Negative Regulator Of PTEN Research Articles

PREX2 mutation serves as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma.

e21504 Background: Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)-a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes. Previous work suggested that PREX2 alterations may enrich for responses to immune checkpoint inhibitors (ICI), validation of function in melanoma is needed. Methods: Using 539-gene target-capture next generation sequencing, we analyzed the PREX2 mutation in 3547 tumor tissue or plasma ctDNA samples (including 122 melanoma) from different patients, and the public database of TACG was also compared. Data from Snyder-64 study (n = 64, anti- CTLA-4 therapy) was retrieved and analysed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Results: In clinical cohort, the frequency of PREX2 mutation in 3547 tumor tissue or plasma ctDNA samples from different patients was 5.94 % (211 in 3547). Meanwhile, the frequency of PREX2 mutation in TCGA cohort was 5.06 % (555 in 10953). In melanoma datebase, the frequency of PREX2 mutation in 122 melanoma tumor tissue or plasma ctDNA samples from different patients was 6.55 % (78 in 122). Meanwhile, the frequency of PREX2 mutation in melanoma in TCGA cohort was 25.56 % (113 in 422). We further analyzed Kaplan-Meier curves from Snyder-64 study (n = 64, anti- CTLA-4 therapy). In Snyder-64 study melanoma cohort, mutation of PREX2 was associated with higher neoantigen load (P = 0.02) and higher mutation count (P = 0.0027) in melanoma. PREX2 mutation was associated with prolonged overall survival (OS) trend compared with PREX2 wt in melanoma cohort (P = 0.09). Conclusions: In our study, the frequency of PREX2 mutation in pan cancers and melanoma was investigated in clinical and TCGA cohort, which might provide useful information to guide precision medicine. PREX2 mutation may serve as a novel predictor of response to anti-PD-1/PD-L1 treatment in melanoma via upregulating neoantigen load and mutation count.

Upregulation of DJ-1 expression in melanoma regulates PTEN/AKT pathway for cell survival and migration.

Cutaneous melanoma is known to be one of the most dangerous skin cancers because of its metastatic functions. Today, it is essential to investigate specific biomarkers for the target treatment in many diseases including cancers. DJ-1 protein, also known as Parkinson disease 7, has various functions associated with cancer progression including cell survival and migration. Phosphatase and tensin homolog (PTEN) is a tumor suppressor that regulates the PI3K/AKT signaling pathway and its mutations have been reported to frequently occur in many cancers such as thyroid, breast and skin. Recently, DJ-1 has been identified as a negative regulator of PTEN in many human cancer cells. However, the impacts and relationship of DJ-1 and PTEN have not been studied yet in melanoma. To confirm the expression of DJ-1 and PTEN in melanoma compared to normal skin tissues and find out functions of DJ-1 in melanoma cells, Western blot analysis and immunohistochemical staining were used. Transfection of G361 cells with DJ-1-specific small interfering RNA was performed to figure out the roles of DJ-1 and the relationship between DJ-1 and PTEN in melanoma cells. In our study, the DJ-1 protein was significantly increased with loss of PTEN protein in melanoma compared to that in normal skin. Inhibition of DJ-1 in G361 cells induced apoptosis, and suppressed cell survival and migration. Furthermore, suppression of DJ-1 in G361 cells increased the expression of cleaved caspase-3, cleaved PARP, Bax, p53, and Daxx as well as PTEN, while it decreased expression of survivin, caspase-3, and PARP. Also, downregulated DJ-1 inhibited phosphorylation of AKT in G361 cells. Collectively, DJ-1 overexpression could affect the proliferative and invasive capabilities of melanoma cells via regulating the PTEN/AKT pathway and apoptosis-related proteins. This study suggests that DJ-1 may be a potential target for the treatment of melanoma.

MiR-203 regulates DJ-1 expression and affects proliferation, apoptosis and DDP resistance of pancreatic cancer cells.

