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This paper provides a brief explanation and a detailed documentation of the current version of the Quarterly Japanese Economic Model (Q-JEM), which has been developed and constantly updated since the mid-2000s at Research and Statistics Department, Bank of Japan. Q-JEM is a large-scale hybrid-type macroeconomic model that pursues both long-run theoretical coherence and short-run empirical validity, as is the Federal Reserve Board's FRB/US model. The model captures various aspects of Japan's economy, including inflation dynamics, the zero lower bound on nominal interest rates, linkages with overseas economies, and the effects of population aging and declining potential economic growth.

Mucosal T cells are the most likely direct effectors in host anti-human papillomavirus adaptive immunity and regression of cervical intraepithelial neoplasia (CIN) lesions. There are no studies addressing intraepithelial lymphocytes (IELs) in CIN lesions.Cervical lymphocytes were collected using cytobrushes from patients with CIN and analyzed by FACS analysis. Comparisons were made between populations of cervical T cells in CIN regressors and non-regressors.A median of 74% of cervical lymphocytes were CD3(+) T cells. Populations of integrin αEβ7(+) IEL in CIN lesions varied markedly among patients (6-57%). Approximately half of integrin β7(+) T cells were CD45RA-negative memory T cells. The number of integrin αEβ7(+) cells among cervical T cells was significantly higher in CIN regressors when compared to non-regressors.Higher cervical IEL numbers are associated with spontaneous regression of CIN. Accumulation of cervical integrin αEβ7(+) IEL may be necessary for local adaptive effector functions.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression, primarily at the post-transcriptional level. Growing evidence suggests that miRNAs function as oncogenes or tumor suppressors in human cancers. The down-regulation of miR-145 has been reported in many types of human cancer, including prostate cancer (PC), suggesting that miR-145 functions as a tumor suppressor. Using the PC cell lines, PC3 and DU145, gain-of-function assays revealed that miR-145 transfection inhibited cell proliferation, migration and invasion. Fascin homolog 1 (FSCN1), an actin-bundling protein, is a candidate target gene of miR-145 based on genome-wide gene expression analysis. A luciferase reporter assay showed a significantly decreased signal at two miR-145 target sites at the 3'UTR of FSCN1, suggesting that miR-145 directly regulates FSCN1. In FSCN1 loss-of-function assays, cell growth, migration and invasion were all inhibited, implying that FSCN1 is associated with the progression of PC. The identification of tumor suppressive miRNAs and their target genes could provide new insights into the potential mechanisms of prostate carcinogenesis.

We report two cases of spontaneous urinary rupture caused by primary ureteral or renal pelvic cancer. Case 1: A 76-year-old man presented with macrohematuria and left back pain. Magnetic resonance imaging showed left middle ureteral tumor and rupture of upper ureter. Left nephroureterectomy was performed. Histological findings revealed urothelial carcinoma, G2, pT1, lt-u0, ew0, ly0, v1. At five months postoperatively, he died of lymph node metastases after two courses of adjuvant chemotherapy. Case 2: A 59-year-old man presented with macrohematuria and left back pain. Computer tomography showed left renal pelvic tumor with extravasation of urine. Left nephroureterectomy was performed. Examination of surgical specimen revealed a renal pelvic tumor and rupture hole at the renal pelvis. Histological finding revealed urothelial carcinoma, G3, pT3, lt-u0, ly0, v1. One course of adjuvant chemotherapy was performed. At six months postoperatively, he was free from recurrence.

In the last decade, abundant evidence has suggested that the insulin-like growth factor (IGF) family comprises a multi-component network of molecules involved in the regulation of both physiological and pathological growth processes in the prostate. The IGF axis plays an important role in the tumorigenesis and neoplastic growth of prostate cancer. Epidemiological observations indicate that circulating IGF-I levels are positively associated with increased risk of prostate cancer. Activation of IGF-I receptor (IGF-IR) by IGF-I has mitogenic and anti-apoptotic effects on normal and malignant prostate cells. Therapeutic alternatives in men with progressive prostate cancer after androgen ablation are very limited and more effective therapies are needed for such patients. Inactivation of the IGF-I axis represents a potential target to treat androgen-independent prostate cancer. This review addresses epidemiological studies of IGF-I and therapeutic strategies including reduction of IGF-I levels, inhibition of IGF-IR and the signaling mechanisms involved.

