Activation of Erk by sonic hedgehog independent of canonical hedgehog signalling

Chang, Hong; Li, Qing; Moraes, Ricardo; Lewis, Michael T.; Hamel, Paul A.

doi:10.1016/j.biocel.2010.04.016

Cited by 55 publications

(82 citation statements)

References 74 publications

(73 reference statements)

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“…Since the Hh signaling pathway has been associated with MAPK/ERK pathway in different cancer [43][44][45][46] , furthermore our results indicate that the pathway is also notably correlated to expressions of p-ERK1/2 in HCC tissues. To confirm these results, we treated a HCC cell line, Bel-7402 cells, with KAAD-cyc, Shh, U0126, or PD98059 in vitro.…”

Section: Discussionsupporting

confidence: 53%

“…Therefore we investigated the mechanisms of the Hh signaling pathway in HCC invasion and metastasis. Gli1, a transcription factor activated in the Hh pathway, significantly enhanced tumor growth and metastases of other cancers through the activation of ERK1/2 [42,45] . Overexpression of MMP-9 is also a key factor for tumor invasion and metastasis [47,48,55] .…”

Section: Discussionmentioning

confidence: 99%

“…For example, it also can activate ERK1/2 in the breast epithelial cell [45] . However, other studies have revealed that in cancer the MAPK signaling pathway regulates Hh signaling, specifically Gli activity and expression [46] .…”

Section: Introductionmentioning

confidence: 99%

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Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

Lü

Zhao

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the role of Hedgehog (Hh) signaling pathway in the invasion and metastasis of human hepatocellular carcinoma (HCC). Methods: Eighty six HCC tissues samples and HCC cell line Bel-7402 were examined. The protein expression of sonic hedgehog (Shh), nuclear glioma-associated oncogene-1 (Gli1), MMP-9 and p-ERK1/2 in HCC was analyzed using immunohistochemistry and Western blot analysis. Boyden chamber assay and wound-healing assay were used to quantify the invasion and metastasis of Bel-7402 cells. Results: In 86 HCC tissue samples, the positive ratio of Shh and nucleus Gli1 was 67.44% (58/86) and 60.47% (52/86), respectively; the expression of nucleus Gli1 was correlated with the tumor pathological grade (P=0.034), and with the ability of the tumor to invade and metastasize (P=0.001); the expression of nucleus Gli1 was also correlated with p-ERK1/2 (P=0.031) and with MMP-9 (P=0.034). Neither Shh, nor nucleus Gli1 was observed in normal liver tissue. KAAD-cyclopamine (KAAD-cyc), a specific inhibitor of the Hh pathway, at the concentrations of 1 and 4 μmol/L inhibited the invasion and migration of Bel-7402 cells and decreased the expression of Gli1 in nucleus and MMP-9, p-ERK1/2 proteins in Bel-7402 cells. On the other hand, Shh, a ligand of the Hh pathway, at the concentration of 0.5 μg/mL produced opposite effects. The MAPK pathway inhibitors U0126 and PD98059 at the concentrations of 5 and 10 μmol/L inhibited invasion and metastasis of Bel-7402 cells induced by Shh, and decreased the expression of p-ERK1/2 and MMP-9. However, U0126 and PD98059 had no effect on the expression of Gli1. Conclusion: Hh signaling pathway mediates invasion and metastasis of human HCC by up-regulating the protein expression of MMP-9 via ERK pathway.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

Lü

Zhao

et al. 2012

Acta Pharmacol Sin

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“…33 To investigate whether ERK activation might be involved in noncanonical HH signaling in CLL cells, we investigated the effect of the presence of stromal cells on ERK phosphorylation in CLL cells with the use of intracellular p-ERK staining. Interestingly, Response rates to SMO inhibitor treatment in the different genetic subgroups in CLL are shown.…”

Section: Noncanonical Hh Signaling In Cll Cells Is Partially Mediatedmentioning

confidence: 99%

“…32 Noncanonical HH signaling was described in mammary gland cells, inducing direct ERK activation downstream of the PTCH1 receptor without involvement of the SMO receptor. 33 Diverse roles of HH signaling are described in hematologic malignancies. Although HH signaling mediated by SMO is required for maintenance of the leukemic stem cell population in chronic myeloid leukemia, 34,35 it is dispensable for the development of acute leukemias induced by the MLL-AF9 36 fusion gene or T-cell acute lymphoblastic leukemia induced by an activated form of NOTCH.…”