DJ-1 is a negative regulator of PTEN and plays a role in tumorigenesis. Abnormal miR-203 expression is associated with pancreatic cancer. Bioinformatics analysis showed a targeted relationship between miR-203 and DJ-1 3'-UTR. This study investigated whether miR-203 regulates DJ-1 expression and its role in pancreatic cancer cell proliferation, apoptosis, and cisplatin (DDP) resistance. The Dual-Luciferase reporter gene assay validated the targeted regulation between miR-203 and DJ-1. The DDP-resistant cell line SW1990/DDP was established and divided into miR-NC group and miR-203 mimic group followed by analysis of the expression of DJ-1, PTEN and p-AKT, cell apoptosis, and proliferation. There was a targeted relationship between miR-203 and DJ-1 mRNA. The expression of miR-203 in SW1990/DDP cells was significantly lower than that in SW1990 cells, while the expression of DJ-1 mRNA and protein was significantly higher than that in SW1990 cells. Compared with miR-NC group, the expression of DJ-1 and p-AKT protein in SW1990/DDP cells was significantly decreased in miR-203 mimic transfection group, while the expression of PTEN was significantly increased with increased cell apoptosis and decreased cell proliferation, as well as reduced DDP resistance. The decreased expression of miR-203 and the increased expression of DJ-1 is associated with drug resistance in pancreatic cancer cells. Elevated miR-203 can inhibit the expression of DJ-1, affect the activity of PTEN-PI3K/AKT pathway, inhibit the proliferation of pancreatic cancer cells, induce cell apoptosis, and reduce DDP resistance of pancreatic cancer cells.

Over-expression of DJ-1 attenuates effects of curcumin on colorectal cancer cell proliferation and apoptosis.

The phosphatase and tensin homologue deleted on chromosome ten (PTEN) acts as a tumor suppressor gene by inhibiting the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. DJ-1, a negative regulator of PTEN, is associated with the pathogenesis of a variety of tumors. Curcumin (Cur) is a phenolic compound that is extracted from various plant rhizomes with various anti-tumor pharmacological effects. This study aimed to investigate the effects of Cur on proliferation and apoptosis of colorectal cancer cells. Human normal colorectal epithelial cell line (NCM460) and colorectal cancer cell line (SW480 and SW620) were cultured in vitro. Real-time quantitative PCR (RT-PCR) and western blot were used to detect DJ-1 and PTEN mRNA and protein, respectively. Cell apoptosis was determined with flow cytometry. SW480 cells were divided into control, 20 μM Cur treatment group, Cur+pcDNA3.1-Blank group and Cur+pcDNA3.1-DJ-1 group. Cell proliferation activity was evaluated with EdU staining. Comparing with NCM460 cells, DJ-1 was significantly increased, while PTEN was significantly declined in SW480 and SW620 cells (p<0.05). Cur treatment significantly inhibited SW480 and SW620 cell proliferation and significantly induced apoptosis compared to control group (p<0.05) but showed no significant effects on NCM460 cells. Cur down-regulated DJ-1 level and enhanced PTEN expressions in SW480 cells with dose dependence. The pcDNA3.1-DJ-1 transfection significantly declined PTEN expression, enhanced p-AKT levels, reduced cell apoptosis, and strengthened cell proliferation in SW480 cells treated by Cur (p<0.05). Cur can inhibit colorectal cancer cell proliferation and promote apoptosis by down-regulating DJ-1 expression to regulate the activity of PTEN/PI3K/AKT signaling pathway.

Long intergenic non-coding LINC00657 regulates tumorigenesis of glioblastoma by acting as a molecular sponge of miR-190a-3p.

To detect the aberrantly expressed long non-coding RNAs in glioblastoma, two pairs of glioblastoma and adjacent normal tissues were firstly analyzed by RNA sequencing. Long intergenic non-coding RNA LINC00657 was considered to play a vital role in glioblastoma based on the results of RNA sequencing. Hence, we aimed to investigate the mechanisms by which LINC00657 regulated the tumorigenesis of glioblastoma. The level of LINC00657 in 40 glioblastoma samples and glioblastoma cell lines was detected by RT-qPCR. LINC00657 was significantly decreased in patients with glioblastoma compared with adjacent normal tissues. Overexpression of LINC00657 inhibited proliferation, colony formation, invasion and migration in glioma cells via inducing apoptosis. Dual luciferase report assay indicated LINC00657 was the target of miR-190a-3p. Overexpression of LINC00657 greatly inhibited the relative amount of miR-190a-3p. Besides, miR-190a-3p was found to be a negative regulator of PTEN. Additionally, active-caspase 3 was increased in cells transfected with pcDNA3.1-LINC00657. Finally, in vitro results were further confirmed by in vivo studies using nude mice bearing with glioblastoma tumors. In conclusion, LINC00657 was effective in inhibiting glioblastoma by acting as a molecular sponge of miR-190a-3p to regulate PTEN expression. Therefore, targeting LINC00657 may serve as a potential strategy for the treatment of patients with glioblastoma.