Macroeconomic models are effective tools for central banks in economic projection, including risk assessment. In recent years, a multiple-model approach called the "Suite of Models" has become popular with central banks. This approach advocates the use of multiple models for several purposes, including checks of the robustness of projections. This idea has encouraged major central banks to use different types of models. These include hybrid-type models, which pursue short-run empirical coherence and long-run theoretical consistency, and Dynamic Stochastic General Equilibrium (DSGE) models, which place greater emphasis on theory. At the Bank of Japan, a new hybrid-type model named Q-JEM (Quarterly-Japanese Economic Model) has been recently added to the Bank's suite of models. A suite of models is useful for forecasting and for policy analysis. The use of models, however, requires sufficient understanding on the properties and limitations of each model.

We investigated the clinical efficacy of milnacipran (Serotonin-Noradrenalin Reuptake Inhibitor: SNRI) in prostate cancer patients who suffer from hot flushes. Our study included 12 patients who had taken hormone therapy for at least 3 months prior to the trial entry. All patients had severe hot flushes at least 3 times daily. Among 12 patients, 7 subjects received milnacipran 25 mg orally once a day and 5 subjects received 50mg once a day. The questionnaire was used to measure the frequency and severity of hot flushes at baseline, and at 6 and 12 weeks. At 12 weeks, 9 patients were available for the evaluation. Four patients received 50 mg per day and 5 patients received 25 mg per day. The patients withor =50% decrease in baseline hot flash score were observed in 3 out of 4 who received 50 mg and 2 out of 5 who received 25 mg per day. The frequency of hot flushes had significantly decreased at the 12 weeks period than the baseline in the milnacipran 50 mg per day treatment group (p0.05, paired t-test). Adverse events were observed in 3 patients: 2 cases of nausea and 1 case of constipation. However, all of them were mild to moderate. These results indicated that milnacipran 50 mg per day therapy is effective in the treatment of hot flushes, which is the side effect of hormone therapy for prostate cancer.

Venous air embolism is a rare complication during transurethral resection of the prostate (TURP). We report a case of air embolism during TURP under general anesthesia in a 56-year-old man. Incorrect assembly of the resectoscope-drain aspiration system caused rapid entrainment of air into the vein of the prostate bed. Rapid recognition of the condition and prompt treatment are required.

The aim of the present study was to evaluate the clinical value of the pretreatment serum testosterone (T) level as a potential predictor of prostate cancer risk in screening for prostate cancer.The subjects were 420 patients suspected of having prostate cancer who underwent prostate biopsy, and whose pretreatment T levels were recorded. We checked for association between the presence of prostate cancer and the following clinical factors: pretreatment serum T level, age, pretreatment prostate-specific antigen (PSA) level, digital rectal examination findings, ratio of free to total PSA, prostate volume, and PSA density (PSAD).Overall, there was no significant difference in mean pretreatment T level between patients diagnosed with cancer (3.9+/-2.4 ng/ml) and patients diagnosed with benign prostate disease (BPD; 3.7+/-1.7 ng/ml); diagnosis was based on prostate biopsy. However, among patients with PSA10 ng/ml, the pretreatment T level was significantly higher in patients diagnosed with prostate cancer (4.2+/-2.6 ng/ml) than in patients diagnosed with BPD (3.6+/-1.4 ng/ml) (p=0.007); a similar trend was observed among patients with PSAD0.15 ng/ml/cc. Multivariate analysis indicated that pretreatment T level was an independent significant predictor of positive prostate biopsy (p=0.020). Additionally, the serum T level was significantly lower in patients with a Gleason scoreor=7 (3.7+/-2.1 ng/ml) versus a score7 (4.2+/-1.7 ng/ml) (p=0.030). Also, serum T levels were significantly higher in well-differentiated prostate cancer (4.8+/-2.1 ng/ml) versus moderately differentiated (3.8+/-1.3 ng/ml) or poorly differentiated (3.7+/-1.4 ng/ml) (p0.01).Among relatively low-risk patients, serum T level was an independent significant predictor of positive prostate biopsy, suggesting that the efficiency of prostate cancer screening can be improved by including measurement of serum T level.

