implantation to maintain quality of life.

van der Horst PH, Wang Y, Vandenput I, et al.
Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.
PLoS One. 2012; 7(1):e30840 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT).
METHODOLOGY AND PRINCIPAL FINDINGS: Paraffin sections from patients with (n = 9) or without (n = 9) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa (IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB (IKPRB) and PRA+PRB (IKPRAB) were cultured in presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling.
CONCLUSION: Intact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveilance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype.

Dong H, Zhang H, Liang J, et al.
Digital karyotyping reveals probable target genes at 7q21.3 locus in hepatocellular carcinoma.
BMC Med Genomics. 2011; 4:60 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is a worldwide malignant liver tumor with high incidence in China. Subchromosomal amplifications and deletions accounted for major genomic alterations occurred in HCC. Digital karyotyping was an effective method for analyzing genome-wide chromosomal aberrations at high resolution.
METHODS: A digital karyotyping library of HCC was constructed and 454 Genome Sequencer FLX System (Roche) was applied in large scale sequencing of the library. Digital Karyotyping Data Viewer software was used to analyze genomic amplifications and deletions. Genomic amplifications of genes detected by digital karyotyping were examined by real-time quantitative PCR. The mRNA expression level of these genes in tumorous and paired nontumorous tissues was also detected by real-time quantitative RT-PCR.
RESULTS: A total of 821,252 genomic tags were obtained from the digital karyotyping library of HCC, with 529,162 tags (64%) mapped to unique loci of human genome. Multiple subchromosomal amplifications and deletions were detected through analyzing the digital karyotyping data, among which the amplification of 7q21.3 drew our special attention. Validation of genes harbored within amplicons at 7q21.3 locus revealed that genomic amplification of SGCE, PEG10, DYNC1I1 and SLC25A13 occurred in 11 (21%), 11 (21%), 11 (21%) and 23 (44%) of the 52 HCC samples respectively. Furthermore, the mRNA expression level of SGCE, PEG10 and DYNC1I1 were significantly up-regulated in tumorous liver tissues compared with corresponding nontumorous counterparts.
CONCLUSIONS: Our results indicated that subchromosomal region of 7q21.3 was amplified in HCC, and SGCE, PEG10 and DYNC1I1 were probable protooncogenes located within the 7q21.3 locus.

Tsuji K, Yasui K, Gen Y, et al.
PEG10 is a probable target for the amplification at 7q21 detected in hepatocellular carcinoma.
Cancer Genet Cytogenet. 2010; 198(2):118-25 [PubMed] Related Publications
DNA copy number aberrations in human hepatocellular carcinoma (HCC) cell lines were investigated using a high-density oligonucleotide microarray, and a novel amplification at the chromosomal region 7q21 was detected. Molecular definition of the amplicon indicated that PEG10 (paternally expressed gene 10), a paternally expressed imprinted gene, was amplified together with CDK14 (cyclin-dependent kinase 14; previously PFTAIRE protein kinase 1, PFTK1) and CDK6 (cyclin-dependent kinase 6). An increase in PEG10 copy number was detected in 14 of 34 primary HCC tumors (41%). PEG10, but not CDK14 or CDK6, was significantly overexpressed in 30 of 41 tumors (73%) from HCC patients, compared with their nontumorous counterparts. These results suggest that PEG10 is a probable target, acting as a driving force for amplification of the 7q21 region, and may therefore be involved in the development or progression of HCCs.

Hayward BE, De Vos M, Talati N, et al.
Genetic and epigenetic analysis of recurrent hydatidiform mole.
Hum Mutat. 2009; 30(5):E629-39 [PubMed] Related Publications
Familial biparental hydatidiform mole (FBHM) is a maternal-effect autosomal recessive disorder in which recurrent pregnancy failure with molar degeneration occurs. The phenotype mimics molar pregnancy due to androgenesis, despite the normal genetic makeup of the conceptus. FBHM appears to result from a failure to establish correct maternal epigenetic identity at imprinted loci during oogenesis. Several women affected with FBHM have previously been shown to have biallelic mutations in the NLRP7 gene (NALP7). Here, we present the results of epigenetic and mutational analysis on FBHM patients from 11 families, 10 of them novel. We demonstrate a methylation defect at imprinted loci in tissue from four new FBHM cases. Biallelic NLRP7 mutations, including eight previously undescribed mutations, were found in all but one family. These results indicate for the first time that maternal imprints at some loci may be correctly specified in FBHM conceptions, since differential methylation of SGCE/PEG10 was preserved in all four cases.

