Stratification of prostate cancer patients into low- and high-grade groups using multiparametric magnetic resonance radiomics with dynamic contrast-enhanced image joint histograms.

PURPOSE: This study aimed to investigate the potential of stratification of prostate cancer patients into low- and high-grade groups (GGs) using multiparametric magnetic resonance (mpMR) radiomics in conjunction with two-dimensional (2D) joint histograms computed with dynamic contrast-enhanced (DCE) images. METHODS: A total of 101 prostate cancer regions extracted from the MR images of 44 patients were identified and divided into training (n = 31 with 72 cancer regions) and test datasets (n = 13 with 29 cancer regions). Each dataset included low-grade tumors (International Society of Urological Pathology [ISUP] GG ≤ 2) and high-grade tumors (ISUP GG ≥ 3). A total of 137,970 features consisted of mpMR image (16 types of images in four sequences)-based and joint histogram (DCE images at 10 phases)-based features for each cancer region. Joint histogram features can visualize temporally changing perfusion patterns in prostate cancer based on the joint histograms between different phases or subtraction phases of DCE images. Nine signatures (a set of significant features related to GGs) were determined using the best combinations of features selected using the least absolute shrinkage and selection operator. Further, support vector machine models with the nine signatures were built based on a leave-one-out cross-validation for the training dataset and evaluated with receiver operating characteristic (ROC) curve analysis. RESULTS: The signature showing the best performance was constructed using six features derived from the joint histograms, DCE original images, and apparent diffusion coefficient maps. The areas under the ROC curves for the training and test datasets were 1.00 and 0.985, respectively. CONCLUSION: This study suggests that the proposed approach with mpMR radiomics in conjunction with 2D joint histogram computed with DCE images could have the potential to stratify prostate cancer patients into low- and high-GGs.

Testosterone level in seminal vesicle fluid is a better indicator of erectile function than serum testosterone in patients with prostate cancer.

OBJECTIVES: Semen comprises prostatic fluid and seminal vesicle fluid, and seminal vesicle fluid contains various factors such as prostaglandin E2 (PGE2), zinc, and testosterone, which play important roles in sperm motility. It is not known whether these factors affect erectile function. In this study, we investigated factors in seminal vesicle fluid that may affect erectile function. METHODS: After receiving institutional review board approval, we collected seminal vesicle fluid samples from 134 Japanese patients with localized prostate cancer who underwent robot-assisted radical prostatectomy. We examined the relationship between the results of the Sexual Health Inventory for Men (SHIM), erection hardness score, an original questionnaire on the presence or absence of sexual desire, and concentrations of several factors in seminal vesicle fluid (testosterone, PGE2, transforming growth factor ß1, and 8-hydroxy-2-deoxyguanosine), as well as the serum testosterone level. RESULTS: Median participant age was 67 (range 51-77) years. Median concentrations were as follows: seminal vesicle testosterone 1.85 (range 0.17-4.32) ng/ml and serum testosterone 4.60 (range 1.75-10.82) ng/ml. When the SHIM score was divided into two groups, seminal vesicle testosterone concentration was significantly increased (p = 0.002) in participants with a SHIM score ≥17, and no significant difference was observed in serum testosterone levels (p = 0.661). Multivariate analysis revealed that seminal vesicle testosterone was significantly correlated with the SHIM score (≥17 vs. <17; odds ratio 2.137, 95% confidence interval 1.148-3.978, p = 0.016). CONCLUSIONS: Testosterone levels in seminal vesicle fluid can reflect erectile function in patients with prostate cancer, suggesting that seminal vesicle testosterone is very important for male erectile function.

Gene amplification of YB-1 in castration-resistant prostate cancer in association with aberrant androgen receptor expression.