To evaluate in a retrospective study the improvements in prostate cancer detection rates for patients with a prostate gland larger than 30 cm3 using a systematic 14-core biopsy strategy compared with a systematic 8-core biopsy.We retrospectively assessed 273 patients with screened prostate-specific antigen (PSA) levels of 3.0 to 50.0 ng/mL. A total of 204 patients with a prostate volume of 30 cm3 or larger and with normal digital rectal examination findings were enrolled in this study. Of the 204 patients, 110 underwent 8-core biopsy and 94 underwent 14-core biopsy of the prostate. We compared the cancer detection rates of prostate biopsy between the 8 and 14-core groups using total PSA, free/total PSA ratio, PSA density, and PSA density adjusted by transition zone volume. We also analyzed the Gleason grade of the biopsy core and the radical prostatectomy specimens.Of the 204 patients, 40 (19.5%) were identified as having prostate adenocarcinoma. The cancer detection rate for the 8 and 14-core groups was 14.5% (16 of 110 patients) and 24.5% (23 of 94 patients), respectively. The 14-core biopsy had a statistically significant greater cancer detection rate than did the 8-core group in patients with a prostate volume of 30 to 40 cm3 (36.7% versus 11.8%, respectively, P0.05) and a PSA density adjusted by transition zone volume of 0.38 ng/mL/cm3 or greater (47.8% versus 20.0%, respectively, P0.05). The difference in tumor grade between the 8 and 14-core biopsy samples was not statistically significant.The 14-core prostate needle biopsy is a recommended method for detecting prostate cancer in a large-volume prostate gland without increasing the risk of complications.

Heat shock protein 27 (Hsp27) is a chaperone implicated as an independent predictor of clinical outcome in prostate cancer. Our aim was to characterize changes in Hsp27 after androgen withdrawal and during androgen-independent progression in prostate xenografts and human prostate cancer to assess the functional significance of these changes using antisense inhibition of Hsp27. A tissue microarray was used to measure changes in Hsp27 protein expression in 232 specimens from hormone naive and posthormone-treated cancers. Hsp27 expression was low or absent in untreated human prostate cancers but increased beginning 4 weeks after androgen-ablation to become uniformly highly expressed in androgen-independent tumors. Androgen-independent human prostate cancer PC-3 cells express higher levels of Hsp27 mRNA in vitro and in vivo, compared with androgen-sensitive LNCaP cells. Phosphorothioate Hsp27 antisense oligonucleotides (ASOs) and small interference RNA potently inhibit Hsp27 expression, with increased caspase-3 cleavage and PC3 cell apoptosis and 87% decreased PC3 cell growth. Hsp27 ASO and small interference RNA also enhanced paclitaxel chemosensitivity in vitro, whereas in vivo, systemic administration of Hsp27 ASO in athymic mice decreased PC-3 tumor progression and also significantly enhanced paclitaxel chemosensitivity. These findings suggest that increased levels of Hsp27 after androgen withdrawal provide a cytoprotective role during development of androgen independence and that ASO-induced silencing can enhance apoptosis and delay tumor progression.

We studied the efficiency of second or third line hormonal therapy for prostate cancer relapse after hormone therapy.The study included 70 patients with advanced prostate cancer treated with hormonal therapy, androgen deprivation monotherapy or maximum androgen blockade including surgical or medical castration combined with steroidal antiandrogen, 100 mg chlormadinone acetate daily or nonsteroidal antiandrogens, 375 mg flutamide (FLT) daily or 80 mg bicalutamide (BCL) daily. When the disease relapsed, we discontinued the antiandrogen and evaluated the patient for the antiandrogen withdrawal syndrome (AWS). Thereafter we administrated an alternative antiandrogen and evaluated its effect.The incidence of the AWS after first, second and third line hormonal therapy was 35.8%, 8.0% and 0%, respectively. The efficiency of subsequent hormonal therapy was not related to the occurrence of the AWS. Nonsteroidal antiandrogens as alternative therapies for disease relapse from primary therapy were effective in second line (FLT 38.1%, BCL 44.4%) or in third line (FLT 30.0%, BCL 28.6%) hormonal therapy. Of 5 (80%) patients who responded to second line therapy 4 (80%) had effective third line therapy, while only 1 of 12 (8.3%) second line nonresponders had effective third line therapy (p = 0.003). The survival of second line responders was significantly better than that of nonresponders (5-year survival rate 92.3% vs 23.9%, p0.001), indicating a potential predictive value for second line responsiveness. No significant clinical factor identified second line responsiveness.Subsequent nonsteroidal antiandrogen therapies were effective against prostate cancer relapse after hormonal therapy. The response to third line therapy was more effective and survival was improved from the time of first line therapy relapse among second line responders than that in nonresponders. Our data support the notion that second line responders are androgen independent but still hormonally sensitive.

