-
Paula Vainio,
Maija Wolf,
Henrik Edgren,
Tao He,
Pekka Kohonen,
John-Patrick Mpindi,
Frank Smit,
Gerald Verhaegh, Jack Schalken,
Merja Perälä,
Kristiina Iljin,
Olli Kallioniemi
[show abstract]
[hide abstract]
ABSTRACT: Castration-resistant prostate cancer (CRPC) represents a therapeutic challenge for current medications.
In order to explore the molecular mechanisms involved in CRPC progression and to identify new therapeutic targets, we analyzed a unique sample set of 11 CRPCs and 7 advanced tumors by array-CGH and gene expression microarrays. The genome-wide DNA and RNA data were integrated to identify genes whose overexpression was driven by their amplification. To assess the functional role of these genes, their expression was analyzed in a transcriptional data set of 329 clinical prostate cancers and the corresponding gene products were silenced using RNA interference in prostate cancer cells.
Six recurrent genetic targets were identified in the CRPCs; ATP1B1, AR, FAM110B, LAS1L, MYC, and YIPF6. In addition to AR and MYC, FAM110B emerged as a potential key gene involved in CRPC progression in a subset of the tumors. FAM110B was able to regulate AR signaling in prostate cancer cells and FAM110B itself was regulated by androgens. FAM110B siRNA inhibited the growth of prostate cancer cells in vitro, and this effect was substantially enhanced in androgen deficient conditions. Ectopic FAM110B expression in non-cancerous epithelial prostate cells induced aneuploidy and impaired antigen presentation.
The DNA/RNA gene outlier detection combined with siRNA cell proliferation assay identified FAM110B as a potential growth promoting key gene for CRPC. FAM110B appears to have a key role in the androgen signaling and progression of CRPC impacting multiple cancer hallmarks and therefore highlighting a potential therapeutic target.
The Prostate 09/2011; 72(7):789-802. · 3.48 Impact Factor
-
Paula Vainio,
Santosh Gupta,
Kirsi Ketola,
Tuomas Mirtti,
John-Patrick Mpindi,
Pekka Kohonen,
Vidal Fey,
Merja Perälä,
Frank Smit,
Gerald Verhaegh, Jack Schalken,
Kalle A Alanen,
Olli Kallioniemi,
Kristiina Iljin
[show abstract]
[hide abstract]
ABSTRACT: The arachidonic acid and prostaglandin pathway has been implicated in prostate carcinogenesis, but comprehensive studies of the individual members in this key pathway are lacking. Here, we first conducted a systematic bioinformatic study of the expression of 36 arachidonic acid pathway genes across 9783 human tissue samples. The results showed that the PLA2G7, HPGD, EPHX2, and CYP4F8 genes are highly expressed in prostate cancer. Functional studies using RNA interference in prostate cancer cells indicated that all four genes are also essential for cell growth and survival. Clinical validation confirmed high PLA2G7 expression, especially in ERG oncogene-positive prostate cancers, and its silencing sensitized ERG-positive prostate cancer cells to oxidative stress. HPGD was highly expressed in androgen receptor (AR)-overexpressing advanced tumors, as well as in metastatic prostate cancers. EPHX2 mRNA correlated with AR in primary prostate cancers, and its inhibition in vitro reduced AR signaling and potentiated the effect of antiandrogen flutamide in cultured prostate cancer cells. In summary, we identified four novel putative therapeutic targets with biomarker potential for different subtypes of prostate cancer. In addition, our results indicate that inhibition of these enzymes may be particularly powerful when combined with other treatments, such as androgen deprivation or induction of oxidative stress.
American Journal Of Pathology 02/2011; 178(2):525-36. · 4.89 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: According to the cancer stem cell hypothesis, tumor growth is sustained by a subpopulation of cancer stem/progenitor-like cells. Self-renewal and high clonogenic potential are characteristics shared by normal stem and neoplastic stem/progenitor-like cells. We investigated whether human prostate cancer specimens contain cells with these properties.
