CDKN1C

Gene Summary

Gene:CDKN1C; cyclin dependent kinase inhibitor 1C
Aliases: BWS, WBS, p57, BWCR, KIP2, p57Kip2
Location:11p15.4
Summary:This gene is imprinted, with preferential expression of the maternal allele. The encoded protein is a tight-binding, strong inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation. Mutations in this gene are implicated in sporadic cancers and Beckwith-Wiedemann syndorome, suggesting that this gene is a tumor suppressor candidate. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-dependent kinase inhibitor 1C
Source:NCBIAccessed: 09 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 09 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: CDKN1C (cancer-related)

Decimi V, Fazio G, Dell'Acqua F, et al.
Williams syndrome and mature B-Leukemia: A random association?
Eur J Med Genet. 2016; 59(12):634-640 [PubMed] Related Publications
Williams syndrome (WBS) is a rare neurodevelopmental disorder with specific phenotypic characteristics and cardiac abnormalities, but is not considered as a cancer predisposing condition. However, in rare cases, malignancies have been described in patients with WBS, with hematologic cancer (mainly Burkitt Lymphoma and Acute Lymphoblastic Leukemia) as the most represented. We report here the case of a boy with WS and B-NHL. This is the unique case within the large cohort of patients (n = 117) followed in our institution for long time (mean clinical follow-up, 13 years). We herewith propose that the BCL7B gene, located in the chromosomal region commonly deleted in Williams syndrome, could potentially have a role in this particular association.

Marques LA, Semprebon SC, Niwa AM, et al.
Antiproliferative activity of monastrol in human adenocarcinoma (MCF-7) and non-tumor (HB4a) breast cells.
Naunyn Schmiedebergs Arch Pharmacol. 2016; 389(12):1279-1288 [PubMed] Related Publications
Monastrol is an allosteric inhibitor of the mitotic kinesin Eg5 that exhibits an antiproliferative effect against several cell lines. We investigated the antiproliferative effect of monastrol on human breast adenocarcinoma cells (MCF-7) and mammary epithelial cells (HB4a, non-tumoral). Monastrol treatment decreased cell viability only in MCF-7 tumor cells. Real-time cell growth kinetic analysis showed a decrease in the proliferation of MCF-7 cells exposed to monastrol, while in the HB4a cells, only a concentration of 100 μM was able to induce this effect. In a cell cycle analysis, exposure of MCF-7 cells to monastrol led to an increased population of cells in both the G1 and G2/M phases. In HB4a cells, the proportion of cells in the G2/M phase was increased. Monastrol led to an increased mitotic index in both cell lines. Monastrol was not able to induce cell death by apoptosis in any of the cell lines studied. Gene expression analysis was performed to measure the mRNA levels of cell cycle genes, DNA damage indicator gene, and apoptotic related genes. Treatment with monastrol induced in MCF-7 cells a 5-fold increase in the mRNA levels of the CDKN1A gene, an inhibitor of CDKs related with cell cycle arrest in response a stress stimulus, and a 2-fold decrease in CDKN1C mRNA levels in HB4a cells. These results provide evidence that monastrol has a greater antiproliferative effect on MCF-7 tumor cells compared with non-tumor HB4a cells; however, no selective is observed.

Jha AK, Sharma V, Nikbakht M, et al.
A COMPARATIVE ANALYSIS OF METHYLATION STATUS OF TUMOR SUPPRESSOR GENES IN PAIRED BIOPSY AND SERUM SAMPLES FROM CERVICAL CANCER PATIENTS AMONG NORTH INDIAN POPULATION.
Genetika. 2016; 52(2):255-9 [PubMed] Related Publications
Tumor-specific genetic or epigenetic alterations have been detected in serum DNA in case of various types of cancers. In breast cancer, the detection of tumor suppressor gene hypermethylation has been reported in several body fluids. Promoter hypermethylation of some genes like MYOD1, CALCA, hTERT etc. has also been detected in serum samples from cervical cancer. The present study is the first report on the comparison of promoter hypermethylation of tumor suppressor genes likep14, p15, p16, p21, p27, p57, p53, p73, RARβ2, FHIT, DAPK, STAT1 and-RB1 genes in paired biopsy and serum samples from cervical cancer patients among north Indian population. This is also the first report on the hypermethylation of these genes in serum samples from cervical cancer patients among north Indian population. According to the results of the present study, promoter hypermethylation of these genes can also be detected in serum samples of cervical cancer patients. The sensitivity of detection of promoter hypermethylation in serum samples of cervical cancer patients as compared to paired biopsy samples was found to be around 83.3%. It was observed that promoter hypermethylation was mainly observed in the serum samples in the higher stages and very rarely in the lower stages. The present study clearly showed that serum of patients with cervical cancer can also be used to study methylated genes as biomarkers.

Ueberberg S, Tannapfel A, Schenker P, et al.
Differential expression of cell-cycle regulators in human beta-cells derived from insulinoma tissue.
Metabolism. 2016; 65(5):736-46 [PubMed] Related Publications
INTRODUCTION: The low frequency of beta-cell replication in the adult human pancreas limits beta-cell regeneration. A better understanding of the regulation of human beta-cell proliferation is crucial to develop therapeutic strategies aiming to enhance beta-cell mass.
METHODS: To identify factors that control beta-cell proliferation, cell-cycle regulation was examined in human insulinomas as a model of increased beta-cell proliferation (n=11) and healthy pancreatic tissue from patients with benign pancreatic tumors (n=9). Tissue sections were co-stained for insulin and cell-cycle proteins. Transcript levels of selected cell-cycle factors in beta-cells were determined by qRT-PCR after performing laser-capture microdissection.
RESULTS: The frequency of beta-cell replication was 3.74±0.92% in the insulinomas and 0.11±0.04% in controls (p=0.0016). p21 expression was higher in insulinomas (p=0.0058), and Rb expression was higher by trend (p=0.085), whereas p16 (p<0.0001), Cyclin C (p<0.0001), and p57 (p=0.018) expression levels were lower. The abundance of Cyclin D3 (p=0.62) and p27 (p=0.68) was not different between the groups. The reduced expression of p16 (p<0.0001) and p57 (p=0.012) in insulinomas and the unchanged expression of Cyclin D3 (p=0.77) and p27 (p=0.55) were confirmed using qRT-PCR.
CONCLUSIONS: The expression of certain cell-cycle factors in beta-cells derived from insulinomas and healthy adults differs markedly. Targeting such differentially regulated cell-cycle proteins may evolve as a future strategy to enhance beta-cell regeneration.