Wang C, Xiao Y, Hu Z, et al.
PEG10 directly regulated by E2Fs might have a role in the development of hepatocellular carcinoma.
FEBS Lett. 2008; 582(18):2793-8 [PubMed] Related Publications
PEG10 is an imprinted gene which is up-regulated in hepatocelluar carcinoma (HCC). However, the mechanism of PEG10 regulation remains to be elucidated. In this work the transcription factors E2F-1 and -4 were demonstrated to bind directly to the promoter of PEG10 and thereby regulate its expression. The expression profile of HCC tissues also suggested E2Fs were involved in PEG10 regulation. Further functional analysis showed that PEG10 was involved in the repression of apoptosis induced by serum deprivation and chemotherapeutic drugs. These findings link cancer genetics and epigenetics by showing that E2F acts directly upstream of an anti-apoptosis imprinted gene, PEG10.

Wang J, Tai LS, Tzang CH, et al.
1p31, 7q21 and 18q21 chromosomal aberrations and candidate genes in acquired vinblastine resistance of human cervical carcinoma KB cells.
Oncol Rep. 2008; 19(5):1155-64 [PubMed] Related Publications
Vinblastine (VBL) is used to treat certain kinds of cancer including Hodgkin's lymphoma, lung cancer, breast cancer, testicular cancer and cervical carcinoma. However, the rapid development of resistance during therapy remains a major clinical challenge. In order to reverse cancer cell resistance, the goal of this study was to find differentially expressed genes and chromosomal alterations in multidrug resistant (MDR) KB-v1 cells, further to probe the relationship between drug resistance and differential genes, and chromosomal changes in MDR cancer cells. Comparative genomic hybridization (CGH) analysis of MDR KB-v1 and their parental KB-3-1 cells revealed chromosomal changes; microarray-based expression profiling was carried out by comparing the gene expressions of MDR KB-v1 cells and KB-3-1 cells. We have identified 3 chromosomal gains in regions of 1p31, 7q21 and 18q21 in MDR cells and 10 genes (CYR61, UGTREL7, MBD1, NARS, ATP5A1, ABCB1, ABCB4, PEG10, MCM7, SERPINE1) contained in these regions were also up-regulated in MDR KB-v1 cells. Forty-nine genes were down-regulated when KB-v1 cells were subjected to lower dose or depletion of the drug. We have confirmed some gene expression changes by reverse transcription-polymerase chain reaction and Northern blots. These are the first data describing the relationship of 1p31 and 18q21 chromosomal aberrations and candidate genes in acquired vinblastine-resistance. This study also demonstrates that the combination of CGH and cDNA microarray is a very useful tool to detect drug resistant targets in cancer treatment.

Kim KP, Thurston A, Mummery C, et al.
Gene-specific vulnerability to imprinting variability in human embryonic stem cell lines.
Genome Res. 2007; 17(12):1731-42 [PubMed] Free Access to Full Article Related Publications
Disregulation of imprinted genes can be associated with tumorigenesis and altered cell differentiation capacity and so could provide adverse outcomes for stem cell applications. Although the maintenance of mouse and primate embryonic stem cells in a pluripotent state has been reported to disrupt the monoallelic expression of several imprinted genes, available data have suggested relatively higher imprint stability in the human equivalents. Identification of 202 heterozygous loci allowed us to examine the allelic expression of 22 imprinted genes in 22 human embryonic stem cell lines. Half of the genes examined (IPW, H19, MEG3, MEST isoforms 1 and 2, PEG10, MESTIT1, NESP55, ATP10A, PHLDA2, IGF2) showed variable allelic expression between lines, indicating vulnerability to disrupted imprinting. However, seven genes showed consistent monoallelic expression (NDN, MAGEL2, SNRPN, PEG3, KCNQ1, KCNQ1OT1, CDKN1C). Furthermore, four genes known to be monoallelic or to exhibit polymorphic imprinting in later-developing human tissues (TP73, IGF2R, WT1, SLC22A18) were always biallelic in hESCs. MEST isoform 1, PEG10, and NESP55 showed an association between the variability observed in interline allelic expression status and the DNA methylation of previously identified regulatory regions. Our results demonstrate gene-specific differences in the stability of imprinted loci in human embryonic stem cells and identify disrupted DNA methylation as one potential mechanism. We conclude the prudence of including comprehensive imprinting analysis in the continued characterization of human embryonic stem cell lines.