To evaluate the occurrence and prevalence of microdeletions in the gamma chromosome of patients with azoospermia.DNA from 29 men with idiopathic azoospermia was screened by polymerase chain reaction (PCR) analysis with a set of gamma chromosome specific sequence-tagged sites (STSs) to determine microdeletions in the gamma chromosome.Deletions in the DAZ (deleted in azoospermia) loci sgamma254 and sgamma255 were found in three patients with idiopathic azoospermia, resulting in an estimated frequency of deletions of 10.7% in idiopathic azoospermia men.We conclude that PCR analysis is useful for the diagnosis of microdeletions in the Y chromosome, which is important when deciding the suitability of a patient for assisted reproductive technology such as testicular sperm extracion-intracytoplasmic sperm injection (TESE-ICSI).

BACKGROUND: Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer death among men in developed countries. Disease progression and the development of hormone refractory disease remain major cause of cancer-related death.Understanding the molecular mechanisms of PCa progression and metastatic pathways using currently available genomic approaches would help to improve therapies for and prevention of the disease. Our recent study of microRNA (miRNA) expression signature of PCa has revealed that microRNA-218 (miR-218) was significantly downregulated in cancer tissues, suggesting that miR-218 may be a putative tumor-suppressive miRNA in PCa. The aim of this study was to investigate the functional significance of miR-218 in PCa and to identify novel miR-218-regulated cancer pathways and target genes involved in PCa oncogenesis and metastasis.METHODS: The expression levels of miR-218 were validated using real-time RT-PCR using PCa clinical specimens and cell lines (PC3 and DU145). Cell proliferation, migration and invasion assays were performed to investigate the functional significance of miR-218 and its target gene, LIM and SH3 protein 1 (LASP1) in PCa cell lines.Cells were transfected with mature miR-218 or si-LASP1 by reverse transfection methods. Genome-wide gene expression data and in silico analysis were used to identify the molecular pathways and putative targets regulated by miR-218.The luciferase reporter assay was applied to identify the actual binding site of miR-218 in target gene. The expression of LASP1 was investigated by immunohistochemistry.RESULTS: The expression levels of miR-218 were significantly downregulated in PCa tissues and PCa cell lines. Restoration of miR-218 in PCa cell lines revealed that miR-218 significantly inhibited cancer cell migration and invasion.Gene expression studies and luciferase reporter assays showed that LASP1 was directly regulated by miR-218. Silencing LASP1 resulted in significant inhibition of cell migration and invasion in PCa cells.The expression of LASP1 was upregulated in cancer tissues as demonstrated byimmunohistochemical staining.CONCLUSIONS: The miR-218 was frequently reduced in PCa clinical specimens and appeared to function as a tumor suppressor through regulation of oncogenic LASP1. The identification of novel molecularpathways and targets regulated by the tumor suppressive miRNAs may lead to a better understanding of PCa progression and metastasis, and the development of new therapeutic strategies to treat this disease. Citation Format: Rika Nishikawa, Yusuke Goto, Takashi Kinoshita, Shinichi Sakamoto, Takeshi Chiyomaru, Hideki Enokida, Satoko Kojima, Masayuki Nakagawa, Yukio Naya, Tomohiko Ichikawa, Naohiko Seki. Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion via targeting LASP1 in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4371. doi:10.1158/1538-7445.AM2014-4371