Fujisawa Y, Sakaguchi K, Ono H, et al.
Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma.
J Steroid Biochem Mol Biol. 2016; 159:86-93 [PubMed] Related Publications
Although childhood adrenocortical carcinomas (c-ACCs) with a TP53 mutation are known to produce androgens, detailed steroidogenic characters have not been clarified. Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2-year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time of tumorectomy as a control. The c-ACC produced not only abundant dehydroepiandrosterone-sulfate but also a large amount of testosterone via the Δ5 pathway with Δ5-androstenediol rather than Δ4-androstenedione as the primary intermediate metabolite. Furthermore, the c-ACC was associated with elevated expressions of CYP11A1, CYP17A1, POR, HSD17B3, and SULT2A1, a low but similar expression of CYB5A, and reduced expressions of AKR1C3 (HSD17B5) and HSD3B2. Notably, a Leydig cell marker INSL3 was expressed at a low but detectable level in the c-ACC. Furthermore, molecular studies revealed a maternally inherited heterozygous germline TP53 mutation, and several post-zygotic genetic aberrations in the c-ACC including loss of paternally derived chromosome 17 with a wildtype TP53 and loss of maternally inherited chromosome 11 and resultant marked hyperexpression of paternally expressed growth promoting gene IGF2 and drastic hypoexpression of maternally expressed growth suppressing gene CDKN1C. These results imply the presence of combined steroidogenic properties of fetal adrenal and Leydig cells in this patient's c-ACC with a germline TP53 mutation and several postzygotic carcinogenic events.

Zhang E, He X, Yin D, et al.
Increased expression of long noncoding RNA TUG1 predicts a poor prognosis of gastric cancer and regulates cell proliferation by epigenetically silencing of p57.
Cell Death Dis. 2016; 7:e2109 [PubMed] Free Access to Full Article Related Publications
Recent evidence highlights long noncoding RNAs (lncRNAs) as crucial regulators of cancer biology that contribute to tumorigenesis. LncRNA TUG1 was initially detected in a genomic screen for genes upregulated in response to taurine treatment in developing mouse retinal cells. Our previous study showed that TUG1 could affect cell proliferation through epigenetically regulating HOXB7 in human non-small cell lung cancer. However, the clinical significance and potential role of TUG1 in GC remains unclear. In this study, we found that TUG1 is significantly increased and is correlated with outcomes in gastric cancer (GC). Further experiments revealed that knockdown of TUG1 repressed GC proliferation both in vitro and in vivo. Mechanistic investigations showed that TUG1 has a key role in G0/G1 arrest. We further demonstrated that TUG1 was associated with PRC2 and that this association was required for epigenetic repression of cyclin-dependent protein kinase inhibitors, including p15, p16, p21, p27 and p57, thus contributing to the regulation of GC cell cycle and proliferation. Together, our results suggest that TUG1, as a regulator of proliferation, may serve as a candidate prognostic biomarker and target for new therapies in human GC.

Lissanu Deribe Y, Shi Y, Rai K, et al.
Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma.
Proc Natl Acad Sci U S A. 2016; 113(9):E1296-305 [PubMed] Free Access to Full Article Related Publications
PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By generating an inducible transgenic mouse model we showed an oncogenic role for a truncating PREX2 mutation (PREX2(E824)*) in vivo in the context of mutant NRAS. Using integrative cross-species gene expression analysis, we identified deregulated cell cycle and cytoskeleton organization as significantly perturbed biological pathways in PREX2 mutant tumors. Mechanistically, truncation of PREX2 activated its Rac1 guanine nucleotide exchange factor activity, abolished binding to PTEN and activated the PI3K (phosphatidyl inositol 3 kinase)/Akt signaling pathway. We further showed that PREX2 truncating mutations or PTEN deletion induces down-regulation of the tumor suppressor and cell cycle regulator CDKN1C (also known as p57(KIP2)). This down-regulation occurs, at least partially, through DNA hypomethylation of a differentially methylated region in chromosome 11 that is a known regulatory region for expression of the CDKN1C gene. Together, these findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator.

Sebire NJ, May PC, Kaur B, et al.
Abnormal villous morphology mimicking a hydatidiform mole associated with paternal trisomy of chromosomes 3,7,8 and unipaternal disomy of chromosome 11.
Diagn Pathol. 2016; 11:20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pregnancies affected by non-molar chromosomal abnormality may sometimes demonstrate abnormal chorionic villous morphology that is similar to partial hydatidiform mole. Determination of the underlying aetiology may be difficult in such cases.
CASE PRESENTATION: This report describes a case referred to the regional trophoblastic disease unit as a possible hydatidiform mole that demonstrated both villous dysmorphology and abnormal p57(KIP2) expression. Molecular genotyping revealed that while most chromosomes in the villous tissue were diploid and biparental, chromosomes 3, 7 and 8 were trisomic with an additional paternally derived chromosome. In contrast chromosome 11 showed uniparental disomy of paternal origin a situation more usually associated with complete hydatidiform moles. This unusual case highlights that exceptions may occur to the general rules of both histological morphology and immunoprofile, and that these can be resolved by detailed molecular genetic investigations.
CONCLUSION: The findings confirm that trisomic pregnancies may demonstrate morphological villous features similar to hydatidiform mole, and that loss of p57(KIP2) expression occurs due to an absence of maternally transcribed genes on chromosome 11 and can therefore be independent of androgenetic complete hydatidiform mole.

