FilGAP, a Rac‐specific Rho GTPase‐activating protein, is a novel prognostic factor for follicular lymphoma

Abstract

FilGAP, a Rho GTPase-activating protein (GAP), acts as a mediator of Rho/ROCK (Rho-associated protein kinase)-dependent amoeboid movement, and its knockdown results in Rac-driven mesenchymal morphology. Herein, we focus on the possible roles of FilGAP expression in normal and malignant lymphocytes. Eighty-three cases of follicular lymphoma (FL), 84 of diffuse large B-cell lymphoma (DLBCL), and 25 of peripheral T-cell lymphoma (PTCL), as well as 10 of normal lymph nodes, were immunohistochemically investigated. In normal lymph nodes, FilGAP immunoreactivity was significantly higher in lymphocytes in the mantle zone as compared to those in the germinal center and paracortical areas. In contrast, the expression levels of both cytoplasmic and perinuclear Rac1 were significantly lower in the germinal center as compared to paracortical regions, suggesting that changes in the FilGAP/Rac axis may occur in B-cell lineages. In malignant lymphomas, FilGAP expression was significantly higher in B-cell lymphomas than PTCL, and the immunohistochemical scores were positively correlated with cytoplasmic Rac1 scores in FL and DLBCL, but not in PTCL. Patients with FL and germinal center B-cell-like (GCB)-type DLBCL showing high FilGAP scores had poor overall survival rates as compared to the low-score patients. Moreover, multivariate Cox regression analysis showed that a high FilGAP score was a significant and independent unfavorable prognostic factor in FL, but not in DLBCL. In conclusion, FilGAP may contribute to change in cell motility of B-lymphocytes. In addition, its expression appears to be useful for predicting the behavior of B-cell lymphoma, in particular FL.

ARHGAP24 inhibits cell cycle progression, induces apoptosis and suppresses invasion in renal cell carcinoma

“…Bioinformatics studies determined ARHGAP family (including ARHGAP24) is cancer-associated genes [24, 25], because their genetic alterations lead to carcinogenesis [26]. In particular, ARHGAP24 is an independent prognostic factor of malignant lymphomas [27]. ARHGAP24 is involved in breast cancer cell invasion and migration [28, 29], and it antagonizes mesenchymal invasion [30].…”

“…Further, overexpression of ARHGAP24 in 786-0 and Caki-2 cells significantly decreases tumor cell invasion capability. Interestingly, other studies found that silencing ARHGAP24 impaired breast cancer cell invasion and high ARHGAP24 causes maintenance of amoeboid features of lymphoma [27, 28]. It is possible that the interaction between ARHGAP24 and other molecules is context dependent and function through different molecular pathways in various types of cancer.…”

Possible role of nuclear β‐catenin in resistance to preoperative chemoradiotherapy in locally advanced rectal cancer

“…Human Lgr5 cDNA containing nucleotides 1057–1075 (GenBank accession number http://NM003667) was subcloned into the pCRII vector (Invitrogen, Carlsbad, CA, USA) by use of a polymerase chain reaction‐based strategy with specific primers (forward, 5′‐TTCACCTCCTACCTAGAC‐3′; reverse, 5′‐GGTCCAGCTTTATTAGGG‐3′). Riboprobes were generated by in‐vitro transcription, and ISH assays were carried out as described previously . Cases with >10% cells positive for ISH signals were defined as positive.…”

The RacGAP protein FilGAP is a negative regulator of chemokine‐promoted lymphocyte migration

“…FilGAP is highly expressed in B lymphocyte and B‐cell lymphoma . In addition, high expression of FilGAP was shown as an independent unfavorable prognostic factor in follicular lymphoma, a common type of malignant B‐cell lymphoma . This suggests that FilGAP may contribute to change in motility of B lymphocyte to increase invasion into extracellular matrix.…”

“…Moreover, leukocytes use a distinct migration mode according to their cell type, and the role of Rho GTPases seems to be different among leukocytes . FilGAP is highly expressed in B lymphocyte and B‐cell lymphoma . In addition, high expression of FilGAP was shown as an independent unfavorable prognostic factor in follicular lymphoma, a common type of malignant B‐cell lymphoma .…”