Although Y-box binding protein-1 (YB-1) is known to be overexpressed in prostate cancer, especially castration-resistant prostate cancer (CRPC), the mechanism of its overexpression remains unclear. We aimed to elucidate the mechanism of YB-1 overexpression in CRPC. Gene amplification in CRPC cells and tissues was examined by public database analysis, and digital PCR. The significance of YB-1 amplification for the YB-1/androgen receptor (AR) axis and prognosis was examined by public database analysis and immunohistochemistry. YB-1 amplification was mainly observed in CRPC tissues by public database analysis and confirmed in CRPC cells and tissues by digital PCR. Expression of YB-1 was increased in CRPC tissues compared with treatment-naïve tissues. Furthermore, YB-1 and phosphorylated YB-1 levels were associated with AR and AR V7 expression levels. Finally, YB-1 amplification was associated with poor outcomes in CRPC. Taken together, the present findings suggest that YB-1 amplification contributes to progression to CRPC through regulation of AR and AR V7 expressions, and that YB-1 is a promising therapeutic target in CRPC.

Automated approach for estimation of grade groups for prostate cancer based on histological image feature analysis.

BACKGROUND: There is a low reproducibility of the Gleason scores that determine the grade group of prostate cancer given the intra- and interobserver variability among pathologists. This study aimed to develop an automated approach for estimating prostate cancer grade groups based on features obtained from histological image analysis. METHODS: Fifty-nine patients who underwent radical prostatectomy were selected under the approval of the institutional review board of our university hospital. For estimation, we followed the grade group criteria provided by the International Society of Urological Pathology in 2014. One hundred eight specimen slides obtained from the patients were digitized to extract 110 regions of interest (ROI) from hematoxylin and eosin-stained histological images using a digital whole slide scanner at ×20 magnification with a pixel size of 0.4 µm. Each color pixel value in the ROI was decomposed into six intensities corresponding to the RGB (red, green, and blue) and HSV (hue, saturation, and value) color models. Image features were extracted by histological image analysis, obtaining 54 features from the ROI based on histogram and texture analyses in the six types of decomposed histological images. Then, 40 representative features were selected from the 324 histological image features based on statistically significant differences (P < .05) between the mean image feature values for high (≥3, Gleason score ≥4 + 3) and low (≤2, Gleason score ≤3 + 4) grade groups. The relationship between grade groups and the most representative image feature (ie, complexity) was approximated using regression to estimate real-number grade groups defined by continuous numerical grading. Finally, the grade groups were expressed as the conventional grade groups (ie, integers from 1 to 5) using a piecewise step function. RESULTS: The grade groups were correctly estimated by the proposed approach without errors on training (70 ROIs) and validation (40 ROIs) data. CONCLUSIONS: Our results suggest that the proposed approach may support pathologists during the evaluation of grade groups for prostate cancer, thus mitigating intra- and interobserver variability.

Cigarette smoking augments androgen receptor activity and promotes resistance to antiandrogen therapy.

BACKGROUND: Cigarette smoking is associated with worse outcomes in prostate cancer, whose growth is dependent on androgen receptor (AR) signaling. We aimed to elucidate the biological effect of cigarette smoking on AR signaling and its clinical influence on oncological outcome. METHODS: Gene expression levels after exposure to tobacco smoke condensate (TSC) were evaluated by quantitative real-time polymerase chain reaction and Western blot analysis in prostate cancer cells. Cellular sensitivities to enzalutamide and docetaxel after TSC exposure were evaluated using a prostate cancer cell proliferation assay. Prognosis was compared between current smokers and nonsmokers when treated with AR-axis-targeting (ARAT) agent enzalutamide and docetaxel. RESULTS: Expression of AR variants as well as prostate-specific antigen was augmented after TSC exposure, which occurred after Akt phosphorylation. These inductions were suppressed by Akt inhibitor LY294002 as well as antioxidant N-acetylcysteine. Consistently, TSC exposure augmented cellular resistance to enzalutamide. In clinical data, cigarette smoking was associated with worse progression-free survival and cancer-specific survival when patients with prostate cancer were treated with ARAT agents but not docetaxel. CONCLUSIONS: It was suggested that cigarette smoking leads to detrimental oncological outcome when prostate cancer patients are treated with ARAT agents through induction of aberrant AR signaling. Accordingly, we recommend that patients with advanced prostate cancer should refrain from cigarette smoking.