Sun C, Huang C, Li S, et al.
Hsa-miR-326 targets CCND1 and inhibits non-small cell lung cancer development.
Oncotarget. 2016; 7(7):8341-59 [PubMed] Free Access to Full Article Related Publications
Hsa-miRNA-326 (miR-326) has recently been discovered having anticancer efficacy in different organs. However, the role of miR-326 on non-small cell lung cancer (NSCLC) is still ambiguous. In this study, we investigated the role of miR-326 on the development of NSCLC. The results indicated that miR-326 was significantly down-regulated in primary tumor tissues and very low levels were found in NSCLC cell lines. Ectopic expression of miR-326 in NSCLC cell lines significantly suppressed cell growth as evidenced by cell viability assay, colony formation assay and BrdU staining, through inhibition of cyclin D1, cyclin D2, CDK4 and up-regulation of p57(Kip2) and p21(Waf1/Cip1). In addition, miR-326 induced apoptosis, as indicated by concomitantly with up-regulation of key apoptosis protein cleaved caspase-3, and down-regulation of anti-apoptosis protein Bcl2. Moreover, miR-326 inhibited cellular migration and invasiveness through inhibition of matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene CCND1 was revealed to be a putative target of miR-326, which was inversely correlated with miR-326 expression in NSCLC. Taken together, our results demonstrated that miR-326 played a pivotal role on NSCLC through inhibiting cell proliferation, migration, invasion, and promoting apoptosis by targeting oncogenic CCND1.

Chen J, Yao ZX, Chen JS, et al.
TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome.
J Clin Invest. 2016; 126(2):527-42 [PubMed] Free Access to Full Article Related Publications
Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder, and individuals with this disease have a substantially increased risk (~800-fold) of developing tumors. Epigenetic silencing of β2-spectrin (β2SP, encoded by SPTBN1), a SMAD adaptor for TGF-β signaling, is causally associated with BWS; however, a role of TGF-β deficiency in BWS-associated neoplastic transformation is unexplored. Here, we have reported that double-heterozygous Sptbn1+/- Smad3+/- mice, which have defective TGF-β signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. Moreover, tumorigenesis-associated genes IGF2 and telomerase reverse transcriptase (TERT) were overexpressed in fibroblasts from BWS patients and TGF-β-defective mice. We further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF-β inducible and facilitates TGF-β-mediated repression of TERT transcription via interactions with β2SP and SMAD3. This regulation was abrogated in TGF-β-defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKN1C/KCNQ1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, we propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF-β pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations.

Bhatti TR, Ganapathy K, Huppmann AR, et al.
Histologic and Molecular Profile of Pediatric Insulinomas: Evidence of a Paternal Parent-of-Origin Effect.
J Clin Endocrinol Metab. 2016; 101(3):914-22 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Acquired insulinomas are rare causes of hyperinsulinemic hypoglycemia in children and are much less common than focal lesions of congenital hyperinsulinism. The latter are known to be associated with isodisomy for paternally transmitted ATP-sensitive potassium channel mutations on 11p15; however, the molecular basis for pediatric insulinomas is not well characterized.
OBJECTIVE: The purpose of this study was to characterize the histopathological and molecular defects in a large group of 12 pediatric insulinomas seen at The Children's Hospital of Philadelphia.
RESULTS: Twelve children with insulinomas were seen between 1971 and 2013, compared to 201 cases with focal congenital hyperinsulinism seen between 1997 and 2014. The age of insulinoma patients ranged from 4-16 years at the time of surgery. Features of MEN1 syndrome were present in five of the 12, including four cases with heterozygous mutations of MEN1 on 11q. Immunohistochemical analysis revealed nuclear loss of p57 staining consistent with loss of the maternal 11p15 allele in 11 of the 12 insulinomas, including all five MEN1-associated tumors. Imbalance of the paternal 11p allele was confirmed by single nucleotide polymorphism genotyping and methylation assays of the 11p imprinting control loci in four of five MEN1-associated tumors and six of seven sporadic insulinomas. In addition, single nucleotide polymorphism genotyping revealed extensive tumor aneuploidy beyond chromosome 11.
CONCLUSIONS: These data indicate that MEN1 mutations are more common in insulinomas in children than in adults. Aneuploidy of chromosome 11 and other chromosomes is common in both MEN1 and non-MEN1 insulinomas. The novel observation of a paternal parent-of-origin effect in all MEN1 and most non-MEN1 tumors suggests a critical role for imprinted growth-regulatory genes in the 11p region in the genesis of β-cell endocrine tumors in children.

Sun C, Sang M, Li S, et al.
Hsa-miR-139-5p inhibits proliferation and causes apoptosis associated with down-regulation of c-Met.
Oncotarget. 2015; 6(37):39756-92 [PubMed] Free Access to Full Article Related Publications
Hsa-miRNA-139-5p (miR-139-5p) has recently been discovered having anticancer efficacy in different organs. However, the role of miR-139-5p on lung cancer is still ambiguous. In this study, we investigated the role of miR-139-5p on development of lung cancer. Results indicated miR-139-5p was significantly down-regulated in primary tumor tissues and very low levels were found in a non-small cell lung cancer (NSCLC) cell lines. Ectopic expression of miR-139-5p in NSCLC cell lines significantly suppressed cell growth through inhibition of cyclin D1 and up-regulation of p57(Kip2). In addition, miR-139-5p induced apoptosis, as indicated by up-regulation of key apoptosis gene cleaved caspase-3, and down-regulation of anti-apoptosis gene Bcl2. Moreover, miR-139-5p inhibited cellular metastasis through inhibition of matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene c-Met was revealed to be a putative target of miR-139-5p, which was inversely correlated with miR-139-5p expression. Taken together, our results demonstrated that miR-139-5p plays a pivotal role in lung cancer through inhibiting cell proliferation, metastasis, and promoting apoptosis by targeting oncogenic c-Met.

