Epithelial-mesenchymal-transition (EMT) in response to TGFβ contributes to normal development, wound healing and tumor progression. The present study provides evidence for a critical role of β5-integrin in the TGFβ-induced EMT and the tumorigenic potential of carcinoma cells. We show that the αvβ-integrin subunits are upregulated during the TGFβ-induced EMT and this response requires Smad transcription factors. Depletion of αv-integrin by siRNA blocked the EMT response whereas knock-down of β1-integrin had no effect. Importantly, depletion of β5-integrin blocked the TGFβ-induced EMT impairing adhesion to cell-matrix and integrin signaling, but did not change expression of E-cadherin and TGFβ-target genes. Accordingly, the EMT process and integrin signaling were blocked by cRGD peptide interfering with cell-matrix adhesion or by inhibition of focal adhesion kinase, indicating the importance of β5-integrin-mediated adhesions in EMT. Finally, depletion of β5-integrin significantly reduced invasiveness of breast carcinoma cells. Thus, the β5-integrin adhesions contribute to the TGFβ-induced EMT and the tumorigenic potential of carcinoma cells.

JunB helps set in motion the transcriptional program necessary for the epithelial–mesenchymal transition and tissue fibrosis in response to TGF-β.

The process of epithelial‐mesenchymal transition (EMT) is important in tissue fibrosis, wound healing and cancer. Transforming growth factor beta (TGF‐β) induces EMT and fibrotic proteins in a variety of responsive cells via a mechanism that is not fully understood. This study identifies a critical role of JunB in the EMT and fibrotic process in response to TGF‐β. Knock‐down of the immediate‐early response gene JunB by siRNA abrogates TGF‐β‐induced disruption of epithelial cell junctions, formation of actin fibers, focal adhesions and expression of fibrotic proteins. JunB contributes to Smad‐mediated repression of Id2 helix‐loop‐helix protein but does not affect the induction of Hmga2, Snail and Slug. Knock‐down of JunB abolishes up‐regulation of ATF3, which is required for Id2 repression. Importantly, JunB contributes to the TGF‐β‐induced fibrotic response by regulating expression of fibronectin, fibulin‐2, tropomyosin (Tpm1) and β3‐integrin, which play critical roles in matrix deposition, cell‐matrix adhesion and actin stress‐fibers. In summary, JunB provides important input in setting the transcriptional program of the EMT and fibrotic responses to TGF‐β. Thus, JunB represents an important target in diseases associated with EMT, including cancer and fibrosis. Grant Funding Source: Supported by R01 CA95263

Since 2010, over 425 Italian medical students participated in D'Youville College's (DYC's) Giovanni Mazzotti Anatomy Conference (GMAC), named in honor of the late president of the Medical School of Bologna and the Italian Anatomy Society. In Italy, students rarely dissect cadavers. Instead, models, drawings, and computer‐generated images are utilized. Conference participants were selected by their professors at their corresponding Italian medical universities for their excellent anatomy competency and proficiency in English.After careful review of the previous five years of data from similar populations, modifications were made to improve data collection and validate results. For this analysis, the written examinations were scrutinized by faculty in the US and Italy for proper word choice and grammar. Exams were available to each student in both English and Italian. The written exams were identical for pre‐ and post‐testing. The practical exams contained identical content for pre‐ and post‐testing, utilizing different cadavers and a re‐arrangement of question order. Results, including scores, were only provided to the students after completion of the conference. Data analysis focused on comparing learning in three specific areas comprising V (viscera), H (head and neck) and E (extremities). After ~100 hours of available laboratory time, pre‐ and post‐examination results were compared. On average, a significant improvement was observed in individual written exam scores by 9% (n=60; p<0.001), practical knowledge scores increased 23% (n=60; p<0.001) with combined anatomical knowledge scores averaging a 16% increase (n=60; p<0.001). Overall, the cadaver dissection experience increased the practical as well as theoretical knowledge of these elite high performing medical students.We expect this collaboration to continue providing a more comprehensive analysis. We thank Todd Stevens and Russ Gullekson for their work with the Italian students in the anatomy laboratory. We also thank our collaborators, Professors Falconi & Manzoli (U of Bologna), Zecchi & Orlandini (U of Florence), Papa (U of Naples), Nori (U of Salerno), Sette (Rome's Tor Vergata) and Forni (U of Pisa).Support or Funding InformationSupported by the GMAC and approved through the IRB of DYC.

Transforming growth factor‐β1 (TGF‐β1) is a member of the TGF‐β superfamily of cytokines, which are involved in a wide variety of biological functions such as proliferation, differentiation, migration, and apoptosis. TGF‐β1 binds to a receptor complex and stimulates a set of signaling events leading to changes in gene expression and cell behavior. TGF‐β1 specifically has been shown to be a key player in wound repair and modulation of the immune response. Microarray analysis of normal mouse mammary epithelial cells (NMuMG) treated with TGF‐β1, indicated that the interleukin‐1 family member interleukin‐33 (IL‐33) is repressed by TGF‐β1. IL‐33 is passively released following tissue damage and functions as an alarmin, alerting the immune system to the presence of tissue damage. The goal of this study was to determine if TGF‐β1 decreased the amount of IL‐33 passively released by cells following tissue damage. We utilized previously established methods of inducing passive release of IL‐33 in cell culture. Pretreatment of cells with TGF‐β1 resulted in significantly lower levels of released IL‐33 following induction of tissue damage.These studies may identify a novel therapeutic target for treatment of diseases such as psoriasis, asthma and Crohn's disease. All of these diseases are associated with elevated levels of IL‐33 as well as altered TGF‐β responses. Further investigation of the immune cells affected by repression of IL‐33 could provide information into the specific mechanism of action.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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