Psoas muscle volume is correlated with sexual activity and erectile dysfunction among patients with localised prostate cancer.

Several endocrinological and physical activities orchestrate men's sexual activities. To determine whether body composition calculated by computed tomography measurements is useful for estimating sexual function, we evaluated sexual function of localised prostate cancer patients using the Sexual Health Inventory for Men score, an original questionnaire, and computed tomography and magnetic resonance imaging. The imaging was performed to determine body composition, particularly the psoas muscle. Univariate and multivariate analyses were performed to identify factors affecting sexual activity. The multivariate analysis showed that the volume of the psoas muscle was significantly correlated with sexual activity (odds ratio [95% confidence interval]) (2.507 [1.029-6.109], p = 0.043) and erectile dysfunction (0.261 [0.098-0.692], p = 0.006). We concluded that the psoas muscle is an important predictor of sexual activity and erectile function.

Collateral resistance to taxanes in enzalutamide-resistant prostate cancer through aberrant androgen receptor and its variants.

Currently, the optimal sequential use of androgen receptor (AR) axis-targeted agents and taxane chemotherapies remains undetermined. We aimed to elucidate the resistance status between taxanes and enzalutamide, and the functional role of the AR axis. Enzalutamide-resistant 22Rv1 cells showed collateral resistance to taxanes, including docetaxel and cabazitaxel. However, taxane-resistant cells showed no collateral resistance to enzalutamide; taxane-resistant cells expressed comparable protein levels of full-length AR and AR variants. Knockdown of both full-length AR and AR variants rendered cells sensitive to taxanes, whereas knockdown of AR variants sensitized cells to enzalutamide, but not to taxanes. In contrast, overexpression of full-length AR rendered cells resistant to taxanes. Consistently, the prostate-specific antigen response and progression-free survival in docetaxel chemotherapy were worse in cases with prior use of ARAT agents compared with cases without. Collateral resistance to taxanes was evident after obtaining enzalutamide resistance, and aberrant AR signaling might be involved in taxane resistance.

Mineralocorticoid receptor signaling affects therapeutic effect of enzalutamide.

BACKGROUND: Corticosteroids play important roles in prostate cancer therapeutics. However, their role when combined with enzalutamide remains obscure. Then, we aimed to elucidate the functional and clinical impact of corticosteroids on steroid receptors in androgen receptor (AR)-targeting therapy utilizing enzalutamide. METHODS: The therapeutic effect was studied according to concomitant use of corticosteroids in 86 men treated with enzalutamide. The sensitivity to various agents was evaluated using cytotoxicity assays in prostate cancer cells. Gene expression levels were evaluated by quantitative real-time polymerase chain reaction in prostate cancer cells and tissues. RESULTS: The therapeutic effect of enzalutamide was particularly lessened with concomitant treatment with dexamethasone. Consistently, dexamethasone increased cellular resistance to enzalutamide while prednisolone and aldosterone decreased cellular resistance to enzalutamide in prostate cancer cells. Inversely, mineralocorticoid receptor (MR) knockdown augmented the activity of AR signaling and the cellular resistance to enzalutamide. CONCLUSIONS: MR plays a critical role in resistance to AR-targeting therapies, which may be overcome by activation of MR signaling.

Serum testosterone before and during androgen-deprivation therapy, and prognosis between cigarette smokers and nonsmokers with metastatic prostate cancer.

Cigarette smoking is suggested to influence androgen milieu, which is closely associated with pathogenesis and prognosis of prostate cancer. In this study, we investigated the association between serum testosterone level before or during androgen-deprivation therapy (ADT) as well as prognoses and cigarette smoking status among men with metastatic prostate cancer. Serum testosterone level before ADT in current smokers (n = 6, median [interquartile range, IQR]; 454 ng/ml [426-478 ng/ml]) was significantly higher than that in nonsmokers (n = 26, median [IQR]; 397 ng/ml [312-435 ng/ml]). Serum testosterone level during ADT in current smokers (n = 7, median [IQR]; 7 ng/ml [3-11 ng/ml]) was comparable with that in nonsmokers (n = 55, median [IQR]; 9 ng/ml [3-20 ng/ml]). Progression-free survival and overall survival were comparable between current smokers and nonsmokers when adjusted with serum testosterone level before ADT or during ADT. These results suggest adequate pharmacological effect of ADT, even in current smokers. However, serum testosterone level before ADT was higher in current smokers. Thus, we need to interpret serum testosterone level in current smokers with caution.