Cancer associated fibroblasts (CAFs) are responsible for tumor growth, angiogenesis, invasion, and metastasis. Matrix metalloproteinase (MMP)-9 secreted from cancer stroma populated by CAFs is a prerequisite for cancer angiogenesis and metastasis. Omega-3 polyunsaturated fatty acids (omega-3 PUFA) have been reported to have anti-tumor effects on diverse types of malignancies. Fat-1 mice, which can convert omega-6 to omega-3 PUFA independent of diet, are useful to investigate the functions of endogenous omega-3 PUFA. To examine the effect of omega-3 PUFA on tumorigenesis, TC-1 cells, a murine epithelial cell line immortalized by human papillomavirus (HPV) oncogenes, were injected subcutaneously into fat-1 or wild type mice. Tumor growth and angiogenesis of the TC-1 tumor were significantly suppressed in fat-1 compared to wild type mice. cDNA microarray of the tumors derived from fat-1 and wild type mice revealed that MMP-9 is downregulated in fat-1 mice. Immunohistochemical study demonstrated immunoreactivity for MMP-9 in the tumor stromal fibroblasts was diffusely positive in wild type whereas focal in fat-1 mice. MMP-9 was expressed in primary cultured fibroblasts isolated from fat-1 and wild type mice but was not expressed in TC-1 cells. Co-culture of fibroblasts with TC-1 cells enhanced the expression and the proteinase activity of MMP-9, although the protease activity of MMP-9 in fat-1-derived fibroblasts was lower than that in wild type fibroblasts. Our data suggests that omega-3 PUFAs suppress MMP-9 induction and tumor angiogenesis. These findings may provide insight into mechanisms by which omega-3 PUFAs exert anti-tumor effects by modulating tumor microenvironment.

Objective: The Bcl6 gene encodes a sequence-specific transcriptional repressor and is ubiquitously expressed in adult murine tissues including heart muscle. The objective of this study was to examine the role of Bcl6 in cardiac myocytes. Method: We developed Bcl6 -deficient (Bcl6−/−) mice and histologically examined hearts from these mice. Results: Massive myocarditis with eosinophilic infiltration occurred in Bcl6−/− mice after 4–6 weeks of age. Since expression of the Bcl6 gene was induced in normal cardiac myocytes after 2 weeks of age and thereafter detected through adulthood, loss of Bcl6 in mature cardiac myocytes may be related to the induction of eosinophilic myocarditis. To examine the effects of eosinophils from Bcl6−/− mice on normal hearts, bone marrow cells from Bcl6−/− mice were adoptively transferred into sublethally irradiated RAG1-deficient mice. Although massive eosinophilic infiltration was detected in conjunctivas and spleens from the chimeric mice, myocarditis was never observed. Electron microscopic analysis of cardiac myocytes from Bcl6−/− mice revealed a spectrum of degenerative changes prior to eosinophilic infiltration. Conclusion: Bcl6 may not be essential for the maturation of cardiac myocytes but may play a role in protecting mature cardiac myocytes from eosinophilic inflammation.

The BCL6 gene, which has been identified from the chromosomal translocation breakpoint in B-cell lymphomas, functions as a sequence-specific transcriptional repressor. We cloned a novel Bcl6-homologous gene, BAZF (encoding Bcl6-associated zinc finger protein). The predicted amino acid sequence of BAZF indicated that the BTB/POZ domain and the five repeats of the Kruppel-like zinc finger motif are located in the NH2-terminal region and the COOH-terminal region, respectively. BAZF associated with Bcl6 at the BTB/POZ domain and localized in the nucleus. Since zinc finger motifs of BAZF were 94% identical to those of Bcl6 at the amino acid level, BAZF bound specifically to the DNA-binding sequence of Bcl6 and functioned as a transcriptional repressor. The repressor activity was associated with both the BTB/POZ domain and the middle portion of BAZF. The 17-amino-acid sequence in the middle portion was completely conserved between BAZF and Bcl6, and the conserved region was critical for the repressor activity. Expression of BAZF mRNA, like that of Bcl6 mRNA, was induced in activated lymphocytes as an immediate-early gene. Therefore, the biochemical character of BAZF is similar to that of Bcl6 although the tissue expression pattern of BAZF differs from that of Bcl6. This is apparently the first report of a gene family whose members encode zinc finger proteins with the BTB/POZ domain.