Increased miR-142 and decreased DJ-1 enhance the sensitivity of pancreatic cancer cell to adriamycin.

Phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) signaling pathway is related to tumorigenesis by up-regulating survivin. Phosphatase and tensin homologue deleted on chromosome ten (PTEN) can suppress PI3K/AKT signaling pathway, while DJ-1 is the negative regulator of PTEN. DJ-1 up-regulation is closely correlated with the occurrence, progression, and drug resistance of pancreatic cancer. MicroRNA-142 (MiR-142) is significantly declined in pancreatic cancer tissue. Bioinformatics analysis demonstrated that complementary binding site exists between miR-142 and DJ-1. This investigation, therefore, aimed to study the role of miR-142 in the regulation of DJ-1-PTEN/PI3K/AKT/Survivin signaling pathway as well as in pancreatic cancer cell proliferation, apoptosis, and adriamycin (ADM) resistance. Dual luciferase assay was performed to assess the targeted relationship between miR-142 and DJ-1. MiR-142, DJ-1, and PTEN expressions in SW1990 cells and drug-resistant SW1990/ADM cells were compared. SW1990/ADM cells were divided into five groups, including mimic-NC, miR-142 mimic, small interfere normal control (si-NC), si-DJ-1, and miR-142 mimic + si-DJ-1 groups. DJ-1, PTEN, phosphorylated-AKT (p-AKT), and Survivin expressions were tested. Cell apoptosis was determined by flow cytometry. Cell proliferation was evaluated by EdU staining. MiR-142 targeted inhibited DJ-1 expression. MiR-142, PTEN, and cell apoptosis significantly down-regulated, while DJ-1, p-AKT, Survivin, and cell proliferation significantly elevated in SW1990/ADM cells compared with SW1990 cells. MiR-142 mimics and/or si-DJ-1 transfection markedly reduced DJ-1, p-AKT, and Survivin expressions enhanced PTEN level, attenuated cell proliferation, enhanced cell apoptosis, and weakened ADM resistance. MiR-142 over-expression weakened ADM resistance in pancreatic cancer cells by targeting DJ-1 to enhance PTEN expression and attenuate PI3K/AKT signaling pathway activity.

Fortunellin-Induced Modulation of Phosphatase and Tensin Homolog by MicroRNA-374a Decreases Inflammation and Maintains Intestinal Barrier Function in Colitis.

Activation of phosphatase and tensin homolog (PTEN) is known to induce cell apoptosis. MicroRNA-374a (miR-374a), which can suppress PTEN expression, has been found abnormally expressed in inflammatory bowel disease (IBD). Fortunellin is a citrus flavonoid that is a potential anti-inflammation agent in inflammatory diseases. The present study investigated the effects and mechanisms underlying fortunellin-induced inhibition of PTEN in IBD. Colitis was established in rats by the intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid to mimic human ulcerative colitis, which is the main type of IBD. miR-374a expression was measured by quantitative real-time polymerase chain reaction, and the regulation of PTEN by miR-374a was evaluated by dual luciferase reporter assay. Western blotting was used to measure the corresponding protein expression. Fortunellin ameliorated colitis symptoms, including excessive inflammation and oxidative stress. Fortunellin decreased epithelial cell apoptosis through inhibiting PTEN expression in colitis. Fortunellin-induced downregulation of PTEN could be counteracted by miR-374a depletion. Moreover, knockdown of miR-374a in vivo partly inhibited the effects of fortunellin on rat colitis. In conclusion, PTEN inhibition contributes to the amelioration effects of fortunellin on colitis. It was confirmed that fortunellin targets miR-374a, which is a negative regulator of PTEN. This study provides novel insights into the pathological mechanisms and treatment alternatives of colitis.