FOXO3a Expression Regulated by ERK Signaling is Inversely Correlated With Y-Box Binding Protein-1 Expression in Prostate Cancer.

BACKGROUND: FOXO3a is a member of the forkhead O transcription factors. FOXO3a induces the factors that contribute to cell cycle arrest and is considered a tumor suppressor in several malignant tumors. Y-box binding protein-1 (YB-1) is a multifunctional protein whose high expression is correlated with poor prognoses in various malignant tumors. In the current study, we investigated the relationship between FOXO3a and YB-1 to validate their functional roles in prostate cancer. METHODS: Western blotting and cytotoxicity assays were conducted in prostate cancer cells, LNCaP, and 22Rv1 cells. We also evaluated the protein expressions of FOXO3a and YB-1 in human prostate cancer tissues, using radical prostatectomy specimens. Then, we investigated the correlations between protein expressions and clinicopathologic parameters. RESULTS: We found that both FOXO3a and YB-1 proteins were phosphorylated by ERK signaling, resulting in FOXO3a inactivation and YB-1 activation in LNCaP and 22Rv1 cells. Inversely, inhibition of MEK or treatment with metformin activated FOXO3a through inactivation of ERK signaling and suppressed the viability of LNCaP and 22Rv1 cells in a dose-dependent manner. In immunohistochemical analysis, FOXO3a nuclear expression was inversely correlated with YB-1 nuclear expression (P < 0.0001). Furthermore, high FOXO3a nuclear expression was inversely correlated with a higher Gleason grade (P < 0.0001) and higher preoperative PSA (P = 0.0437). CONCLUSIONS: These results showed that in prostate cancer, FOXO3a, and YB-1 play inverse reciprocal roles as a tumor-suppressor gene and oncogene, respectively, through their master regulator ERK. Prostate 77:145-153, 2017. © 2016 Wiley Periodicals, Inc.

Suppression of LIM and SH3 Domain Protein 1 (LASP1) Negatively Regulated by Androgen Receptor Delays Castration Resistant Prostate Cancer Progression.

BACKGROUND: LIM and SH3 domain protein 1 (LASP1) has been implicated in several human malignancies and has been shown to predict PSA recurrence in prostate cancer. However, the anti-tumor effect of LASP1 knockdown and the association between LASP1 and the androgen receptor (AR) remains unclear. The aim of this study is to clarify the significance of LASP1 as a target for prostate cancer, and to test the effect of silencing LASP1 in vivo using antisense oligonucleotides (ASO). METHODS: A tissue microarray (TMA) was performed to characterize the differences in LASP1 expression in prostate cancer treated after hormone deprivation therapy. Flow cytometry was used to analyze cell cycle. We designed LASP1 ASO for knockdown of LASP1 in vivo studies. RESULTS: The expression of LASP1 in TMA was increased after androgen ablation and persisted in castration resistant prostate cancer (CRPC). Also in TMA, compared with LNCaP cell, LASP1 expression is elevated in CRPC cell lines (C4-2 and VehA cells). Interestingly, suppression of AR elevated LASP1 expression conversely, AR activation decreased LASP1 expression. Silencing of LASP1 reduced cell growth through G1 arrest which was accompanied by a decrease of cyclin D1. Forced overexpression of LASP1 promoted cell cycle and induced cell growth which was accompanied by an increase of cyclin D1. Systemic administration of LASP1 ASO with athymic mice significantly inhibited tumor growth in CRPC xenografts. CONCLUSIONS: These results indicate that LASP1 is negatively regulated by AR at the transcriptional level and promotes tumor growth through induction of cell cycle, ultimately suggesting that LASP1 may be a potential target in prostate cancer treatment. Prostate 77:309-320, 2017. © 2016 Wiley Periodicals, Inc.