e15521 Background: Almost renal cancers are renal cell carcinoma (RCC). Short term treatment results are excellent with 90% or more disease specific and overall survival at 5year. Follow up schedule of NCCN guideline for low risk group was up to 5 years after surgery. Although, we have experienced late recurrence in such a low risk cases. Therefore, we examined the recurrence of T1 and T2 renal carcinoma in our institute, retrospectively. Methods: Between March 1997 and September 2009, 580 patients with renal carcinoma were undergone surgical excision of renal tumor at Chiba University Hospital. In these cases,349 patients were T1 without metastasis. We analyzed the clinopathological deta of these 349 patents. Univariate and multivariate analysis were conducted to identify the prognostic factor of T1a or T1b patients with surgical excision. Results: During follow up, 5, 10, 15 and 20 years overall survival rate(OS) of T1a were 98.1%, 98.1%, 90.6% and 90.6%, respectively. Those of T1b were 95.8%, 92.7%, 90.2% and 90.2%, respectively. 5, 10, 15 and 20 years disease free survival rate (DFS) of T1a was 93.1%, 86.6%, 76.8%, 38.4%, respectively. 5, 10, 15 and 20 years DFS of T1b was 82.9 %, 66.5%, 58%, 50.8% ,respectively. 33% of metastasis was lung 10% of metastasis was contralateral kidney. Conclusions: 20 years OS of T1a was an excellent, however, 20 years DFS was 38.4%. Life expectancy of Japanese men and women in 2009 were 79.59 years old and 86.44 years old. Almost patients with T1a renal carcinoma might have a late recurrence. We think it is necessary to long follow p schedule for T1 cancer and partial nephrectomy is recommended.

(Background) Prostate cancer (PCa) is the most frequently diagnosed and second leading cause of cancer death among men in developing countries. Hormone-refractory PCa is currently difficult to treat and most clinical trials for advanced PCa have shown limited benefits, with disease progression and metastasis to bone or other sites. Thus, new prognostic markers and effective treatment strategies are urgently needed. Our expression signatures of human cancer including prostate cancer revealed that the expression of microRNA-1 (miR-1) and microRNA-133a (miR-133a) were significantly reduced in cancer cells. In human genome, miR-1 and miR-133a located same chromosomal regions called cluster. In this study, we investigated the functional significance of miR-1 and miR-133a and identified the novel molecular targets regulated by miR-1 and miR-133a commonly in PCa. (Methods) Cell proliferation, invasion and migration assays were performed by restoration of mature miR-1 and/or miR-133a in PCa cell lines (PC3 and DU145). Genome-wide gene expression analysis was performed to identify the molecular targets of miR-1 and miR-133a by microarray methods. A luciferase reporter assay was used to identify the actual binding site between miR-1 and miR-133a and its candidate target genes. Cell proliferation, invasion and migration assays were performed to investigate the targets genes in PCa cell lines. To investigate of expression of candidate target gene, immunohistochemistry was performed by using PCa tissue microarray. (Results) Restoration of miR-1 and/or miR-133a significantly inhibited cell proliferation, migration and invasion in cancer cells. Genome-wide molecular targets search and luciferase reporter assay showed that 6 genes: Transgelin2 (TAGLN2), WD repeat domain 78 (WDR78), chromosome 4 open reading frame 34 (C4orf34), purine nucleoside phosphorylase (PNP), LAG1 homologue, ceramide synthase 2 (LASS2) and syntaxin binding protein (STXBP4) had putative target sites of both miR-1 and miR-133a in their 3′UTR. Among them, PNP mRNA was highly expressed in the PCa clinical specimen compered with non-PCa tisses. The mRNA and protein expression levels of PNP were markedly downregulated in miR-1 and miR-133a -transfected PCa cells. A luciferase reporter assay suggested that miR-1 and miR-133a directly bind to specific sites on 3′UTR of PNP mRNA. Silencing of the target genes inhibited cell proliferation, migration, and invasion in PCa cells. Immunohistochemistry showed that PNP expression level was significantly higher in PCa than normal prostate tissues. (Conclusions) miR-1 and miR-133a function as tumor suppressor in PCa. PNP was directly regulated by tumor suppressive miR-1 and miR-133a commonly. PNP may function as oncogenes in PCa. Tumor suppressive miR-1 and miR-133a mediates novel molecular targets provide new insights of molecular mechanisms of PCa oncogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3166. doi:1538-7445.AM2012-3166

