This project is based on our findings that high expression of Human Germinal center Associated Lymphoma (HGAL) - a new gene that we cloned and characterized - is an independent predictor of prolonged survival of diffuse large B cell lymphoma (DLBCL) and Hodgkin's disease (HD) patients. Recently, we demonstrated that HGAL mediates IL-6-induced inhibition of germinal center (GC) B-cell migration. We demonstrated that IL-6 induces Lyn-mediated phosphorylation of the HGAL C-terminal tyrosine and causes HGAL relocalization to podosome-like structures and spike-like filopodia. We showed interactions between endogenous HGAL and myosin II and delineated HGAL domains responsible for the interaction. We provided evidence that HGAL phosphorylation results in increased interaction with the myosin II and demonstrated that knockdown of endogenous HGAL ameliorates the inhibitory effects of the IL-6 on cell migration. Taken together, these results identified HGAL as a physiological mediator of IL-6 effects on lymphocyte migration and suggest that HGAL expression in GC-derived lymphomas may limit tumor dissemination and predispose to better clinical outcome. However, despite the marked progress in identifying HGAL role in cellular processes, the precise mechanisms of HGAL-mediated inhibition of cell migration and consequent predisposition to better clinical outcome of tumors expressing HGAL are presently unknown. Our preliminary data demonstrates that HGAL may affect cell motility by interacting with myosin II and/or by increasing RoA activity. However, these effects need to be further investigated. In this project we will: 1) Determine effects of HGAL on myosin II function;2) Determine effects of HGAL on a member of the small Rho GTPase family - RhoA protein and its effectors;3) Determine the role of HGAL myristoylation and palmytoylation on its inhibitory effects on cell motility;and 4) Determine the effects of HGAL expression in transgenic mice model on lymphocyte differentiation, maturation, motility and lymphomagenesis. These studies will expand our knowledge on biology of the GC lymphocytes, with specific emphasis on lymphocyte motility and migration. Furthermore, these studies will reveal potentially new mechanisms regulating dissemination and progression of lymphoid tumors. These mechanistic studies may provide novel approaches for new therapeutic.

Public Health Relevance

Ability to predict patients'outcome at the time of diagnosis is of paramount significance. We have previously cloned a new gene- HGAL that was demonstrated to be an important prognostic biomarker in Hodgkin's and non-Hodgkin's lymphomas. We have shown previously that HGAL inhibit tumors migration and dissemination. Herein we will investigate molecular mechanisms of HGAL-induced inhibition of cell migration. These findings will not only elucidate the mechanisms of tumor dissemination but also will identify a new potential molecular target for novel therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109335-08
Application #
8463466
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mufson, R Allan
Project Start
2004-07-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$228,585
Indirect Cost
$70,301
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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