Targeting ribosomal S6 kinases/Y-box binding protein-1 signaling improves cellular sensitivity to taxane in prostate cancer.

BACKGROUND: Taxanes are the only cytotoxic chemotherapeutic agents proved to prolong the survival in patients with castration-resistant prostate cancer. However, because of intrinsic and acquired resistances to taxanes, their therapeutical efficiencies are modest, bringing only a few months of survival benefit. Y-box binding protein-1 (YB-1) promotes cancer cell resistance to various anticancer treatments, including taxanes. Here, we aimed to elucidate the mechanism of taxane resistance by YB-1 and examined overcoming resistance by targeting YB-1 signaling. METHODS: Gene and protein expression levels were evaluated by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. We evaluated the sensitivity of prostate cancer cells to taxanes using cytotoxicity assays. RESULTS: Natural taxane paclitaxel from Taxus brevifolia activated the Raf-1/extracellular signal-regulated kinase (ERK) pathway, leading to an activation of ribosomal S6 kinases (RSK)/YB-1 signaling. Activated Raf-1/ERK pathway was blunted by YB-1 knockdown in prostate cancer cells, indicating regulation between Raf-1/ERK signaling and YB-1. In addition, ERK or RSK was activated in taxane-resistant prostate cancer cells, resulting in YB-1 activation. YB-1 knockdown as well as RSK inhibition using RSK-specific siRNA or the small molecule inhibitor SL0101 successfully blocked activation of YB-1, leading to suppression of prostate cancer growth and sensitization to paclitaxel. CONCLUSIONS: Taken together, these findings indicate that RSK/YB-1 signaling contributes to taxane resistance, and implicate the therapeutics targeting RSK/YB-1 signaling such as RSK inhibitor as a promising novel therapy against prostate cancer, especially in combination with taxane.

Inhibition of RSK/YB-1 signaling enhances the anti-cancer effect of enzalutamide in prostate cancer.

BACKGROUND: Previously, we have shown that Y-box binding protein-1 (YB-1) regulates androgen receptor (AR) expression and contributes to castration resistance. However, the mechanism of YB-1 activation remains unknown. In this study, we aimed to elucidate the mechanism and role of YB-1 activation in relation to castration resistance as well as enzalutamide resistance, with a view to developing a novel therapeutic concept for castration-resistant prostate cancer (CRPC) treatment. METHODS: The expression and phosphorylation levels of ribosomal S6 kinase 1 (RSK1), YB-1 and AR were examined by quantitative PCR and Western blotting using prostate cancer cells. In addition, the effects of YB-1 inhibition using specific siRNA and small molecule inhibitor SL0101 on AR expression as well as combination treatment with enzalutamide and SL0101 were examined. RESULTS: We found that androgen deprivation, as well as treatment with the next-generation anti-androgen enzalutamide, induced RSK1 and YB-1 activation followed by AR induction, which could be reversed by YB-1 shutdown and RSK inhibitor SL0101. SL0101 and enzalutamide exerted a synergistic tumor-suppressive effect on cell proliferation in androgen-dependent prostate cancer LNCaP cells, as well as castration-resistant C4-2 cells. Furthermore, the phosphorylation levels of RSK1 and YB-1 were elevated in castration- and enzalutamide-resistant cells, compared with their parental cells. CONCLUSIONS: Taken together, these findings indicate that RSK1/YB-1 signaling contributes to castration as well as enzalutamide resistance, and that the therapeutic targeting of RSK1/YB-1 signaling would be a promising novel therapy against prostate cancer, especially CRPC when combined with enzalutamide.

The feature of metabolic syndrome is a risk factor for biochemical recurrence after radical prostatectomy.