Hu S, Liu L, Chang EB, et al.
Butyrate inhibits pro-proliferative miR-92a by diminishing c-Myc-induced miR-17-92a cluster transcription in human colon cancer cells.
Mol Cancer. 2015; 14:180 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Compromised colonic butyrate production resulting from low dietary fiber or altered gut microbiota may promote colon neoplasia. Previous reports indicate these actions are mediated in part by altered levels of miRNAs, including suppressed expression of the oncogenic miR-17-92a cluster. Here, we sought to identify the mechanisms underlying these effects of butyrate in colon cancer.
METHODS: miR-92a levels were measured in archived human colon cancer and adjacent normal colon specimens by microarray and quantitative RT-PCR (qPCR). The effects of butyrate and other histone deacetylase inhibitors (suberoylanilide hydroxamic acid (SAHA) and valproic acid) on primary (pri-miR17-92a), precursor and mature miR-92a were analyzed in HCT-116 and HT-29 human colon cancer cells using qPCR. The effects of butyrate, SAHA and valproic acid on protein levels of c-Myc, Drosha and p57 were measured in HCT-116 cells using immunoblotting. Regulation of C13orf25 promoter activity by butyrate was analyzed by luciferase reporter assay using modified pGL3 constructs containing a wild-type or mutated c-Myc binding site. Expression of c-Myc was modulated using siRNA or adenovirus vectors. p57 mRNA and protein were measured before and after transfection with miR-92a-mimic molecules. Following butyrate treatment and miR-92a-mimic transfection, apoptosis was analyzed by TUNEL staining and caspase-3 immunoblotting.
RESULTS: Microarray, confirmed by qPCR, revealed a seven-fold increase in miR-92a levels in sporadic human colon cancer tissue compared to adjacent normal colon. Treating human colon cancer cells with butyrate reduced the levels of pri-miR17-92a, precursor and mature miR-92a, as well as c-Myc. SAHA and valproic acid had similar effects. Mutation of the c-Myc binding site diminished butyrate's inhibitory effects on C13orf25 promoter activity. Silencing c-Myc expression reduced miR-92a levels. c-Myc over-expression neutralized butyrate-induced attenuation of pri-miR17-92a. Exogenous miR-92a inhibited butyrate-induced p57 expression and reversed the beneficial actions of butyrate on colon cancer cell proliferation and apoptosis.
CONCLUSIONS: Our findings identify a novel cellular mechanism whereby butyrate inhibits miR-92a transcription by reducing c-Myc, thus augmenting p57 levels. These actions diminish colon cancer cell proliferation and stimulate apoptosis. This newly described regulation of oncogenic miRNA biogenesis expands our understanding of colon cancer cell biology and identifies novel therapeutic targets.

Yao Z, Hu K, Huang H, et al.
shRNA-mediated silencing of the RFC3 gene suppresses hepatocellular carcinoma cell proliferation.
Int J Mol Med. 2015; 36(5):1393-9 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies worldwide. Replication factor C (RFC) plays an important role in DNA replication and checkpoint control during the cell cycle. RFC is comprised of one large subunit [replication factor C, subunit 1 (RFC1)] and four small subunits [replication factor C, subunits 2-5 (RFC2‑5)]. The role of RFC3 in the development of HCC is, as of yet, not fully understood. In the present study, western blot analysis and reverse-transcription-quantitative PCR were used to measure the expression levels of replication factor C, subunit 3 (RFC3) in HCC tissues and HCC cells. Lentivirus-mediated RFC3-specific short hairpin RNA (shRNA) was used to knock down the expression of RFC3 in HCC cells in order to examine the effects of RFC3 on HCC cell proliferation and growth. Furthermore, the expression levels of cell cycle‑related proteins were also measured in the HCC cells in which RFC3 was knocked down. Our results revealed that the expression level of RFC3 was markedly upregulated in the HCC tissues and cells. In addition, MTS and cell growth assays were used to determine the viability and proliferation of the HCC cells in which RFC3 was knocked down, and the results revealed that both cell viability and proliferation were effectively suppressed. The downregulation of RFC3 expression led to HCC cell cycle arrest in the S phase, partly by regulating the epression of cell cycle-related proteins, such as p21, p53, p57 and cyclin A. The results of the present study suggest that RFC3 plays an important role in the development of HCC, and may thus be a potential biological target in the treatment of HCC.

Mazur PK, Herner A, Mello SS, et al.
Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma.
Nat Med. 2015; 21(10):1163-71 [PubMed] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.

Li H, Kong X, Cui G, et al.
Rapamycin restores p14, p15 and p57 expression and inhibits the mTOR/p70S6K pathway in acute lymphoblastic leukemia cells.
Int J Hematol. 2015; 102(5):558-68 [PubMed] Related Publications
The aim of the present study was to investigate the effects of rapamycin and its underlying mechanisms on acute lymphoblastic leukemia (ALL) cells. We found that the p14, p15, and p57 genes were not expressed in ALL cell lines (Molt-4 and Nalm-6) and adult ALL patients, whereas mTOR, 4E-BP1, and p70S6K were highly expressed. In Molt-4 and Nalm-6 cells exposed to rapamycin, cell viability decreased and the cell cycle was arrested at the G1/S phase. Rapamycin restored p14, p15, and p57 gene expression through demethylation of the promoters of these genes. As expected, rapamycin also increased p14 and p15 protein expression in both Molt-4 and Nalm-6 cells, as well as p57 protein expression in Nalm-6 cells. Rapamycin additionally decreased mTOR and p70S6K mRNA levels, as well as p70S6K and p-p70S6K protein levels. However, depletion of mTOR by siRNA did not alter the expression and promoter methylation states of p14, p15, and p57. These results indicate that the inhibitory effect of rapamycin may be due mainly to increased p14, p15, and p57 expression via promoter demethylation and decreased mTOR and p70S6K expression in ALL cell lines. These results suggest a potential role for rapamycin in the treatment of adult ALL.