NMR uncovers direct interaction between human NEDD4-1 and p34SEI−1

PTEN, an important tumor suppressor and a key regulator of the PI3K/AKT signaling pathway, is often deleted/mutated in different types of cancer. The E3 ubiquitin ligase NEDD4-1 catalyzes the polyubiquitination of PTEN, thereby acting as a negative regulator of PTEN. Stability of NEDD4-1, in turn, is tightly controlled by a 34 kDa oncoprotein, p34SEI−1 and it regulates PTEN degradation and activates PI3K/AKT pathway, resulting in cancer metastasis. p34SEI−1 affects not only the expression of NEDD4-1 during transcription and translation but also the subcellular localization of PTEN. This emphasizes the need to understand, at molecular level, the interaction between NEDD4-1 and p34SEI−1. A recent study showed that NEDD4-1 interacts with p34SEI−1 via its WWI domain. However, a detailed interaction for molecular level is yet unknown. We report that the WW1 domain of NEDD4-1 recognizes the SERTA domain containing the proline rich region (PRR motif) in p34SEI−1. TALOS analysis based on NMR data confirms three conserved β-sheets in NEDD4-1 WW1 and the central β-sheet of NEDD4-1 WW1 plays a role for protein stability by the backbone dynamics experiments. NMR titration data revealed the binding site for p34SEI−1 with NEDD4-1. Our data will provide insights into the molecular mechanism of NEDD4-1 and p34SEI−1 interaction, which will be directly used for drug design which inhibits the molecular interaction involved in different cancer signaling.

Abstract 4694: Whole-exome sequencing of gastric cancer identifies germline PIK3R1 variant as a novel genetic biomarker for a PI3K beta-isoform selective inhibitor, GSK2636771

Abstract BACKGROUND: PI3K signaling is one of the most frequently altered pathways in gastric cancer (GC), and PI3K beta-isoform selective inhibitors have anti-tumor effects with tolerable toxicities in PTEN loss driven tumors. This study aimed to identify novel genetic predictive factors for a PI3K beta-isoform selective inhibitor through a whole-exome analysis of GC cell lines. METHODS: We comprehensively analyzed the genetic alterations in 40 GC cell lines using whole-exome sequencing (WES) and identified specific genetic alterations with sensitivity to GSK2636771, a PI3K beta-isoform selective inhibitor. RESULTS: We identified frequent genetic alterations in PI3K family genes (PIK3CA: 20%, PIK3C2B: 15%, PIK3CD 13%, PIK3CG: 25%, PIK3R1: 30%, PIK3R2: 100%). While no deletion or mutation of PTEN was detected, 40% exhibited a loss of PTEN protein expression. Intriguingly, we noticed germline PIK3R1 variant, M326I (rs3730089), was significantly related to the increased sensitivity to GSK2636771 (IC50: 20.6±9.0 vs 43.5±26.8 μM, p = 0.001), with a stronger association than that of PTEN loss (IC50: 27.5±13.9 vs. 41.7±28.0 μM, p = 0.047). GC cell lines with higher variant allele frequency of PIK3R1 tended to be more sensitive to GSK2636771. Moreover, PIK3R1 M326I was associated with increased p85α expression (p = 0.0198) and decreased PTEN expression in GC cell lines (p = 0.008); same findings were also confirmed in human GC tissues. Furthermore, a correlation analysis of PIK3R1 and PTEN expressions in GC tissues revealed the reciprocal association between these two proteins (R2 = 0.223, p = 0.002), suggesting the possible mechanistic role of PIK3R1 as a negative regulator of PTEN, or vice versa in GC. Next, among various cytotoxics, oxaliplatin was significantly more effective in PIK3R1 M326I variant GC cells (p = 0.028), supporting the combination of GSK2636771 and oxaliplatin for further clinical development in GC. Finally, by using both the PIK3R1 M326I and PTEN loss in combination, we were able to predict the response to GSK2636771 more accurately in GC cells. CONCLUSION: Through WES analysis of GC cell panels, we identified a germline PIK3R1 variant, M326I, as a novel genetic biomarker that provides a more accurate prediction of response to GSK2636771 when used in combination with PTEN loss. Citation Format: Chan Kim, Woo Sun Kwon, Sun Young Rha, Sun Kyung Kang, Hyoki Kim, Carolyn Buser-Doepner, Li Yan, Rakesh Kumar, Hyun Cheol Chung. Whole-exome sequencing of gastric cancer identifies germline PIK3R1 variant as a novel genetic biomarker for a PI3K beta-isoform selective inhibitor, GSK2636771. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4694. doi:10.1158/1538-7445.AM2015-4694

Resveratrol regulates PTEN/Akt pathway through inhibition of MTA1/HDAC unit of the NuRD complex in prostate cancer