BACKGROUND AND OBJECTIVE: To examine the association between the features of metabolic syndrome (MetS) (obesity, hypertension, diabetes mellitus, and dyslipidemia) and the risk of biochemical recurrence (BCR) after radical prostatectomy in patients with prostate cancer. METHODS: This study included 283 Japanese patients with localized prostate cancer who were treated with radical prostatectomy between 2008 and 2012. Their oncological outcomes and the prognostic significance of several clinicopathological factors, as well as the features of MetS, were analyzed. RESULTS: Of 283 men who underwent radical prostatectomy, 49 (17.2%) subsequently developed BCR with a median postoperative follow-up of 14.8 months. Among the clinicopathological factors, prostate-specific antigen (PSA) level at diagnosis, pathological stage, pathological Gleason score, and lymph-node involvement were independent risk factors for BCR in multivariate analysis. In addition, the number of metabolic risk factors was also an independent risk factor for BCR. CONCLUSIONS: The features of MetS were linked with poorer outcome after radical prostatectomy among Japanese men. Further investigations are needed to determine the effect of improving MetS on prostate cancer prognosis.

The oncological outcomes and risk stratification in docetaxel chemotherapy for castration-resistant prostate cancer.

OBJECTIVE: To clarify the risk factors and develop a refined risk-stratification model to help in the appropriate selection of docetaxel chemotherapy in patients with castration-resistant prostate cancer. METHODS: This study included 97 Japanese patients with castration-resistant prostate cancer who were treated with 70-75 mg/m(2) docetaxel and 10 mg prednisone every 3 or 4 weeks from 2008 to 2013. The oncological outcomes and prognostic significance of clinicopathological factors were analyzed, and significant prognostic factors were used to develop a risk-stratification model. RESULTS: Prostate-specific antigen decline was observed in 75 patients (77.3%), including 43 (44.3%) who achieved a prostate-specific antigen decline of ≥ 50%. The median progression-free survival and overall survival were 5.1 and 20.8 months, respectively. Univariate analysis identified performance status, alkaline phosphatase value, visceral metastasis, duration from diagnosis, duration from initiation of hormone treatment and prior treatment with estramustine as significant predictors of overall survival. Among these, alkaline phosphatase value, visceral metastasis and duration from initiation of hormone treatment were independent prognostic factors in multivariate analysis. Furthermore, risk classification according to the number of independent risk factors present effectively stratified survival among docetaxel-treated castration-resistant prostate cancer patients. CONCLUSIONS: Oncologic outcomes in Japanese patients with castration-resistant prostate cancer receiving docetaxel chemotherapy were comparable to or slightly better than those in Western populations, and the risk-stratification model developed in this study may help to predict prognosis and contribute to the selection of suitable therapy after castration resistance.

Comparison of Testosterone Level of Seminal Vesicle Fluid in Patients With Prostate Cancer Versus Other Malignancies.

BACKGROUND/AIM: Testosterone is essential for prostate cancer development and growth. This study aimed to investigate the relationship between testosterone in seminal vesicles and prostate cancer incidence and its malignant phenotype. PATIENTS AND METHODS: After obtaining institutional review board approval, seminal vesicle fluid samples were collected from patients who underwent prostatectomy or cystectomy. Pathological review demonstrated that 26 patients had benign prostate tissue and 149 had prostate cancer. First, testosterone levels in seminal vesicle fluid from benign prostate and prostate cancer samples were compared. Next, the relationship between pathological stage, International Society of Urological Pathology (ISUP) score, and testosterone concentrations in seminal vesicle fluid in the prostate cancer group were examined. RESULTS: Testosterone in seminal vesicles was significantly higher in the prostate cancer group [median (range), 1.94 (0.17-4.32) ng/ml] than in the benign prostate group (mainly bladder cancer) [1.45 (0.60-2.78) ng/ml] (p=0.001). Testosterone in seminal vesicles showed no difference in relation to pathological stage (pT2 vs. pT3) or ISUP score (12 vs. 345) (p=0.480 and p=0.964, respectively). Neoadjuvant chemotherapy for other cancers (e.g., bladder or rectal cancer) significantly reduced testosterone in seminal vesicles (p=0.013). Multivariate regression analysis revealed that testosterone in seminal vesicles was significantly correlated with prostate cancer, and not with neoadjuvant chemotherapy (p=0.023, p=0.457, respectively). CONCLUSION: Testosterone in seminal vesicles may contribute to prostate cancer incidence, but has no relationship with pathological grading.