Sun C, Liu Z, Li S, et al.
Down-regulation of c-Met and Bcl2 by microRNA-206, activates apoptosis, and inhibits tumor cell proliferation, migration and colony formation.
Oncotarget. 2015; 6(28):25533-74 [PubMed] Free Access to Full Article Related Publications
Hsa-miRNA-206 (miR-206), highly expressed in skeletal muscle, has recently been discovered to have anticancer properties in different tissues. However, the role of miR-206 on lung cancer is still ambiguous. In this study, we investigated the role of miR-206 on the development of lung cancer. The results indicated that miR-206 expression was suppressed in lung cancer tissues and very low levels were found in non-small cell lung cancer (NSCLS) cell lines. Transient transfection of miR-206 into cultured A549 and SK-MES-1 cells led to significant decrease in cell growth, migration, invasion and colony formation, and promoted cell apoptosis. Using bioinformatics, we identified putative miR-206 binding sites within the 3'-untranslated region (3'-UTR) of the human c-Met and Bcl2 mRNA. The expression of c-Met and Bcl2 proteins were shown to be down-regulated after treated with miR-206 by subsequent Western blot and qRT-PCR analysis. Conversely, up-regulation of c-Met and Bcl2 were confirmed in tissue samples of human lung cancer, with its level inversely correlated with miR-206 expression. In addition, miR-206 also decreased the gene expression of MMP-9, CCND1 and CCND2 while increased the gene expression of p57 (Kip2) in A549 and SK-MES-1 cells. Taken together, our results demonstrated that miR-206 suppressed c-Met and Bcl2 expression in NSCLS and could function as a potent tumor suppressor in c-Met/Bcl2-over expressing tumors. Inhibition of miR-206 function could contribute to aberrant cell proliferation, migration, invasion and apoptosis, leading to NSCLS development.

Guo H, Li Y, Tian T, et al.
The role of cytoplasmic p57 in invasion of hepatocellular carcinoma.
BMC Gastroenterol. 2015; 15:104 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Our previous research suggested that p57 downregulation could accelerate the growth and invasion of hepatocellular carcinoma in vitro and in vivo.
AIM: To evaluate the role of cytoplasmic p57 and its regulatory mechanism during hepatocellular carcinoma invasion.
METHODS: We examined the subcellular localization of p57 by immunohistochemistry in 45 pairs of cancerous tissues and adjacent non-cancerous tissues. Moreover, we generated stable p57 knockdown hepatoma cell lines to investigate the mechanism of cytoplasmic p57-mediated regulation of invasion by immunoprecipitation, confocal immunofluorescence microscopy and western blot of nuclear and cytoplasmic extracts.
RESULTS: Our results showed that cytoplasmic expression of p57 was reduced in specimens from patients with capsular invasion and metastasis (P < 0.05). Moreover, the level of p-cofilin was decreased in the group lacking cytoplasmic p57 expression (P < 0.05). Co-expression of p57 and p-cofilin was reduced in specimens from patients with tumors at later stages (III + IV), tumors showing capsular invasion and metastatic tumors. We further observed that p57 downregulation decreased the assembly of p57 and LIM domain kinase 1 and its kinase activity, subsequently reducing the level of p-cofilin in the cytoplasm.
CONCLUSIONS: Cytoplasmic p57 might be a key regulator in hepatocellular carcinoma invasion via the LIM domain kinase 1/p-cofilin pathway.

Sasaki S, Sasaki Y, Kunimura T, et al.
Clinical Usefulness of Immunohistochemical Staining of p57 kip2 for the Differential Diagnosis of Complete Mole.
Biomed Res Int. 2015; 2015:905648 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Can polymer-based immunohistochemical staining of p57(kip2) replace DNA analysis as an inexpensive means of differentiating complete mole from partial mole or hydropic abortion?
METHODS AND MATERIALS: Original paraffin-embedded tissue blocks from 14 equivocal cases were turned over to our laboratory and examined by immunohistochemical staining of p57(kip2).
RESULTS: Four of the 14 cases showed clearly negative nuclear staining in cytotrophoblasts and villous stromal cells: these results were fully concordant with the control staining. The remaining 10 cases showed apparently positive staining in cytotrophoblasts and villous stromal cells. Without DNA analysis we are able to clearly differentiate the 4 cases of complete mole among the 14 equivocal cases. During follow-up, secondary low-risk gestational trophoblastic neoplasia (GTN) developed in 1 of the 4 cases of complete mole: the GTN was treated by single-agent chemotherapy. No subsequent changes were observed during follow-up in the other cases.
CONCLUSION: Polymer-based immunohistochemical staining of p57(kip2) (paternally imprinted gene, expressed from maternal allele) is a very effective method that can be used to differentiate androgenetic complete mole from partial mole and hydropic abortion. We might be able to avoid the cost of DNA analysis.

Bazot Q, Paschos K, Skalska L, et al.
Epstein-Barr Virus Proteins EBNA3A and EBNA3C Together Induce Expression of the Oncogenic MicroRNA Cluster miR-221/miR-222 and Ablate Expression of Its Target p57KIP2.
PLoS Pathog. 2015; 11(7):e1005031 [PubMed] Free Access to Full Article Related Publications
We show that two host-encoded primary RNAs (pri-miRs) and the corresponding microRNA (miR) clusters--widely reported to have cell transformation-associated activity--are regulated by EBNA3A and EBNA3C. Utilising a variety of EBV-transformed lymphoblastoid cell lines (LCLs) carrying knockout-, revertant- or conditional-EBV recombinants, it was possible to demonstrate unambiguously that EBNA3A and EBNA3C are both required for transactivation of the oncogenic miR-221/miR-222 cluster that is expressed at high levels in multiple human tumours--including lymphoma/leukemia. ChIP, ChIP-seq, and chromosome conformation capture analyses indicate that this activation results from direct targeting of both EBV proteins to chromatin at the miR-221/miR-222 genomic locus and activation via a long-range interaction between enhancer elements and the transcription start site of a long non-coding pri-miR located 28 kb upstream of the miR sequences. Reduced levels of miR-221/miR-222 produced by inactivation or deletion of EBNA3A or EBNA3C resulted in increased expression of the cyclin-dependent kinase inhibitor p57KIP2, a well-established target of miR-221/miR-222. MiR blocking experiments confirmed that miR-221/miR-222 target p57KIP2 expression in LCLs. In contrast, EBNA3A and EBNA3C are necessary to silence the tumour suppressor cluster miR-143/miR-145, but here ChIP-seq suggests that repression is probably indirect. This miR cluster is frequently down-regulated or deleted in human cancer, however, the targets in B cells are unknown. Together these data indicate that EBNA3A and EBNA3C contribute to B cell transformation by inhibiting multiple tumour suppressor proteins, not only by direct repression of protein-encoding genes, but also by the manipulation of host long non-coding pri-miRs and miRs.