Metastasis associated protein 1 (MTA1) is a component of the nucleosome remodeling and deacetylating (NuRD) complex which mediates gene silencing and is overexpressed in several cancers. We reported earlier that resveratrol, a dietary stilbene found in grapes, can down-regulate MTA1. In the present study, we show that PTEN is inactivated by MTA1 in prostate cancer cells. Further, we show that resveratrol promotes acetylation and reactivation of PTEN via inhibition of the MTA1/HDAC complex, resulting in inhibition of the Akt pathway. In addition, we show that MTA1 knockdown is sufficient to augment acetylation of PTEN indicating a crucial role of MTA1 itself in the regulation of PTEN acetylation contributing to its lipid phosphatase activity. Acetylated PTEN preferentially accumulates in the nucleus where it binds to MTA1. We also show that MTA1 interacts exclusively with PTEN acetylated on Lys125 and Lys128, resulting in diminished p-Akt levels. Finally, using orthotopic prostate cancer xenografts, we demonstrate that both resveratrol treatment and MTA1 knockdown enhance PTEN levels leading to a decreased p-Akt expression and proliferation index. Taken together, our results indicate that MTA1/HDAC unit is a negative regulator of PTEN which facilitates survival pathways and progression of prostate cancer and that resveratrol can reverse this process through its MTA1 inhibitory function.

Tumorigenesis role and clinical significance of DJ-1, a negative regulator of PTEN, in supraglottic squamous cell carcinoma

BackgroundDJ-1 can induce the tumor cell proliferation and invasion via down-regulating PTEN in many malignant tumors, and correlated to prognostic significance. However, the tumorigenesis role and clinical significance of DJ-1 in supraglottic squamous cell carcinoma (SSCC) is unclear. We aimed to evaluate the DJ-1 the relationship between DJ-1 and clinicopathological data including patient survival.MethodsThe expression of DJ-1 and PTEN in SSCCs (52) and adjacent non-cancerous tissues (42) was assessed by immunohistochemistry (IHC), and the relationship between DJ-1 and clinicopathological data was analyzed.ResultsDJ-1 was detected mainly in SSCCs (88.5%) and less frequently in adjacent non-cancerous tissues (21.0%). PTEN expression was detected in 46.2% of SSCCs and in 90.5% of adjacent non-cancerous tissues. DJ-1 expression was linked to nodal status (P = 0.009), a highly significant association of DJ-1 expression with shortened patient overall survival (5-year survival rate 88.0% versus 53.9%; P = 0.007; log rank test) was demonstrated.ConclusionsOur data suggested that DJ-1 over-expression was linked to nodal status, and might be an independent prognostic marker for patients with SSCC.

Melanoma genome sequencing reveals frequent PREX2 mutations

Melanoma is notable for its metastatic propensity, lethality in the advanced setting, and association with ultraviolet (UV) exposure early in life1. To obtain a comprehensive genomic view of melanoma, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-UV exposed hairless skin of the extremities (3 and 14 per Mb genome), intermediate in those originating from hair-bearing skin of the trunk (range = 5 to 55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 - a PTEN-interacting protein and negative regulator of PTEN in breast cancer2 - as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumor formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumors revealed genomic evidence of UV pathogenesis and discovered a new recurrently mutated gene in melanoma.

Upregulated DJ-1 promotes renal tubular EMT by suppressing cytoplasmic PTEN expression and Akt activation

Recently, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is suggested as a new agent in the fighting against fibrogenesis. In tumor, DJ-1 is identified as a negative regulator of PTEN. But the expression of DJ-1 and the regulation of PTEN in fibrosis are unclear. Renal fibrosis was induced in 5/6 subtotal nephrectomy rat model. Human proximal tubular epithelial cells (HKC) were treated with transforming growth factor-beta 1 (TGF-β1), or transfected with DJ-1 or PTEN. Confocal microscope was used to investigate the localization of DJ-1 and PTEN. The selective phosphoinositide-3 kinase (PI3K) inhibitor, LY294002, was administered to inhibit PI3K pathway. The DJ-1 and PTEN expression, markers of epithelial-mesenchymal transition (EMT) and Akt phosphorylation were measured by RT-PCR, Western blotting or immunocytochemistry. In vitro, after HKC cells were stimulated with 10 ng/mL TGF-β1 for 72 h, the expression of DJ-1 was increased, and that of PTEN was decreased. In vivo, the same results were identified in 5/6-nephrectomized rats. In normal HKC cells, most of DJ-1 protein localized in cytoplasm, and little in nucleus. TGF-β1 upregulated DJ-1 expression in both cytoplasma and nuclei. In contrary, TGF-β1 emptied cytoplasmic PTEN protein into nucleus. Overexpression of DJ-1 decreased the expression of PTEN, promoted the activation of Akt and the expression of vimentin, and also led to the loss of cytoplasmic PTEN. Contrarily, overexpression of PTEN protected HKC cells from TGF-β1-induced EMT. In conclusion, DJ-1 is upregulated in renal fibrosis and DJ-1 mediates EMT by suppressing cytoplasmic PTEN expression and Akt activation.