Wang X, Yuling H, Yanping J, et al.
CCL19 and CXCL13 synergistically regulate interaction between B cell acute lymphocytic leukemia CD23+CD5+ B Cells and CD8+ T cells.
J Immunol. 2007; 179(5):2880-8 [PubMed] Related Publications
Interacting with T cells, cytokine-producing B cells play a critical protective role in autoimmune diseases. However, the interaction between malignant B and T cells remains to be fully elucidated. In a previous study, we have reported that ligation of CCL19-CCR7 and CXCL13-CXCR5 activates paternally expressed gene 10 (PEG10), resulting in an enhancement of apoptotic resistance in B-cell acute lymphocytic leukemia (B-ALL) CD23+CD5+ B cells. Here, we report that B-ALL CD23+CD5+ B cells produce IL-10 at high level, which can be further elevated by costimulation with CCL19 and CXCL13. CCL19/CXCL13-activated B-ALL CD23+CD5+ B cells, in turn, increase IL-10 expression in syngeneic CD8+ T cells in a B cell-derived IL-10-dependent manner and requiring a cell-cell contact. IL-10 secreted from B-ALL CD23+CD5+ B cells in vitro impairs tumor-specific CTL responses of syngeneic CD8+ T cells. The impairment of cytotoxicity of syngeneic CD8+ T cells is escalated by means of CCL19/CXCL13-induced up-regulation of IL-10 from B-ALL CD23+CD5+ B cells. Moreover, using a short hairpin RNA to knockdown PEG10, we provide direct evidence that increased expression of PEG10 in B-ALL CD23+CD5+ B cells is involved in malignant B-T cell interaction, contributing to the up-regulation of IL-10 expression, as well as to the impairment of cytotoxicity of syngeneic CD8+ T cells. Thus, malignant B-ALL CD23+CD5+ B cells play an immunoregulatory role in controlling different inflammatory cytokine expressions. IL-10 may be one of the critical cellular factors conferring B-ALL CD23+CD5+ B cells to escape from host immune surveillance.

Kainz B, Shehata M, Bilban M, et al.
Overexpression of the paternally expressed gene 10 (PEG10) from the imprinted locus on chromosome 7q21 in high-risk B-cell chronic lymphocytic leukemia.
Int J Cancer. 2007; 121(9):1984-93 [PubMed] Related Publications
We report high expression of the maternally imprinted gene PEG10 in high-risk B-CLL defined by high LPL mRNA expression. Differential expression was initially identified by microarray analysis and confirmed by real time PCR in 42 B-CLL patients. mRNA expression ranged from 0.3- to 375.4-fold compared to normal peripheral blood mononuclear cells (PBMNC). Expression levels in CD19+ B-CLL cells were 100-fold higher than in B-cells from healthy donors. PEG10 expression levels in B-CLL patient samples remained stable over time even after chemotherapy. High PEG10 expression correlated with high LPL expression (p=0.001) and a positive Coombs' test (p=0.04). Interestingly, similar expression patterns were observed for the neighbouring imprinted gene sarcoglycan-epsilon (SGCE). Monoallelic expression and maintained imprinting of PEG10 were found by allele- or methylation-specific PCR. The intensity of intracellular staining of PEG10 protein corresponded to mRNA levels as confirmed by immunofluorescence staining. Short term knock-down of PEG10 in B-CLL cells and HepG2 cells was not associated with changes in cell survival but resulted in a significant change in the expression of 80 genes. However, long term inhibition of PEG10 led to induction of apoptosis in B-CLL cells. Our data indicate (i) a prognostic value of PEG10 in B-CLL patients; (ii) specific deregulation of the imprinted locus at 7q21 in high-risk B-CLL; (iii) a potential functional and biological role of PEG10 protein expression. Altogether, PEG10 represents a novel marker in B-CLL.