Wang L, Ye X, Cai X, et al.
Curcumin suppresses cell growth and invasion and induces apoptosis by down-regulation of Skp2 pathway in glioma cells.
Oncotarget. 2015; 6(20):18027-37 [PubMed] Free Access to Full Article Related Publications
Studies have demonstrated that curcumin exerts its tumor suppressor function in a variety of human cancers including glioma. However, the exact underlying molecular mechanisms remain obscure. Emerging evidence has revealed that Skp2 (S-phase kinase associated protein 2) plays an oncogenic role in tumorigenesis. Therefore, we aim to determine whether curcumin suppresses the Skp2 expression, leading to the inhibition of cell growth, invasion, induction of apoptosis, and cell cycle arrest. To this end, we conducted multiple methods such as MTT assay, Flow cytometry, Wound healing assay, invasion assay, RT-PCR, Western blotting, and transfection to explore the functions and molecular insights of curcumin in glioma cells. We found that curcumin significantly inhibited cell growth, suppressed cell migration and invasion, induced apoptosis and cell cycle arrest in glioma cells. Furthermore, we observed that overexpression of Skp2 promoted cell growth, migration, and invasion, whereas depletion of Skp2 suppressed cell growth, migration, and invasion and triggered apoptosis in glioma cells. Mechanistically, we defined that curcumin markedly down-regulated Skp2 expression and subsequently up-regulated p57 expression. Moreover, our results demonstrated that curcumin exerts its antitumor activity through inhibition of Skp2 pathway. Collectively, our findings suggest that targeting Skp2 by curcumin could be a promising therapeutic approach for glioma prevention and therapy.

Yoshizawa S, Fujiwara K, Sugito K, et al.
Pyrrole-imidazole polyamide-mediated silencing of KCNQ1OT1 expression induces cell death in Wilms' tumor cells.
Int J Oncol. 2015; 47(1):115-21 [PubMed] Related Publications
KvDMR (an intronic CpG island within the KCNQ1 gene) is one of the imprinting control regions on human chromosome 11p15.5. Since KvDMR exists within the promoter region of KCNQ1OT1 (antisense transcript of KCNQ1), it is likely that genomic alterations of this region including deletion, paternal uniparental disomy and de-methylation in maternal allele lead to aberrant overexpression of KCNQ1OT1. Indeed, de-methylation of KvDMR accompanied by uncontrolled overexpression of KCNQ1OT1 occurs frequently in Beckwith-Wiedemann syndrome (BWS), and around 10% of BWS patients developed embryonal tumors (Wilms' tumor or hepatoblastoma). These observations strongly suggest that silencing of KCNQ1OT1 expression might suppress its oncogenic potential. In the present study, we designed two pyrrole-imidazole (PI) polyamides, termed PI-a and PI-b, which might have the ability to bind to CCAAT boxes of the KCNQ1OT1 promoter region, and investigated their possible antitumor effect on Wilms' tumor-derived G401 cells. Gel retardation assay demonstrated that PI-a and PI-b specifically bind to their target sequences. Microscopic observations showed the efficient nuclear access of these PI polyamides. Quantitative real-time PCR analysis revealed that the expression level of KCNQ1OT1 was significantly decreased when treated with PI-a and PI-b simultaneously but not with either PI-a or PI-b single treatment. Consistent with these results, the combination of PI-a and PI-b resulted in a significant reduction in viability of G401 cells in a dose-dependent manner. Furthermore, FACS analysis demonstrated that combinatory treatment with PI-a and PI-b induces cell death as compared with control cells. Taken together, our present observations strongly suggest that the combinatory treatment with PI polyamides targeting KCNQ1OT1 might be a novel therapeutic strategy to cure patients with tumors over-expressing KCNQ1OT1.

Zhang J, Gong X, Tian K, et al.
miR-25 promotes glioma cell proliferation by targeting CDKN1C.
Biomed Pharmacother. 2015; 71:7-14 [PubMed] Related Publications
MicroRNAs (miRNA) have oncogenic or tumor-suppressive roles in the development and growth of human glioma. Glioma development is also associated with alteration in the activities and expression of cell cycle regulators, and miRNAs are emerging as important regulators of cell cycle progression. Here, we show that miR-25 is overexpressed in 91% of examined human glioma tissues and 4 out of 6 human glioma cell lines. MiR-25 increases cell proliferation in two independent glioma cell lines. Ectopic expression of miR-25 was found to reduce CDKN1C protein levels by directly targeting its 3'-untranslated region (UTR). Notably, ablation of endogenous miR-25 rescued CDKN1C expression and significantly decreased glioma cell proliferation by facilitating normal cell cycle progression. Our clinical investigation found CDKN1C and miR-25 levels were inversely correlated. Lastly, downregulation of CDKN1 by siRNA blocked the activity of miR-25 on promoting glioma cell proliferation. Overall, our results for the first time show an oncogenic role of miR-25 in human glioma by targeting CDKN1C and that miR-25 could potentially be a therapeutic target for glioma intervention.

