Prostate cancer (PCa), a highly incident and heterogeneous malignancy, mostly affects men from developed countries. Increased knowledge of the biological mechanisms underlying PCa onset and progression are critical for improved clinical management. MicroRNAs (miRNAs) deregulation is common in human cancers, and understanding how it impacts in PCa is of major importance. MiRNAs are mostly downregulated in cancer, although some are overexpressed, playing a critical role in tumor initiation and progression. We aimed to identify miRNAs overexpressed in PCa and subsequently determine its impact in tumorigenesis. MicroRNA expression profiling in primary PCa and morphological normal prostate (MNPT) tissues identified 17 miRNAs significantly overexpressed in PCa. Expression of three miRNAs, not previously associated with PCa, was subsequently assessed in large independent sets of primary tumors, in which miR-182 and miR-375 were validated, but not miR-32. Significantly higher expression levels of miR-375 were depicted in patients with higher Gleason score and more advanced pathological stage, as well as with regional lymph nodes metastases. Forced expression of miR-375 in PC-3 cells, which display the lowest miR-375 levels among PCa cell lines, increased apoptosis and reduced invasion ability and cell viability. Intriguingly, in 22Rv1 cells, which displayed the highest miR-375 expression, knockdown experiments also attenuated the malignant phenotype. Gene ontology analysis implicated miR-375 in several key pathways deregulated in PCa, including cell cycle and cell differentiation. Moreover, CCND2 was identified as putative miR-375 target in PCa, confirmed by luciferase assay. A dual role for miR-375 in prostate cancer progression is suggested, highlighting the importance of cellular context on microRNA targeting.

Renal cell tumors (RCTs) are the most lethal of the common urological cancers. The widespread use of imaging entailed an increased detection of small renal masses, emphasizing the need for accurate distinction between benign and malignant RCTs, which is critical for adequate therapeutic management. Histone methylation has been implicated in renal tumorigenesis, but its potential clinical value as RCT biomarker remains mostly unexplored. Hence, the main goal of this study was to identify differentially expressed histone methyltransferases (HMTs) and histone demethylases (HDMs) that might prove useful for RCT diagnosis and prognostication, emphasizing the discrimination between oncocytoma (a benign tumor) and renal cell carcinoma (RCC), especially the chromophobe subtype (chRCC). We found that the expression levels of 3 genes—SMYD2, SETD3, and NO66—was significantly altered in a set of RCTs, which was further validated in a large independent cohort. Higher expression levels were found in RCTs compared to normal renal tissues (RNTs) and in chRCCs comparatively to oncocytomas. SMYD2 and SETD3 mRNA levels correlated with protein expression assessed by immunohistochemistry. SMYD2 transcript levels discriminated RCTs from RNT, with 82.1% sensitivity and 100% specificity [area under curve (AUC) = 0.959], and distinguished chRCCs from oncocytomas, with 71.0% sensitivity and 73.3% specificity (AUC = 0.784). Low expression levels of SMYD2, SETD3, and NO66 were significantly associated with shorter disease-specific and disease-free survival, especially in patients with non-organ confined tumors. We conclude that expression of selected HMTs and HDMs might constitute novel biomarkers to assist in RCT diagnosis and assessment of tumor aggressiveness.

Proliferating cancer cells are able to reprogram their energy metabolism, favouring glycolysis even in the presence of oxygen and fully functioning mitochondria. Research is needed to validate the glycolysis-related proteins as prognostic/predictive biomarkers in urothelial bladder carcinoma (UBC), a malignancy tagged by high recurrence rates and poor response to chemotherapy. Here, we assessed GLUT1, HK2, PFKL, PKM2, phospho-PDH, and LDHA immunoexpression in 76 UBC samples, differentiating among urothelial, fibroblast, and endothelial cells and among normoxic versus hypoxic areas. We additionally studied the functional effects of the HK2 inhibitor 2-deoxy-D-glucose (2DG) in “in vitro” and “in vivo” preclinical UBC models. We showed that the expression of the glycolysis-related proteins is associated with UBC aggressiveness and poor prognosis. HK2 remained as an independent prognostic factor for disease-free and overall survival. 2DG decreased the UBC cell’s viability, proliferation, migration, and invasion; the inhibition of cell cycle progression and apoptosis occurrence was also verified. A significant reduction in tumour growth and blood vessel formation upon 2DG treatment was observed in the chick chorioallantoic membrane assay. 2DG potentiated the cisplatin-induced inhibition of cell viability in a cisplatin-resistant subline. This study highlights HK2 as a prognostic biomarker for UBC patients and demonstrates the potential benefits of using 2DG as a glycolysis inhibitor. Future studies should focus on integrating 2DG into chemotherapy design, as an attempt to overcome cisplatin resistance.

Histone methyltransferase PRMT6 plays an oncogenic role of in prostate cancer

A transcriptomic signature mediated by HOXA9 promotes human glioblastoma initiation, aggressiveness and resistance to temozolomide A transcriptomic signature mediated by HOXA9 promotes human glioblastoma initiation, aggressiveness and resistance to temozolomide