Pang EY, Bai AH, To KF, et al.
Identification of PFTAIRE protein kinase 1, a novel cell division cycle-2 related gene, in the motile phenotype of hepatocellular carcinoma cells.
Hepatology. 2007; 46(2):436-45 [PubMed] Related Publications
UNLABELLED: Metastasis is a major cause of cancer morbidity and mortality in individuals with hepatocellular carcinoma (HCC), yet little is known about the underlying molecular basis. Using genetic information derived from chromosome-based comparative genomic hybridization, we have reported previously on regional chromosome 7q21-q22 gains in close association with HCC progression. In this study, we undertook cDNA microarray-based comparative genomic hybridization, to examine the 7q21-q22 region for the involved gene(s) in HCC. High-resolution mapping analysis highlighted 7 candidates, namely PFTAIRE protein kinase 1 (PFTK1), ODAG, CDK6, CAS1, PEX1, SLC25A, and PEG10, within the region. Quantitative reverse transcription (RT)-PCR evaluation further indicated upregulation of a single candidate gene, PFTK1, that correlated significantly with both advanced metastatic HCCs (P = 0.032) and tumor microvascular invasion (P = 0.012). Given that little is known about the function(s) of PFTK1, which is a novel cell division cycle (Cdc)2-related gene, we examined its potential role in the motile phenotype of HCC cells by both ectopic expression and knockdown investigations. RNA-interference knockdown of PFTK1 in invasive Hep3B cells resulted in a significant reduction in cell invasion, chemotactic migration, and cell motility (P < 0.001). Conversely, ectopic expression of PFTK1 in noninvasive HKCI-C3 cells induced substantial cellular invasion and migration (P < or = 0.007). In neither cell line was there any effect on cell viability. Immunofluorescence showed marked filamentous actin polymerizations in PFTK1-expressing cells.
CONCLUSION: In this study, we have thus provided preliminary evidence that overexpression of PFTK1 may confer a motile phenotype in malignant hepatocytes that accounts for the association of upregulation of this gene in metastatic HCC.

Jie X, Lang C, Jian Q, et al.
Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells.
Oncogene. 2007; 26(39):5741-51 [PubMed] Related Publications
The molecular mechanism of striking higher prevalence of hepatocellular carcinoma (HCC) in male subjects has not yet been fully elucidated. Here, we report that androgen receptor (AR) is differentially expressed in different HCC cell lines. AR agonist dihydrotestosterone (DHT) enhances HCC cell growth and apoptotic resistance. Antagonist flutamide (FLU) blocks the effects of DHT on the HCC cell lines. Paternally expressed gene 10 (PEG10) is expressed in HCC cell lines at substantial high level. Using small interfering RNAs against AR and PEG10 in AR- and PEG10-expressing BEL-7404 hepatoma cells and HuH7 hepatoma cells (HuH7) cells, and AR-transfection technique in AR-lacking and PEG10-expressing HepG2 cells, we have confirmed that through upregulation and activation of PEG10, DHT enhances HCC cell growth and apoptotic resistance. We have further demonstrated that DHT upregulates expression of human telomerase reverse transcriptase (hTERT) in HCC cell lines in a PEG10-dependent manner. Moreover, AR directly interacts in vivo with androgen-responsive elements in the regions of promoter and exon 2 of PEG10 gene in HCC cell lines. DHT promotes the hepatoma formation in vivo nude mice through PEG10 activation. AR antagonists (FLU and valproate) inhibit the hepatoma formation. These findings suggest that PEG10 plays an essential role in hepatocarcinogenesis. The PEG10 inhibition can be a novel approach for therapy of HCC.

Jia HL, Ye QH, Qin LX, et al.
Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma.
Clin Cancer Res. 2007; 13(4):1133-9 [PubMed] Related Publications
PURPOSE: Hepatocellular carcinoma (HCC), a common cancer worldwide, has a dismal outcome partly due to the poor identification of early-stage HCC. Currently, one third of HCC patients present with low serum alpha-fetoprotein (AFP) levels, the only clinically available diagnostic marker for HCC. The aim of this study was to identify new diagnostic molecular markers for HCC, especially for individuals with low serum AFP.
EXPERIMENTAL DESIGN: We used the microarray technique to determine the expression profiles of 218 HCC specimens from patients with either high or low serum AFP. From the microarray study, we selected five candidate genes (i.e., GPC3, PEG10, MDK, SERPINI1, and QP-C), which were overexpressed in HCCs. Using quantitative real-time PCR analyses, we validated the expression of these five genes in 50 AFP-normal and 8 AFP-positive HCC specimens and 36 cirrhotic noncancerous hepatic specimens, which include 52 independent specimens not used in microarray analysis.
RESULTS: A significant increase in the expression of the five candidate genes could be detected in most of the HCC samples, including those with normal serum AFP and small tumors. GPC3, MDK, and SERPINI1 encode known serum proteins. Consistently, a significant increase in serum midkine, encoded by MDK, was associated with HCC patients, including those with normal serum AFP. Using prediction analysis of microarray, we showed that a combined score of these five genes can accurately classify noncancerous hepatic tissues (100%) and HCC (71%).
CONCLUSIONS: We suggest that a diagnostic signature approach using a combined score of these five biomarkers rather than a single marker may improve the prediction accuracy of HCC patients, including those with normal serum AFP and smaller-sized tumors.

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