Mussa A, Russo S, De Crescenzo A, et al.
(Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome.
Eur J Hum Genet. 2016; 24(2):183-90 [PubMed] Free Access to Full Article Related Publications
Beckwith-Wiedemann syndrome (BWS) is characterized by cancer predisposition, overgrowth and highly variable association of macroglossia, abdominal wall defects, nephrourological anomalies, nevus flammeus, ear malformations, hypoglycemia, hemihyperplasia, and organomegaly. BWS molecular defects, causing alteration of expression or activity of the genes regulated by two imprinting centres (IC) in the 11p15 chromosomal region, are also heterogeneous. In this paper we define (epi)genotype-phenotype correlations in molecularly confirmed BWS patients. The characteristics of 318 BWS patients with proven molecular defect were compared among the main four molecular subclasses: IC2 loss of methylation (IC2-LoM, n=190), IC1 gain of methylation (IC1-GoM, n=31), chromosome 11p15 paternal uniparental disomy (UPD, n=87), and cyclin-dependent kinase inhibitor 1C gene (CDKN1C) variants (n=10). A characteristic growth pattern was found in each group; neonatal macrosomia was almost constant in IC1-GoM, postnatal overgrowth in IC2-LoM, and hemihyperplasia more common in UPD (P<0.001). Exomphalos was more common in IC2/CDKN1C patients (P<0.001). Renal defects were typical of UPD/IC1 patients, uretheral malformations of IC1-GoM cases (P<0.001). Ear anomalies and nevus flammeus were associated with IC2/CDKN1C genotype (P<0.001). Macroglossia was less common among UPD patients (P<0.001). Wilms' tumor was associated with IC1-GoM or UPD and never observed in IC2-LoM patients (P<0.001). Hepatoblastoma occurred only in UPD cases. Cancer risk was lower in IC2/CDKN1C, intermediate in UPD, and very high in IC1 cases (P=0.009). In conclusion, (epi)genotype-phenotype correlations define four different phenotypic BWS profiles with some degree of clinical overlap. These observations impact clinical care allowing to move toward (epi) genotype-based follow-up and cancer screening.

Cioffi M, Trabulo SM, Sanchez-Ripoll Y, et al.
The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells.
Gut. 2015; 64(12):1936-48 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Cancer stem cells (CSCs) represent the root of many solid cancers including pancreatic ductal adenocarcinoma, are highly chemoresistant and represent the cellular source for disease relapse. However the mechanisms involved in these processes still need to be fully elucidated. Understanding the mechanisms implicated in chemoresistance and metastasis of pancreatic cancer is critical to improving patient outcomes.
DESIGN: Micro-RNA (miRNA) expression analyses were performed to identify functionally defining epigenetic signatures in pancreatic CSC-enriched sphere-derived cells and gemcitabine-resistant pancreatic CSCs.
RESULTS: We found the miR-17-92 cluster to be downregulated in chemoresistant CSCs versus non-CSCs and demonstrate its crucial relevance for CSC biology. In particular, overexpression of miR-17-92 reduced CSC self-renewal capacity, in vivo tumourigenicity and chemoresistance by targeting multiple NODAL/ACTIVIN/TGF-β1 signalling cascade members as well as directly inhibiting the downstream targets p21, p57 and TBX3. Overexpression of miR-17-92 translated into increased CSC proliferation and their eventual exhaustion via downregulation of p21 and p57. Finally, the translational impact of our findings could be confirmed in preclinical models for pancreatic cancer.
CONCLUSIONS: Our findings therefore identify the miR-17-92 cluster as a functionally determining family of miRNAs in CSCs, and highlight the putative potential of developing modulators of this cluster to overcome drug resistance in pancreatic CSCs.

Ma D, Guo D, Li W, Zhao H
Mdig, a lung cancer-associated gene, regulates cell cycle progression through p27(KIP1).
Tumour Biol. 2015; 36(9):6909-17 [PubMed] Related Publications
Mineral dust-induced gene (mdig) can accelerate cell proliferation. The aim of this study is to investigate the mechanism by which mdig regulates cell proliferation. A549 cells were transfected with siRNA specifically targeting mdig. Cell proliferation and cell cycle progression were measured using MTT assay and cell cycle analysis, respectively. Furthermore, real-time reverse transcription quantitative-polymerase chain reaction (RT-qPCR) was performed in A549 cells transfected with mdig siRNA to examine the expression levels of the cell cycle related genes such as p18(INK4c), p19(INK4d), p21(WAF/CIP1), p27(KIP1), p57(KIP2), cyclin D1, and cyclin E. To further explore the effect of mdig on p27(KIP1), the expression levels of total p27(KIP1) and its subtypes pT187-p27(KIP1) and pS10-p27(KIP1) were assessed by Western blotting. In vivo, Western blotting was performed to check the expression levels of mdig and p27(KIP1) in human lung cancer tissues, para-cancerous normal lung tissues, and para-bronchial stumps. Knockdown of mdig induced increases in p27(KIP1), both on mRNA and protein levels. Furthermore, the phosphorylation of p27(KIP1) at its Thr187 site was also inhibited. Importantly, in lung cancer tissues, upregulation of mdig expression accompanies with the downregulation of p27(KIP1) expression and in bronchial stump, vice versa. The data suggest that mdig-mediated inhibition of p27(KIP1) is important for cell proliferation and tumor formation and reveal therapeutic potential of p27(KIP1) for lung cancer.