Prostate cancer remains one of the most prevalent cancers and a major cause of morbidity and mortality in the western world. Disease progression and the development of hormone refractory disease remain major causes of cancer-related death. The understanding of the new molecular pathways of hormone refractory would be helpful in improving diagnosis and therapy of the disease. microRNAs (miRNAs) are small, non-coding RNAs with a length of approximately 22 nucleotides. They regulate gene expression by promoting mRNA cleavage and at the posttranscriptional level by translational suppression. They play important roles in various biological and metabolic processes, including development, differentiation, signal transduction, cell maintenance, and cancer. Bioinformatic predictions indicate that miRNAs regulate more than 30% of the protein coding genes. It is estimated that approximately 1,000 miRNAs exist in the vertebrate genome. An important role for miRNAs in the development of cancer has emerged in recent years. miRNAs are aberrantly expressed in many human cancers, and they may function as oncogenes or tumor suppressors. Up-regulated miRNAs could function as oncogenes by negatively regulating tumor suppressor genes, while down-regulated miRNAs could act as tumor suppressors, inhibiting cancers by regulating oncogenes. Down-regulation of miR-145 has been reported in many types of human cancer, including prostate cancer, suggesting that miR-145 function as a tumor suppressor. In this study, we focused on target identification of miR-145 in prostate cancer, based on gene-wide gene expression analysis of miR-145 transfection cells. According to our expression analysis showed that down-regulated genes (FSCN1, UNG and EIF4EBP2) were identified. Loss-of-function assays revealed that FSCN1 inhibited cell proliferation, migration, and invasion in PC3 and DU145 cells, suggesting FSCN1 function as an oncogene. The identification of tumor suppressive miRNA and their target genes could provide new insights into potential mechanisms of prostate carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 123. doi:10.1158/1538-7445.AM2011-123

The Bcl6 gene is ubiquitously expressed in adult murine tissues and its product functions as a sequence-specific transcriptional repressor. Bcl6-deficient mice displayed eosinophilic inflammation caused by overproduction of Th2 cytokines. The regulatory mechanism of those cytokine productions by Bcl6 is controversial. When CD4+ T cells from Bcl6-deficient and lck-Bcl6-transgenic mice were stimulated with anti-CD3 Abs, production of IL-5 among Th2 type cytokines was preferentially affected by the amount of Bcl6 in the T cells. We found a putative Bcl6-binding sequence (IL5BS) on the 3′ untranslated region in the murine and human IL-5 genes, and specific binding of Bcl6 protein to the sequence was confirmed by gel retardation assay and chromatin immunoprecipitation assay. The binding activity of endogenous Bcl6 was transiently diminished in Th2 but not in Th1 clones after anti-CD3 stimulation. The exogenous Bcl6 repressed expression of the reporter gene with the IL5BS in K562 cells and the repressor activity was lost by a point mutation of the IL5BS. Furthermore, the IL5BS was required for Bcl6 to repress expression of the IL-5 cDNA. Thus, the IL5BS may act as a silencer element for Bcl6 to repress expression of the IL-5 gene.

Bcl6 protein has been detected in testicular germ cells, mainly spermatocytes, of normal mice, but its physiological role is largely unknown. The number of spermatozoa in the cauda epididymis of adult Bcl6-deficient (Bcl6−/−) mice is lower than that of Bcl6+/+ mice. We have found numerous apoptotic spermatocytes at the metaphase I stage with induction of Bax protein in adult Bcl6−/− testes. Developmentally, the incidence of germ cell apoptosis of Bcl6−/− mice was similar to that of Bcl6+/+ mice until six weeks of age and increased after eight weeks of age. The incidence of apoptosis in heterozygous Bcl6+/− mice was also higher than that of Bcl6+/+ mice. Since the activated form of p38 MAP kinase was detected in spermatocytes of adult Bcl6−/− mice, the germ cell apoptosis may be induced by stressors. Treatment of testes of adult Bcl6+/+ mice with a mild hyperthermia resulted in germ cell apoptosis predominantly in metaphase I spermatocytes with induction of Bax protein and activation of p38 MAP kinase and this apoptosis mimics that in adult Bcl6−/− mice. Thus, Bcl6 may play a role as a stabilizer in protecting spermatocytes from apoptosis induced by stressors.