Section: Introductionmentioning

confidence: 99%

Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL

Decker

Zirlik

Djebatchie

et al. 2012

Blood

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Hedgehog (HH) signaling is activated in various lymphoid malignancies, but conflicting results exist about its role in chronic lymphocytic leukemia (CLL). Here, we demonstrate that the expression of essential HH pathway components like GLI1, PTCH1, and the HH ligands is highly diverse in CLL. A subset of 36.7% of 60 tested CLL samples responded to all 3 SMOOTHENED (SMO) inhibitors, whereas 40% were completely resistant. Responsiveness correlated with elevated GLI1 and PTCH1 transcript levels and the presence of trisomy 12, whereas no other karyotype correlated with responsiveness. All trisomy 12 CLLs displayed constitutive HH pathway activation driven by autocrine DESERT HH (DHH) ligand secretion, which could be blocked by the HH-blocking Ab 5E1. Cocultures with DHH-expressing BM stromal cells reduced sensitivity of CLLs to SMOinhibitor treatment by activation of noncanonical ERK phosphorylation directly downstream of the PTCH1 receptor without involvement of SMO and could be overcome by the HH-blocking Ab 5E1 or a combination of SMO and ERK inhibitors. Our results demonstrate that the HHsignaling pathway is an interesting therapeutic target for a subset of patients with CLL, characterized by high GLI1 and PTCH1 transcript levels, and all patients with trisomy 12 and indicate HH-blocking Abs to be favorable over SMO inhibitors in overcoming stroma-mediated protective effects. (Blood. 2012;119(4):997-1007) Introduction B-cell chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in Western countries and is characterized by a progressive accumulation of functionally incompetent Blymphocytes in the peripheral blood, BM, and lymphoid organs. 1,2 Several prognostic markers such as Rai and Binet staging systems, 3,4 immunoglobulin V H gene mutational status, 5 -associated protein 70 (ZAP70) expression 6,7 and cytogenetic abnormalities 8 such as trisomy 12 and del 13q14 can be used to predict the survival outcome and the need for treatment of patients with CLL. 9 Despite encouraging new therapeutic strategies 10 CLL cannot be cured by conventional therapy at present, and only hematopoietic stem cell transplantation has led to complete and ongoing remissions in some patients. 11 The exact pathogenesis of this clinically heterogenous leukemia is still unknown, 12 but it is well established that B-CLL cells are habitually interacting with stromal cells, indicating the importance of the microenvironment for survival of CLL cells. [13][14][15] In our previous work, we demonstrated that the hedgehog (HH) ligands sonic (Shh), indian (Ihh), and desert (Dhh) are produced by stromal cells in lymphoid organs and that the BM promote expansion of murine lymphomas in vitro and in vivo. 16 HH ligands activate the transmembrane receptor PATCHED (PTCH), which abrogates the suppression of the 7-transmembranehelix protein SMOOTHENED (SMO), the key player for signal transduction of the canonical HH pathway. 17 SMO activation leads to production of activating forms of the glioma-associated oncoproteins 1-3 (GLI1-3), the H...

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Hedgehog signaling in the posterior region of the mouse gastrula suggests manifold roles in the fetal-umbilical connection and posterior morphogenesis

Daane

Downs

2011

Dev. Dyn.

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SUMMARY Although many fetal birth defects, particularly those of the body wall and gut, are associated with abnormalities of the umbilical cord, the developmental relationship between these structures is largely obscure. Recently, genetic analysis of mid-gestation mouse embryos revealed that defects in Hedgehog signaling led to omphalocoele, or failure of the body wall to close at the umbilical ring (Matsumaru et al., 2011). However, systematic spatiotemporal localization of Hedgehog signaling in the allantois, or umbilical precursor tissue, and the surrounding regions has not been documented. Here, a combination of reagents, including the Ptc1:lacZ and Runx1:lacZ reporter mice, immunohistochemistry for Smoothened (Smo), Sonic Hedgehog (Shh), and Indian hedgehog (Ihh), and detailed PECAM-1/Flk-1/Runx-1 analysis, revealed robust Hedgehog signaling in previously undocumented posterior sites over an extended period of time (~7.0–9.75 dpc). These included the recently described proximal walls of the allantois (Ventral and Dorsal Cuboidal Mesothelia; VCM and DCM, respectively); the ventral embryonic surface continuous with them; hemogenic arterial endothelia; hematopoietic cells; the hindgut; ventral ectodermal ridge (VER); chorionic ectoderm; and the intraplacental yolk sac (IPY), which appeared to be a site of placental hematopoiesis. This map of Hedgehog signaling in the posterior region of the mouse conceptus will provide a valuable foundation upon which to elucidate the origin of many posterior midline abnormalities, especially those of the umbilical cord and associated fetal defects.

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Activation of Erk by sonic hedgehog independent of canonical hedgehog signalling

Cited by 55 publications

References 74 publications

Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL

Hedgehog signaling in the posterior region of the mouse gastrula suggests manifold roles in the fetal-umbilical connection and posterior morphogenesis

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