Self-renewal and clonogenic potential were assessed by serial passaging of spheres and colony formation, respectively. Gene expression was analyzed by real time PCR. Protein expression was detected by immunocytochemistry. The neoplastic nature of the cells was verified by detection of the TMPRSS2/ERG gene fusion expression.
The epithelial fraction isolated from surgical specimens generated colonies in 68% (19/28) of the patients. Laminin adhesion selected for cells with high clonogenic potential. The epithelial fraction from 85% (42/49) of the patients generated primary prostaspheres. Serial passaging of prostaspheres demonstrated their self-renewal capacity, which is also supported by their expression of the stem cell markers Oct-4, Nanog, Bmi-1, and Jagged-1 mRNA. Cells derived from prostaspheres were more clonogenic than the parental epithelial fraction. The pattern of mRNA expression in prostaspheres resembled that of the basal compartment of the prostate (CK5(+)/CK14(+)/CK19(high)/CK18(-/low)/c-met(+)/AR(-/low)/PSA(-/low)), but also included stem cell markers (CD49b(+)/CD49f(+)/CD44(+)/DeltaNp63(+)/Nestin(+)/CD133(+)). The distribution of marker expression in prostaspheres suggests their heterogeneous cell composition. Prostaspheres expressed significantly higher PSCA mRNA levels than the epithelial fraction.
Human prostate cancer specimens contain neoplastic cells with self-renewal and clonogenic potential, which can be enriched and perpetuated in prostaspheres. Prostaspheres should prove valuable for the identification of prostate cancer stem/progenitor-like cells.
The Prostate 08/2009; 69(15):1683-93. · 3.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: (EN)The present invention relates to vitro diagnosis methods of prostate cancer from a test biological sample, comprising measuring the expression level of KIAA0153 in said test biological sample,as well as to methods for screening compounds inhibiting KIAA0153 gene expression or biological activity and uses of such KIAA0153 inhibiting compounds.
(FR)La présente invention porte sur des procédés de diagnostic in vitro du cancer de la prostate à partir d'un échantillon biologique test, comprenant la mesure du niveau d'expression de KIAA0153 dans ledit échantillon biologique test, ainsi que sur des procédés de criblage de composés inhibant l'expression génique ou l'activité biologique de KIAA0153 et sur des utilisations de tels composés inhibant KIAA0153.
Ref. No: WO/2008/090177, Year: 07/2008
-
Kristiina Iljin,
Maija Wolf,
Henrik Edgren,
Santosh Gupta,
Sami Kilpinen,
Rolf I Skotheim,
Mari Peltola,
Frank Smit,
Gerald Verhaegh, Jack Schalken,
Matthias Nees,
Olli Kallioniemi
[show abstract]
[hide abstract]
ABSTRACT: Translocations fusing the strong androgen-responsive gene, TMPRSS2, with ERG or other oncogenic ETS factors may facilitate prostate cancer development. Here, we studied 18 advanced prostate cancers for ETS factor alterations, using reverse transcription-PCR and DNA and RNA array technologies, and identified putative ERG downstream gene targets from the microarray data of 410 prostate samples. Out of the 27 ETS factors, ERG was most frequently overexpressed. Seven cases showed TMPRSS2:ERG gene fusions, whereas the TMPRSS2:ETV4 fusion was seen in one case. In five out of six tumors with high ERG expression, array-CGH analysis revealed interstitial 2.8 Mb deletions between the TMPRSS2 and ERG loci, or smaller, unbalanced rearrangements. In silico analysis of the ERG gene coexpression patterns revealed an association with high expression of the histone deacetylase 1 gene, and low expression of its target genes. Furthermore, we observed increased expression of WNT-associated pathways and down-regulation of tumor necrosis factor and cell death pathways. In summary, our data indicate that the TMPRSS2:ERG translocation is common in advanced prostate cancer and occurs by virtue of unbalanced genomic rearrangements. Activation of ERG by fusion with TMPRSS2 may lead to epigenetic reprogramming, WNT signaling, and down-regulation of cell death pathways, implicating ERG in several hallmarks of cancer with potential therapeutic importance.
