Ricerc@Sapienza

Background: Organochlorine pesticides (OCPs) are widely distributed in the environment and their toxicity is mostly associated with the molecular mechanisms of endocrine disruption. Among OCPs, particular attention was focused on the effects of β-hexaclorocyclohexane (β-HCH), a widely common pollutant. A detailed epidemiological study carried out on exposed population in the “Valle del Sacco” found correlations between the incidence of a wide range of diseases and the occurrence of β-HCH contamination.

STAT3 is an oncoprotein overexpressed in different types of tumors, including prostate cancer (PCa), and its activity is modulated by a variety of post-translational modifications (PTMs). Prostate cancer represents the most common cancer diagnosed in men, and each phase of tumor progression displays specific cellular conditions: inflammation is predominant in tumor's early stage, whereas oxidative stress is typical of clinically advanced PCa.

Glioblastoma, the most lethal form of brain cancer, is characterized by fast growth, migration and invasion of the surrounding parenchyma, with epithelial-to-mesenchymal transition (EMT)-like process being mostly responsible for tumour spreading and dissemination. A number of actors, including cadherins, vimentin, transcriptional factors such as SNAIL, play critical roles in the EMT process. The interleukin (IL)-6/STAT3 axis has been related to enhanced glioblastoma's migration and invasion abilities as well.

Oncosuppressor TP53 and oncogene STAT3 have been shown to engage an interplay in which they negatively influence each other. Conversely, mutant (mut) p53 may sustain STAT3 phosphorylation by displacing SH2 phosphatase while whether STAT3 could influence mutp53 has not been clarified yet. In this study we found that pharmacologic or genetic inhibition of STAT3 in both glioblastoma and pancreatic cancer cells, carrying mutp53 protein, reduced mutp53 expression level by down-regulating chaperone HSP90 as well as molecules belonging to the mevalonate pathway.

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Many natural compounds are able to control apoptotic signaling pathways particularly by modulating the NFkB and STAT3 cascades. The natural sesquiterpenes ?-caryophyllene (CRY) and beta-caryophyllene oxide (CRYO) exhibited in vitro chemosensitizing properties in different human cancer cell lines, among which liver cancer cells. Cholangiocarcinoma (CCA), that originates at the level of the intrahepatic or extrahepatic bile ducts,is one the most aggressive type of cancer for its chemotherapy resistance and invasiveness.

Prostate cancer (PCa) is a multifactorial disease characterized by the aberrant activity of different regulatory pathways. STAT3 protein mediates some of these pathways and its activation is implicated in the modulation of several metabolic enzymes. A bioinformatic analysis indicated a STAT3 binding site in the upstream region of SHMT2 gene. We demonstrated that in LNCaP, PCa cells' SHMT2 expression is upregulated by the JAK2/STAT3 canonical pathway upon IL-6 stimulation.

This editorial refers to ‘Hypertension and increased endothelialmechanical stretch promotemonocyte differentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide’ by R. Loperena et al., pp. 1547–1563.

The Tyr705 STAT3 constitutive activation, besides promoting PEL cell survival, contributes to the maintenanceof viral latency. We found indeed that its de-phosphorylation by AG490 induced KSHV lytic cycle. Moreover,Tyr705 STAT3 de-phosphorylation, mediated by the activation of tyrosine phosphatases, together with the in-crease of Ser727 STAT3 phosphorylation contributed to KSHV lytic cycle induction by TPA. We then observedthat p53-p21 axis, essential for the induction of KSHV replication, was activated by the inhibition of Tyr705 andby the increase of Ser727 STAT3 phosphorylation.