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The polycystins PC1 and PC2 are emerging as major players in mechanotransduction, a process that influences all steps of the invasion/metastasis cascade. We hypothesized that PC1 and PC2 facilitate cancer aggressiveness. Immunoblotting, RT-PCR, semi-quantitative and quantitative real-time PCR and FACS analyses were employed to investigate the effect of polycystin overexpression in colorectal cancer (CRC) cells. The impact of PC1 inhibition on cancer-cell proliferation was evaluated through an MTT assay. In vitro data were analyzed by Student's t-test. HT29 human xenografts were treated with anti-PC1 (extracellular domain) inhibitory antibody and analyzed via immunohistochemistry to determine the in vivo role of PC1 in CRC. Clinical significance was assessed by examining PC1 and PC2 protein expression in CRC patients (immunohistochemistry). In vivo and clinical data were analyzed by non-parametric tests, Kaplan-Meier curves, log-rank test and Cox model. All statistical tests were two-sided. PC1 overexpression promotes epithelial-to-mesenchymal transition (EMT) in HCT116 cells, while PC2 overexpression results in upregulation of the mTOR pathway in SW480 cells. PC1 inhibition causes reduced cell proliferation in CRC cells inducing tumor necrosis and suppressing EMT in HT29 tumor xenografts. In clinical study, PC1 and PC2 overexpression associates with adverse pathological parameters, including invasiveness and mucinous carcinomas. Moreover, PC1 overexpression appears as an independent prognostic factor of reduced recurrence-free survival (HR 5 1.016, p 5 0.03) and lowers overall survival probability, while aberrant PC2 expression predicts poor overall survival (p 5 0.0468). These results support, for the first time, a direct link between mechanosensing polycystins (PC1 and PC2) and CRC progression.Invasion and metastasis are responsible for 90% of cancerassociated mortality. While the role of biochemical signals in invasion and metastasis is well established, growing evidence reveals that mechanical signals also regulate cancer-cell

Posttranslational modifications of histones are considered as critical regulators of gene expression, playing significant role in the pathogenesis and progression of tumors. Trimethylation of histone 3 lysine 9 (H3K9me3), a repressed transcription mark, is mainly regulated by the histone lysine N-methyltransferases (HKMTs), SUV39H1 and SETDB1. The present study investigated the implication of these HKMTs in glioma progression. SUV39H1 and SETDB1 expression was upregulated in glioma cell lines (GOS-3, 1321N1, T98G, U87MG) and in glioma tissues compared to normal brain being positively correlated with grade and histological malignancy. Suppression by siRNA of the two HKMTs for 24 and 48 h resulted in significantly reduced proliferation of GOS-3 and T98G glioma cells with siSUV39H1 effects been most prominent. Furthermore, HKMTs knockdown-induced apoptosis with a high rate of apoptotic cells have been observed after siSUV39H1 and siSETDB1 for both cell lines. Additionally, suppression of the two HKMTs reduced cell migration and clonogenic ability of both glioma cell lines. Our results indicate overexpression of SETDB1 and SUV39H1 in gliomas. Treatments that alter HKMT expression affect the proliferative and apoptotic rates in glioma cells as well as their migratory and colony formation capacity. These data suggest that both HKMTs and especially SUV39H1 may serve as novel biomarkers for future therapeutic targeting of these tumors.

Transcription factors represent the point of convergence of multiple signaling pathways within eukaryotic cells. Deregulated transcription factors contribute to the pathogenesis of a plethora of human diseases, ranging from diabetes, inflammatory disorders and cardiovascular disease to many cancers, and thus these proteins hold great therapeutic potential. Direct modulation of transcription factor function by small molecules is no longer regarded a Sisyphean task, as recent work in drug discovery has revealed that transcription factors are amenable to drug inhibition. Here in we summarize, recent advances regarding the significance of transcription factors in human diseases and we discuss emerging pharmacological strategies to modulate transcription factor function. J. Cell. Biochem. 117: 2693-2696, 2016. © 2016 Wiley Periodicals, Inc.

Glioblastoma belongs to the most malignant intracranial tumors characterized by indispensable growth and aggressiveness that highly associates with dismal prognosis and therapy resistance. Tumor heterogeneity that often challenges therapeutic schemes is largely attributed to the complex interaction of neoplastic cells with tumor microenvironment (TME). Soluble immunoregulatory molecules secreted by glioma cells attract astrocytes, circulating stem cells and a range of immune cells to TME, inducing a local production of cytokines, chemokines and growth factors that reprogram immune cells to inflammatory phenotypes and manipulate host’s immune response in favor of cancer growth and metastasis. Accumulating evidence indicates that these tolerogenic properties are highly regulated by the constitutive and persistent activation of the oncogenic signal transducer and activator of transcription 3 (STAT3) protein, which impairs anti-tumor immunity and enhances tumor progression. Herein, we discuss current experimental and clinical evidence that highlights the pivotal role of STAT3 in glioma tumorigenesis and particularly in shaping tumor immune microenvironment in an effort to justify the high need of selective targeting for glioma immunotherapy.

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