Salomon A, Keramidas M, Maisin C, Thomas M
Loss of β-catenin in adrenocortical cancer cells causes growth inhibition and reversal of epithelial-to-mesenchymal transition.
Oncotarget. 2015; 6(13):11421-33 [PubMed] Free Access to Full Article Related Publications
Adrenal carcinoma (ACC) is a rare neoplasm with a poor outcome. Aberrant expression of β-catenin has been found in approximatively 30% of ACC. We herein studied its effects on the growth of the human ACC cell line H295R. The cells were infected with short hairpin RNA (shRNA)-mediated silencing β-catenin. Two shRNAs used induced down-regulation of β-catenin protein levels. The expression of these shRNAs decreased cell growth and increased H295R cells in S and G2/M phases. This cytostatic effect is due to a decrease of phosphorylated MAPK and to an up-regulation expression of the cyclin-dependent kinase inhibitors p57(KIP2), p21(CIP) and p27(KIP1). In addition, the knockdown of β-catenin decreased phosphorylated Akt and increased apoptosis. Finally, loss of β-catenin was sufficient to induce the reversal of the epithelial-to-mesenchymal transition. We then transplanted these genetically modified H295R cells in Scid mice. Tumor growth suppression was achieved by the two shRNAs showing in vitro efficacy. Proliferation was not reduced in silenced tumors. In contrast, p57, p27 and p21 proteins were found expressed at high levels in silenced tumors along with an increase in apoptotic cells. These findings indicate that β-catenin loss in H295R cells inhibits tumor growth by inducing transcriptional and functional changes.

Zhang F, Mijiti M, Ding W, et al.
(+)‑Terrein inhibits human hepatoma Bel‑7402 proliferation through cell cycle arrest.
Oncol Rep. 2015; 33(3):1191-200 [PubMed] Related Publications
Hepatoma is a common malignant tumor. Thus, the development of a high‑efficacy therapeutic drug for hepatoma is required. In this study, (+)‑terrein isolated from the marine sponge‑derived Aspergillus terreus PF‑26 against cell growth, apoptosis and cell cycle were assessed by MTT and flow cytometry. mRNA array containing 73 cell cycle‑related genes and three cell morphology‑related genes was generated and its performance evaluated. The cell cycle pathway map was created using the pathview package. The results showed that (+)‑terrein inhibited the growth of Bel‑7402 cells with alterations in cell morphology and a reduced transcript expression of cell morphology genes (fibronectin, N‑cadherin, and vimentin). In addition, flow cytometric analysis revealed that (+)‑terrein arrested the Bel‑7402 cell cycle without inducing apoptosis. Based on multiple mRNA analysis, the downregulated expression of the CCND2, CCNE2, CDKN1C, CDKN2B, ANAPC, PKMYT1, CHEK2 and PCNA genes was observed in 10 µM (+)‑terrein‑treated Bel‑7402 cells (>2‑fold and P≤0.05), compared with the controls. Thus, the antiprolife-rative mechanism of (+)‑terrein against Bel‑7402 cells may be due to the cell cycle arrest by blocking cell cycle gene expression and changing cell morphology.

Huang Y, Su MW, Jiang X, Zhou Y
Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma.
Blood. 2015; 125(9):1435-43 [PubMed] Related Publications
TOX is a nuclear factor essential for the development of CD4(+) T cells in the thymus. It is normally expressed in low amounts in mature CD4(+) T cells of the skin and the peripheral blood. We have recently discovered that the transcript levels of TOX were significantly increased in mycosis fungoides, the most common type of cutaneous T-cell lymphoma (CTCL), as compared to normal skin or benign inflammatory dermatoses. However, its involvement in advanced CTCL and its biological effects on CTCL pathogenesis have not been explored. In this study, we demonstrate that TOX expression is also enhanced significantly in primary CD4(+)CD7(-) cells from patients with Sézary syndrome, a leukemic variant of CTCL, and that high TOX transcript levels correlate with increased disease-specific mortality. Stable knockdown of TOX in CTCL cells promoted apoptosis and reduced cell cycle progression, leading to less cell viability and colony-forming ability in vitro and to reduced tumor growth in vivo. Furthermore, TOX knockdown significantly increased 2 cyclin-dependent kinase (CDK) inhibitors, CDKN1B and CDKN1C. Lastly, blocking CDKN1B and CDKN1C reversed growth inhibition of TOX knockdown. Collectively, these findings provide strong evidence that aberrant TOX activation is a critical oncogenic event for CTCL.

Delogu S, Wang C, Cigliano A, et al.
SKP2 cooperates with N-Ras or AKT to induce liver tumor development in mice.
Oncotarget. 2015; 6(4):2222-34 [PubMed] Free Access to Full Article Related Publications
Mounting evidence indicates that S-Phase Kinase-Associated Protein 2 (SKP2) is overexpressed in human hepatocellular carcinoma (HCC). However, the role of SKP2 in hepatocarcinogenesis remains poorly delineated. To elucidate the function(s) of SKP2 in HCC, we stably overexpressed the SKP2 gene in the mouse liver, either alone or in combination with activated forms of N-Ras (N-RasV12), AKT1 (myr-AKT1), or β-catenin (ΔN90-β-catenin) protooncogenes, via hydrodynamic gene delivery. We found that forced overexpression of SKP2, N-RasV12 or ΔN90-β-catenin alone as well as co-expression of SKP2 and ΔN90-β-catenin did not induce liver tumor development. Overexpression of myr-AKT1 alone led to liver tumor development after long latency. In contrast, co-expression of SKP2 with N-RasV12 or myr-AKT1 resulted in early development of multiple hepatocellular tumors in all SKP2/N-RasV12 and SKP2/myr-AKT1 mice. At the molecular level, preneoplastic and neoplastic liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice exhibited a strong induction of AKT/mTOR and Ras/MAPK pathways. Noticeably, the tumor suppressor proteins whose levels have been shown to be downregulated by SKP2-dependent degradation in various tumor types, including p27, p57, Dusp1, and Rassf1A were not decreased in liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice. In human HCC specimens, nuclear translocation of SKP2 was associated with activation of the AKT/mTOR and Ras/MAPK pathways, but not with β-catenin mutation or activation. Altogether, the present data indicate that SKP2 cooperates with N-Ras and AKT proto-oncogenes to promote hepatocarcinogenesis in vivo.

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