COX2: A Prognostic Inflammogenic Marker Drives Cervical Carcinogenesis In Vivo Through NFκB/IAP/p53Axis

Cycloxygenase2, a prostaglandin synthesizing enzyme is a key player in inflammation-induced vasculogenesis that enables tumor growth. This study explores the central role of COX2 and its relative prosurvival proteins in evoking inflammatory events during development of an in vivo cervical cancer model upon chronic treatment with 3-methylcholanthrene (3MC; a chemical carcinogen) in virgin-female Swiss Albino mice. Chronic painting of mice cervix with 3MC solution triggered the persistent expression and activity of COX2; eventuating in overexpression of major prosurvival molecules (NFκB, XIAP, survivin, GM-CSF1) and proliferative antigens (Ki67, PCNA). COX2-arbitrated prosurvival signaling subsequently deranged the expression profiles of tumor supressor proteins (p53/Acetyl-p53, p21, Rb) within the cervix. COX2 helmed molecular alterations successively surged leukocyte influx within cervix; catering in localized inflammation which gradually distorted its tissue architecture. Cervical carcinogenesis was further braced by higher levels of systemic-ROS and RNS, escalated iNOS activity and compromised anti-oxidant enzyme capacities, which were accompanied by splenomegaly. Additionally, circulation of blood-leucocytes with damaged DNA throughout the mice body, envisaged the impact of cervix-limited inflammation upon the mice physiology. Conclusively, the present study deciphered the role of COX2 effectuated NFκB/IAP/p53 functions in sequestering the contributors of localized and systemic inflammogenesis for propelling 3MC-mediated cervical carcinogenesis in vivo.

Bayesian copy number detection and association in large-scale studies

Germline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging. We developed an approach called CNPBayes to identify latent batch effects, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. We demonstrate this approach in a Pancreatic Cancer Case Control study of 7,598 participants where the major sources of technical variation were not captured by study site and varied across the genome. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Supressor Candidate 3 (TUSC3). This study provides a robust Bayesian inferential framework for estimating copy number and evaluating the role of copy number in heritable diseases.

Mir-30a and lin28b conform a double-negative feedback loop regulated by pi3k modulating thyroid cancer progression

Background. Our recent results showed that tumor supressor miR-30a is firmly downregulated in Thyroid carcinomas. On the other hand, recent studies showed RNA- and DNA- binding proteins LIN28B and HMGA2 induce EMT, thus playing an important role in dedifferentiation and cancer malignification. Finally, latterly several authors agreed on the importance of a robust activation of PI3K for thyroid cancer emergency and progression.Aim: to study the link between the emergency of LIN28B and HMGA2, miR-30a silencing and PI3K hyperactivation, and to determine their effect on thyroid cancer progression.Methors. MiRNA targets computational predictions were performed with MiRanda algorythm. LIN28B and miR-30a expression vectors were transfected in ATC derived and normal thyroid cell lines; mRNA and protein levels were determined by qPCR, Luciferase and Western Blot. Invasion, proliferation and cell cycle assays were performed in Transwell, cell counter, and FACScan respectively.Results. MiRanda algorythm identified multiple miR30a recognition elements in all LIN28B, HMGA2 and PI3K effectors. LIN28B expression correlated with PI3K activating mutations in ATC derived cell lines. Overexpression of miR30a resulted in LIN28B, HMGA2, and several PI3K effectors silencing, and in an increase in p27(Kip) protein levels. Inversely, LIN28B overexpressing cells showed a decrease in miR30a levels and an increased expression of HMGA2 and PI3K effectors. The general outcome was a significant decrease in invasion and proliferation in miR-30a overexpressing cells and, conversely, an increase in these parameters by LIN28B.Conclusions. These data suggest the existence of a PI3K regulated feedback with a double-negative loop between miR-30a and LIN28B. Here, PI3K activation acts to switch the steady states. Initially, high miR-30a levels repress LIN28B expression. After PI3K is activated, LIN28B is produced and miR-30a is repressed. This state reinforces PI3K hyperactivation. Thus, the feedback implements a tumoral gene expression shift, contributing to thyroid cancer progression.