STAT3 facilitates amoeboid movement in diffuse large B-cell lymphoma
| Autor: | Yu-Tien Chan, 詹郁恬 |
|---|---|
| Rok vydání: | 2017 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 105 Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell malignancy and it is one of the most common types of lymphoma in adults. A major clinical character of DLBCL is that the dissemination of DLBCL occurs early in the disease course and skip metastasis is frequently observed in DLBCL, which is distinct from the process of solid tumor metastasis. However, the mechanism that drives the unique movement mode of DLBCL remains elusive. Here we show that the major movement mode of DLBCL in a 3D culture system is amoeboid-type movement, which is originally noted in leukocytes migration. The speed of amoeboid movement is fast and it is proteolysis independent, which explains the unique dissemination character of DLBCL. Here, we find that STAT3 activation induces IL-10 expression to constitute a positive feedback loop in DLBCL. Activated STAT3 regulates microtubule dynamics and releases ARHGEF2 to activate RhoA. In addition, we also demonstrate the involvement of ezrin/radixin/moesin (ERM) proteins in amoeboid movement of DLBCL. Furthermore, STAT3-mediated microtubule dynamics also regulates the interaction between ICAM-2 and ERM proteins leading to DLBCL migration. Both the pan-JAK inhibitor ruxolitinib and the microtubule-stabilizing agent taxol effectively suppress DLBCL dissemination in vivo. Analysis of clinical samples reveals that STAT3-driven amoeboid movement is particularly important for the stage I-to-II transition. This study elucidates the mechanism of DLBCL dissemination and also indicates a potential strategy for treating disseminated DLBCL. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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