Cancer Research 12/2006; 66(21):10242-6. · 7.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The vast majority of androgen-dependent prostate tumors progress toward incurable, androgen-independent tumors. The identification of androgen-responsive genes, which are still actively transcribed in the tumors of patients who have undergone androgen ablation, may shed light on the molecular mechanisms underlying this phenomenon. To address this question, we chose the Dunning R3327 rat model system, in which the progression from androgen-dependent to -independent tumors is represented by several transplantable prostate-derived tumors. Gene expression profiles were analyzed in normal rat prostates and in the prostates of rats 14 days after castration by use of microarrays containing approximately 5,000 oligonucleotides, together representing more than 4,800 known rat genes. These expression profiles were compared with similarly obtained expression profiles of androgen-dependent and androgen-independent rat prostate tumors. By doing so, a series of known and novel prostate cancer-associated androgen-responsive genes was identified. Within this series, we were able to identify several clusters of genes that are differentially regulated in the various prostate tumors. These genes may serve as (i) novel prognostic identifiers and (ii) novel therapeutic targets.
Genes Chromosomes and Cancer 08/2005; 43(3):273-83. · 3.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In renal cell carcinoma (RCC) cell lines, expression of the RCC-associated antigen G250 correlates with hypomethylation of the investigated CpG dinucleotides in the G250 promoter region, despite the absence of a CpG island. To gain insight into the molecular mechanism leading to G250 expression in vivo, we ascertained whether this correlation between G250 gene expression and the methylation status of the G250 gene also existed in primary RCC and normal kidney tissue.
G250 mRNA and protein expression was determined by reverse transcriptase-polymerase chain reaction, fluorescence activated cell sorting analysis, and immunohistochemistry in 15 RCC cell lines and 13 paired primary RCC/normal kidney tissue specimens. The methylation status of the G250 gene was determined by bisulfite genomic sequencing.
RCC cell lines revealed a clear correlation between G250 expression and hypomethylation. In contrast, no hypomethylation was observed in primary RCC compared with normal kidney tissue. The CpG dinucleotides investigated were generally completely methylated in RCC, as well as in normal kidney tissue. Furthermore, a primary culture of RCC tissue revealed increasing hypomethylation of the G250 gene in successive passages, suggesting that the G250 hypomethylation observed in vitro is tissue culture induced.
The methylation status of the G250 gene correlated with G250 expression in vitro but not in vivo.
Urology 09/2002; 60(2):357-62. · 2.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Analysis of keratin (K) expression discriminates luminal (K18) and intermediate (K5/18) cells in prostate carcinoma, while basal (K5/14) cells are absent. Intermediate cells have been proposed as targets of malignant transformation in prostate cancer and precursors of androgen-independent tumor progression. We demonstrate localization of hepatocyte growth factor (HGF) receptor c-MET in intermediate cells in both normal and malignant prostate epithelium.
Receptor localization was analyzed using triple staining for c-MET, K5, K14, and K18. The percentage of strongly c-MET positive cells was determined in 15 prostate cancer patients undergoing androgen-deprivation and 14 patients without neo-adjuvant treatment. Effects of HGF were investigated on prostate cancer cell line DU145.
c-MET expression in non-malignant epithelium was strong in intermediate cells absent in differentiated cells, and heterogeneous in basal cells. In prostate cancer, intermediate cells displayed high c-MET levels coupled with mild expression in differentiated cells. During androgen-deprivation, 7.6% of tumor cells revealed high c-MET expression compared to 1.7% without treatment (P = 0.02). Matrigel penetration of DU145 was 8.2 +/- 1.7 mm(2) after HGF stimulation compared to 3.6 +/- 2.4 mm(2) in controls (P < 0.02).