The potential role of DJ-1 in fibrogenesis: A double-edged sword?

Fibrogenesis is a frequent pathogenesis in the processes of many diseases from the initial-stage to the end-stage. Unfortunately, mechanisms of fibrogenesis are complex and not fully understood by now. Recently, researches have proved that oxidative stress participates in the process of fibrosis. Some studies suggest that PTEN, a tumor suppressor, is down-regulated in fibrosis, and it will be a new agent for fighting against fibrogenesis. DJ-1, an oncogene product, has been identified as a protein with various functions in cellular transformation, oxidative stress response and transcriptional regulation, and it is considered as a negative regulator of PTEN in tumor. DJ-1 is also observed overexpression in hepatic fibrosis, but the specific effects of it are obscure. We hypothesize that DJ-1 is a double-edged sword in fibrogenesis: DJ-1 may hamper oxidative damage; overexpression of DJ-1 possibly promote fibrogenesis through depressing the expression of PTEN and activating PI3K/Akt pathway subsequently.

Expression and clinical role of DJ-1, a negative regulator of PTEN, in ovarian carcinoma

The aim of this study was to analyze the expression and clinical role of DJ-1, a negative regulator of PTEN (phosphatase and tensin homolog deleted on chromosome 10), in ovarian carcinoma, and investigate the putative association between DJ-1 levels and expression of its transcriptional regulators specificity protein 1 (Sp1) and specificity protein 3 (Sp3). Effusions (n = 72) and solid tumors (n = 57, 42 primary and 15 metastases) were analyzed for DJ-1 messenger RNA (mRNA) expression using reverse transcriptase-polymerase chain reaction. Most specimens (48 effusions, 50 solid tumors) were additionally analyzed for Sp1 and Sp3 mRNA expression. PTEN protein expression was analyzed in 201 effusions and 92 solid tumors using immunohistochemistry. DJ-1 mRNA was expressed in more than 80% of specimens, with no preferential anatomical site. DJ-1 expression was positively associated with Sp1 expression in effusions (P = .03) and with Sp1 (P = .02) and Sp3 (P = .002) expression in solid tumors. In effusions, DJ-1 expression was higher in postchemotherapy compared with prechemotherapy specimens (P = .012). Higher DJ-1 levels (P = .027) and more advanced FIGO stage (IV versus III; P = .003) correlated with shorter progression-free survival in univariate analysis for patients with postchemotherapy effusions. PTEN expression was low in effusions and solid tumors (23% and 13%, respectively), and its expression showed no association with DJ-1 levels or survival. Our data show that DJ-1 is frequently expressed in advanced-stage ovarian carcinoma at all anatomical sites and is coexpressed with its transcriptional regulators Sp1 and Sp3. In contrast, PTEN expression is infrequent in this disease. These findings may provide one of the molecular mechanisms that mediate cancer cell survival and aggressiveness in this tumor.

The Role of AEBP1 in Sex-Specific Diet-Induced Obesity

Obesity is an important risk factor for heart disease, diabetes, and certain cancers, but the molecular basis for obesity is poorly understood. The transcriptional repressor AEBP1, which functions as a negative regulator of PTEN through a protein-protein interaction, is highly expressed in the stromal compartment of adipose tissues, including proliferative preadipocytes, and its expression is abolished in terminally differentiated, nonproliferative adipocytes. Here we show that transgenic overexpression of AEBP1 during adipogenesis coupled with a high-fat diet (HFD) resulted in massive obesity in female transgenic (AEBP1(TG)) mice via adipocyte hyperplasia. AEBP1 levels dynamically changed with aging, and HFD induced AEBP1 expression in females. Thus, HFD-fed AEBP1(TG) females display hyperinduction of AEBP1 and a marked reduction of PTEN level with concomitant hyperactivation of the survival signal in white adipose tissue. Our results suggest that AEBP1 plays a key functional role in in vivo modulation of adiposity via fat-cell proliferation and is involved in a sex-specific susceptibility to diet-induced obesity by the estrogen signaling pathway.