TGFβ-mediated activation of Smad1 in B-cell non-Hodgkin's lymphoma and effect on cell proliferation

Munoz, Olivier; Fend, Falko; Beaumont, Rosalie de; Husson, HervÃ©; Astier, Anne; Freedman, Arnold S.

doi:10.1038/sj.leu.2403485

Cited by 34 publications

(32 citation statements)

References 46 publications

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“…Ligandindependent tumor growth is known to arise from loss of PTCH or Sufu repressor function due to mutation, or activating mutations in the Shh effector SMO (12, 13), or due to increased expression of other cross-talking signaling pathways such as transforming growth factor-h signaling (32,33), which can increase the expression of GLI transcription factors independent of hedgehog ligand (34). Our results suggest that subset of MCL such as blastoid MCL could arise due to mutation in genes associated with Shh-GLI signaling or other cross-talking signaling, which would constitutively activate the signaling target genes such as GLI that will further regulate the growth of MCL.…”

Section: Discussionmentioning

confidence: 99%

Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma

Hegde

Munger

Emanuel

et al. 2008

Molecular Cancer Therapeutics

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Mantle cell lymphoma (MCL) has one of the worst clinical outcomes among the B-cell lymphomas, with a median survival of only 3 to 4 years. Therefore, a better understanding of the underlying mechanisms that regulate MCL proliferation/survival is needed to develop an effective therapy. Because sonic hedgehog (Shh)-GLI signaling has been shown to be important in the proliferation and survival of several cancers, and no such information is available for MCL, this study was undertaken. Our results show that the molecules associated with Shh-GLI signaling, such as PTCH and SMO receptors, and GLI1 and GLI2 target transcription factors were expressed in the human MCL cell lines and primary MCL cells from patients. Perturbation of this signaling in the presence of exogenous Shh/cyclopamine significantly (P < 0.001) influenced the proliferation of JVM2 MCL cells. Furthermore, down-regulation of GLI transcription factors using antisense oligonucleotides not only resulted in significantly (P < 0.001) decreased proliferation of the MCL cells but also significantly (P < 0.05) increased their susceptibility to chemotherapeutic drug, doxorubicin. Also, downregulation of GLI decreased cyclin D1 and BCL2 transcript levels, which suggests that these key molecules might be regulated by GLI in MCL. Thus, our results indicate a significant role for Shh-GLI signaling in the proliferation of MCL, and molecular targeting of GLI is a potential therapeutic approach to improve the treatment for MCL.

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Section: Discussionmentioning

confidence: 99%

Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma

Hegde

Munger

Emanuel

et al. 2008

Molecular Cancer Therapeutics

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“…Overexpression of Smad 1 occurs in follicular lymphoma cells and is characterised by the t (14; 18) bcl2/IgH translocation [87]. In adult T cell leukaemia and tropical spastic paraparesis, human T cell lymphotropic virus type 1 is a causative factor.…”

Section: Bmp's In Cancermentioning

confidence: 99%

Common critical pathways in embryogenesis and cancer

2006

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“…[5][6][7][8] Smad1 is an important transducer of both BMP-2 and TGF-b signals and has been shown to enhance tumor progression. [9][10][11][12][13][14] Smad1 is also involved in the crosstalk between BMP/TGF-b and Ras/MEK pathways and regulation of these pathways is critical for tumor progression. 15,16 Although it is known that Smad1 directly regulates transcription of a variety of genes implicated in tumor growth such as collagen IV, 17 myc 18 and p21WAF1/Cip1, 19 it is not yet clear what mediates Smad1 expression.…”

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confidence: 99%

Induction of Smad1 by MT1‐MMP contributes to tumor growth

Freudenberg

Chen

2007

Intl Journal of Cancer

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MT1-MMP is a key integral membrane protease, which regulates tumor growth by cleaving extracellular matrix components, activating growth factors and receptors, and consequently, triggering downstream signals. To study what genes or pathways are mediated by endogenous MT1-MMP during tumor growth in vivo, we stably suppressed endogenous MT1-MMP in human tumor cells using RNA interference (RNAi). Tumor growth was significantly reduced in tumors derived from MT1-MMP-suppressed cells relative to control cells; the effect was rescued in cells engineered to re-express MT1-MMP expression. Gene expression profiling of cultured and tumor-derived cells by DNA microarray and realtime RT-PCR revealed that Smad1 expression was upregulated in MT1-MMP-expressing cells and rapidly growing tumors; this was confirmed in 4 additional tumor cell lines. Furthermore, tumor growth of MT1-MMP-expressing cells was reduced when Smad1 was suppressed by RNAi. We also found that the active form, but not the latent form, of TGF-b was capable in promoting Smad1 expression and 3D cell proliferation in MT1-MMP-suppressed cells. In addition, a dominant-negative form of the TGF-b Type II receptor reduced Smad1 expression in MT1-MMP-expressing cells. Thus, we propose that MT1-MMP functions, in part, to promote tumor growth by inducing the expression of Smad1 via TGFb signaling. 1 The catalytic domain is necessary for the activation of many other proteases such as proMMP-2 and the processing of extracellular matrix (ECM) components, which have been thought to be important for its tumor-promoting ability. Hotary et al. 4 have shown that MT1-MMP regulates cellular proliferation in both three-dimensional (3D) collagen and within the tumor microenvironment by controlling cell geometry within the confines of the 3D ECM, a function that requires pericellular proteolysis of the ECM.MT1-MMP may also play a role in tumor growth by activating growth factors and receptors. Although a potential signaling pathway controlling MT1-MMP-dependent tumor growth is not available, many signaling pathways are associated with tumor growth. For instance, bone morphogenetic protein-2 (BMP-2) and transforming growth factor-b (TGF-b) and their associated signaling pathways can promote growth. [5][6][7][8] Smad1 is an important transducer of both BMP-2 and TGF-b signals and has been shown to enhance tumor progression.9-14 Smad1 is also involved in the crosstalk between BMP/TGF-b and Ras/MEK pathways and regulation of these pathways is critical for tumor progression. 15,16Although it is known that Smad1 directly regulates transcription of a variety of genes implicated in tumor growth such as collagen IV, 17 The purpose of our study was to determine a functional linkage between MT1-MMP and a signaling pathway that regulates tumor growth. We stably suppressed endogenous MT1-MMP expression in human tumor cells using a novel RNA interference (RNAi) vector to study MT1-MMP-dependent tumor growth in vivo. This approach enabled us to use gene expression profiling to determine potenti...

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TGFβ-mediated activation of Smad1 in B-cell non-Hodgkin's lymphoma and effect on cell proliferation

Cited by 34 publications

References 46 publications

Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma

Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma

Common critical pathways in embryogenesis and cancer

Induction of Smad1 by MT1‐MMP contributes to tumor growth

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