δ-Catenin, a Wnt/ß-catenin modulator, reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming.

Mutations of Wnt/ß-catenin signaling pathway has essential roles in development and cancer. Although ß-catenin and adenomatous polyposis coli (APC) gene mutations are well established and are known to drive tumorigenesis, discoveries of mutations in other components of the pathway lagged, which hinders the understanding of cancer mechanisms. Here we report that δ-catenin (gene designation: CTNND2), a primarily neural member of the ß-catenin superfamily that promotes canonical Wnt/ß-catenin/LEF-1-mediated transcription, displays exonic mutations in human prostate cancer and promotes cancer cell survival adaptation and metabolic reprogramming. When overexpressed in cells derived from prostate tumor xenografts, δ-catenin gene invariably gives rise to mutations, leading to sequence disruptions predicting functional alterations. Ectopic δ-catenin gene integrating into host chromosomes is locus nonselective. δ-Catenin mutations promote tumor development in mouse prostate with probasin promoter (ARR2PB)-driven, prostate-specific expression of Myc oncogene, whereas mutant cells empower survival advantage upon overgrowth and glucose deprivation. Reprogramming energy utilization accompanies the downregulation of glucose transporter-1 and poly (ADP-ribose) polymerase cleavage while preserving tumor type 2 pyruvate kinase expression. δ-Catenin mutations increase ß-catenin translocation to the nucleus and hypoxia-inducible factor 1α (HIF-1α) expression. Therefore, introducing δ-catenin mutations is an important milestone in prostate cancer metabolic adaptation by modulating ß-catenin and HIF-1α signaling under glucose shortage to amplify its tumor-promoting potential.

Diffusion-weighted MRI of the normal adult pancreas: the effect of age on apparent diffusion coefficient values.

AIM: To investigate and characterize the effect of age on apparent diffusion coefficient (ADC) values in the normal adult pancreas using diffusion-weighted magnetic resonance imaging (DWI). MATERIALS AND METHODS: Five hundred and fifty-nine adult patients without pancreatic disease, ranging from 20-81 years of age (mean 50.9 years; 436 men, 123 women), were included in this study. Breath-hold single-shot echo-planar DWI (b-values = 0, 500 s/mm(2)) was employed to determine the ADCs across all patients. Dependency of ADCs on age was characterized using a Spearman rank-order correlation test. RESULTS: Across the age spectrum, there was no significant correlation between ADC and age (p = 0.409). CONCLUSION: The findings of the present study suggest that the effect of age on ADCs can be excluded from the diagnosis of pancreatic diseases and design of future studies using breath-hold single-shot DWI and ADCs (as calculated with b-values of 0 and 500 s/mm(2)).

Adiponectin inhibits oxidative stress in human prostate carcinoma cells.

BACKGROUND: Emerging data suggest that obesity increases the risk of aggressive prostate cancer (PC), but the mechanisms underlying this relationship remain to be fully elucidated. Oxidative stress (OS) is a key process in the development and progression of PC. Adiponectin, an adipocyte-specific hormone, circulates at relatively high levels in healthy humans, but at reduced levels in obese subjects. Moreover, case-control studies also document lower levels of serum adiponectin in PC patients compared with healthy individuals. METHODS: Human 22Rv1 and DU-145 PC cell lines were examined for the generation of OS and detoxification of reactive oxygen species after treatment with adiponectin. Normality was confirmed using the Shapiro-Wilk test and results were analyzed using a one-way analysis of variance. RESULTS: We demonstrate that adiponectin increased cellular anti-oxidative defense mechanisms and inhibited OS in a significant and dose-dependent manner. We show that adiponectin treatment decreased the generation of superoxide anion in both cell lines, whereas the transcript levels of NADPH oxidase (NOX)2 and NOX4 increased. We also found indications of an overall anti-oxidative effect, as the total anti-oxidative potential, catalase activity and protein levels, and manganese superoxide dismutase protein levels increased significantly (P<0.05) in both cell lines after treatment with adiponectin. CONCLUSION: Lower levels of adiponectin in obese individuals may result in higher levels of prostatic OS, which may explain the clinical association between obesity, hypoadiponectinemia and PC.

Increased nucleotide polymorphic changes in the 5'-untranslated region of delta-catenin (CTNND2) gene in prostate cancer.

Cancer pathogenesis involves multiple genetic and epigenetic alterations, which result in oncogenic changes in gene expression. delta-Catenin (CTNND2) is overexpressed in cancer, although the mechanisms of its upregulation are highly variable. Here we report that in prostate cancer, the methylation of CpG islands in the delta-catenin promoter was not a primary regulatory event. There was also no delta-catenin gene amplification. However, using the single-strand conformation polymorphism analysis, we observed the increased nucleotide changes in the 5'-untranslated region of delta-catenin gene in human prostate cancer. At least one such change (-9 G>A) is a true somatic point mutation associated with a high Gleason's score, poorly differentiated prostatic adenocarcinoma. Laser capture microdissection coupled with PCR analyses detected the mutation only in cancerous but not in the adjacent benign prostatic tissues. Using chimeric genes encoding the luciferase reporter, we found that this mutation, but not a random mutation or a mutation that disrupts an upstream open reading frame, resulted in a remarkably higher expression and enzyme activity. This mutation did not affect transcriptional efficiency, suggesting that it promotes delta-catenin translation. This is the first report of delta-catenin gene mutation in cancer and supports the notion that multiple mechanisms contribute to its increased expression in carcinogenesis.

Adult prostate sarcoma: radiological-clinical correlation.

AIM: To describe the imaging features and the correlation with clinical findings of adult prostate sarcoma. MATERIALS AND METHODS: Radiological data of seven adult male patients with prostate sarcoma, documented by pathological examination of specimens, were analysed retrospectively. Radiological features were correlated with clinical and pathological findings. RESULTS: The mean age of the study population was 45.8 years (range 21-76 years). The mean value of the serum prostate specific antigen (PSA) in seven patients was 1.59 ng/ml (range 0.735-3.72 ng/ml). Five patients had leiomyosarcomas and two had rhabdomyosarcomas. The most common symptom was urinary obstruction (n=7) and the most common sign was the markedly enlarged prostate as revealed by digital rectal examination (n=7). The mean size of the tumours was 8.7 x 7.2 x 7 cm (range 6.5 x 5x 6.5 to 12.1 x 10.2 x 8.9 cm). Tumours were round (n=4), lobular (n=2), or irregular (n=1). Two tumours occupied the majority of the prostate and five occupied the entire prostate. One tumour appeared as a homogeneous mass, and six tumours contained cystic areas on computed tomography (CT) and magnetic resonance imaging (MRI). Tumours enhanced avidly on contrast-enhanced CT (n=5) and MRI (n=2). Magnetic resonance spectroscopy (MRS; n=2) showed the ratio of choline:citrate to be 1.6 and 10.75. Tumour invasion was present in the bladder (n=3) and rectum (n=1). CONCLUSIONS: Adult prostate sarcoma was characteristically shown to be a large and heterogeneous mass with rapid, hypervascular and heterogeneous enhancement on CT and MRI. The main MRS feature was a marked increase in the choline:citrate ratio. The clinical manifestations corresponded mainly to local mass effects and tumour invasion.