Intermediate cells in normal and malignant prostate epithelium express high c-MET levels, indicating that they are prone to stromal invasion in prostate carcinoma.
The Prostate 05/2002; 51(2):98-107. · 3.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Increased length of the CAG repeat in the androgen receptor gene may be related to male subfertility. Expansion to 38-62 CAG repeats leads to the neurodegenerative disorder with male infertility called Kennedy's disease. Recently it was suggested that slight expansion is related to male subfertility. In this study we investigated the association of male subfertility with the length of CAG repeats in the androgen receptor.
CAG repeat length in the androgen receptor gene was investigated in 75 subfertile men, who were mainly candidates for intracytoplasmic sperm injection. Sperm parameters varied from azoospermia to severe oligoasthenoteratozoospermia. The control group consisted of 70 men who predominantly had bladder cancer. DNA was isolated from peripheral blood and genotyping was performed with polymerase chain reaction based methods.
No statistically significant difference in the mean length of the CAG repeat plus or minus standard deviation was noted in subfertile men and controls (22.2 +/- 3.1 and 21.7 +/- 3.4, respectively). The length of the CAG repeat in the androgen receptor was not related to the degree of impaired spermatogenesis or clinical characteristics of the subfertile men.
Increased length of CAG repeats in the androgen receptor gene is not a risk factor for male subfertility.
The Journal of Urology 03/2002; 167(2 Pt 1):621-3. · 3.75 Impact Factor
-
Nicolas Wicker,
Annaïck Carles,
Ian Mills,
Maija Wolf,
Abhi Veerakumarasivam,
Henrik Edgren,
Fabrice Boileau,
Bohdan Wasylyk, Jack Schalken,
David Neal,
Olli-Pekka Kallioniemi,
Olivier Poch
Wicker , N , Carles , A , Mills , I , Wolf , M , Veerakumarasivam , A , Edgren , H , Boileau , F , Wasylyk , B , Schalken , J , Neal , D , Kallioniemi , O & Poch , O 2007 , ' A new look towards BAC-based array CGH through a comprehensive comparison with oligo-based array CGH ' , BMC Genomics , vol 2007 / 8 , no. 84 .
-
Kristiina Iljin,
Maija Wolf,
Henrik Edgren,
Santosh Gupta,
Sami Kilpinen,
Rolf Skotheim,
Mari Peltola,
Frank Smit,
Gerald Verhaegh, Jack Schalken,
Matthias Nees,
Olli Kallioniemi
[show abstract]
[hide abstract]
ABSTRACT: Cancer Research Vol.66 Nr.21, 10242 - 10246 Translocations fusing the strong androgen-responsive gene, TMPRSS2, with ERG or other oncogenic ETS factors may facilitate prostate cancer development. Here, we studied 18 advanced prostate cancers for ETS factor alterations, using reverse transcription-PCR and DNA and RNA array technologies, and identified putative ERG downstream gene targets from the microarray data of 410 prostate samples. Out of the 27 ETS factors, ERG was most frequently overexpressed. Seven cases showed TMPRSS2:ERG gene fusions, whereas the TMPRSS2:ETV4 fusion was seen in one case. In five out of six tumors with high ERG expression, array-CGH analysis revealed interstitial 2.8 Mb deletions between the TMPRSS2 and ERG loci, or smaller, unbalanced rearrangements. In silico analysis of the ERG gene coexpression patterns revealed an association with high expression of the histone deacetylase 1 gene, and low expression of its target genes. Furthermore, we observed increased expression of WNT-associated pathways and down-regulation of tumor necrosis factor and cell death pathways. In summary, our data indicate that the TMPRSS2:ERG translocation is common in advanced prostate cancer and occurs by virtue of unbalanced genomic rearrangements. Activation of ERG by fusion with TMPRSS2 may lead to epigenetic reprogramming, WNT signaling, and down-regulation of cell death pathways, implicating ERG in several hallmarks of cancer with potential therapeutic importance.