Relationship between body composition and hormone sensitivity for androgen deprivation therapy in patients with metastatic prostate cancer.

BACKGROUND: To evaluate the relationship between body composition and the oncological outcome of androgen deprivation therapy (ADT), we investigated whether body composition features including the psoas muscle may be predictive factors of ADT. METHODS: This study enrolled patients with hormone-naïve metastatic prostate cancer who were treated with primary ADT from April 1996 to November 2013 at Kyushu University Hospital and who underwent a computed tomography scan before primary ADT for calculating body fat percentage, psoas muscle ratio (psoas muscle, cm3/height, cm), and body mass index. RESULTS: Of the 178 patients enrolled, 60 patients died during follow-up. Median follow-up was 32 months, and progression-free survival and overall survival (OS) were 28 and 80 months, respectively. Multivariate analysis revealed that the psoas muscle ratio was correlated with OS (hazard ratio: 0.448; 95% confidence interval = 0.206-0.922; p = 0.028). CONCLUSIONS: This study demonstrated that higher psoas muscle ratio predicts longer OS among patients with nonlocalized prostate cancer treated with primary ADT.

Paternally Expressed Gene 10 (PEG10) Promotes Growth, Invasion, and Survival of Bladder Cancer.

Paternally expressed gene 10 (PEG10) has been associated with neuroendocrine muscle-invasive bladder cancer (MIBC), a subtype of the disease with the poorest survival. In this work, we further characterized the expression pattern of PEG10 in The Cancer Genome Atlas database of 412 patients with MIBC, and found that, compared with other subtypes, PEG10 mRNA level was enhanced in neuroendocrine-like MIBC and highly correlated with other neuroendocrine markers. PEG10 protein level also associated with neuroendocrine markers in a tissue microarray of 82 cases. In bladder cancer cell lines, PEG10 expression was induced in drug-resistant compared with parental cells, and knocking down of PEG10 resensitized cells to chemotherapy. Loss of PEG10 increased protein levels of cell-cycle regulators p21 and p27 and delayed G1-S-phase transition, while overexpression of PEG10 enhanced cancer cell proliferation. PEG10 silencing also lowered levels of SLUG and SNAIL, leading to reduced invasion and migration. In an orthotopic bladder cancer model, systemic treatment with PEG10 antisense oligonucleotide delayed progression of T24 xenografts. In summary, elevated expression of PEG10 in MIBC may contribute to the disease progression by promoting survival, proliferation, and metastasis. Targeting PEG10 is a novel potential therapeutic approach for a subset of bladder cancers.

Predictive Factors for Residual Cancer in Second Transurethral Resection for Non-muscle-invasive Bladder Cancer.

BACKGROUND/AIM: The significance of second transurethral resection (TUR), and identification of predictive factors for residual cancer remain unrevealed. This study aimed to find residual cancer and up-staging rates, as well as predictive factors for residual cancer, in patients who undergo second TUR for non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Patients who underwent second TURs for NMIBC between 2015 and 2017, were included in the study and their clinicopathological characteristics were analyzed for predictors of residual cancer. RESULTS: Among 143 Japanese patients whose tumors were initially diagnosed as high-risk NMIBC, residual cancers detected at second TURs were, Tis: n=22 (15.4%), Ta: n=15 (10.5%) and T1: n=29 (20.3%). No patients showed up-staging from NMIBC to MIBC. The presence of carcinoma-in situ at initial TUR was an independent risk factor for any residual cancer (Tis, Ta and T1), non-flat residual cancer (Ta and T1), and flat residual cancer (Tis). CONCLUSION: The presence of carcinoma-in situ is suggested to be an independent predictor of residual cancer. This may help guide decisions to perform second TUR.