Autocrine stimulation by osteopontin plays a pivotal role in the expression of the mitogenic and invasive phenotype of RET/PTC-transformed thyroid cells

Castellone, Maria Domenica; Celetti, Angela; Guarino, Vincenza; Cirafici, Anna Maria; Basolo, Fulvio; Giannini, Raffaello; Medico, Enzo; Kruhøffer, Mogens; Ørntoft, Torben F.; Curcio, Francesco; Fusco, Alfredo; Melillo, Rosa Marina; Santoro, Massimo

doi:10.1038/sj.onc.1207322

Cited by 42 publications

(35 citation statements)

References 37 publications

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“…Thyroid carcinoma overexpresses CD44 and such overexpression is associated to the oncogenic conversion of the ERK signaling pathway (18,19). Moreover, as in other cell types (42), CD44 was expressed in prospectively identified thyroid cancer stem cells that induce tumors when injected orthotopically into mouse thyroid (43).…”

Section: Discussionmentioning

confidence: 86%

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CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells

et al. 2012

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CD44 is a marker of cancer stem-like cells and epithelial-mesenchymal transition that is overexpressed in many cancer types, including thyroid carcinoma. At extracellular and intramembranous domains, CD44 undergoes sequential metalloprotease-and g-secretase-mediated proteolytic cleavage, releasing the intracellular protein fragment CD44-ICD, which translocates to the nucleus and activates gene transcription. Here, we show that CD44-ICD binds to the transcription factor CREB, increasing S133 phosphorylation and CREB-mediated gene transcription. CD44-ICD enhanced CREB recruitment to the cyclin D1 promoter, promoting cyclin D1 transcription and cell proliferation. Thyroid carcinoma cells harboring activated RET/PTC, RAS, or BRAF oncogenes exhibited CD44 cleavage and CD44-ICD accumulation. Chemical blockade of RET/PTC, BRAF, metalloprotease, or g-secretase were each sufficient to blunt CD44 processing. Furthermore, thyroid cancer cell proliferation was obstructed by RNA interference-mediated knockdown of CD44 or inhibition of g-secretase and adoptive CD44-ICD overexpression rescued cell proliferation. Together, these findings reveal a CD44-CREB signaling pathway that is needed to sustain cancer cell proliferation, potentially offering new molecular targets for therapeutic intervention in thyroid carcinoma. Cancer Res; 72(6);

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Section: Discussionmentioning

confidence: 86%

“…CD44 is overexpressed in PTC and in cell lines harboring RET/PTC or BRAF oncogenes (18,19). Here, we show that CD44-ICD triggers activation of the CREB transcription factor; in thyroid cancer cells, RET/PTC-BRAF signaling cascade uses such a CD44-ICD-CREB axis to sustain cell proliferation.…”

Section: Introductionmentioning

confidence: 87%

CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells

et al. 2012

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“…The expression of SPP1͞CD44 has been shown to be triggered by RET͞PTC oncogenes in rat thyroid cells and to sustain tumor cell proliferation and invasion (37).…”

Section: Discussionmentioning

confidence: 99%

Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene

Borrello

Alberti

Fischer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

306

260

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Rearrangements of the RET receptor tyrosine kinase gene generating RET͞PTC oncogenes are specific to papillary thyroid carcinoma (PTC), the most frequent thyroid tumor. Here, we show that the RET͞PTC1 oncogene, when exogenously expressed in primary normal human thyrocytes, induces the expression of a large set of genes involved in inflammation and tumor invasion, including those encoding chemokines (CCL2, CCL20, CXCL8, and CXCL12), chemokine receptors (CXCR4), cytokines (IL1B, CSF-1, GM-CSF, and G-CSF), matrix-degrading enzymes (metalloproteases and urokinase-type plasminogen activator and its receptor), and adhesion molecules (L-selectin). This effect is strictly dependent on the presence of the RET͞PTC1 Tyr-451 (corresponding to RET Tyr-1062 multidocking site). Selected relevant genes (CCL20, CCL2, CXCL8, CXCR4, L-selectin, GM-CSF, IL1B, MMP9, UPA, and SPP1͞OPN) were found up-regulated also in clinical samples of PTC, particularly those characterized by RET͞PTC activation, local extrathyroid spread, and lymph node metastases, when compared with normal thyroid tissue or follicular thyroid carcinoma. These results, demonstrating that the RET͞PTC1 oncogene activates a proinflammatory program, provide a direct link between a transforming human oncogene, inflammation, and malignant behavior.chemokines ͉ inflammation ͉ papillary thyroid carcinoma ͉ gene expression

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“…[16][17][18][19] OPN enhances tumoral cell proliferation increasing the malignant phenotype 16,17,25,26 and its downregulation in cancer cells reduces their growth and tumorigenicity in mice. 27 In line with these observations we found that OPN enhances HMCLs proliferation and increases IL-6 proproliferative effect on myeloma cells.…”

Section: Discussionmentioning

confidence: 99%

Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients

et al. 2005

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Osteopontin (OPN) is a multifunctional bone matrix glycoprotein that is involved in angiogenesis, cell survival and tumor progression. In this study we show that human myeloma cells directly produce OPN and express its major regulating gene Runx2/Cbfa1. The activity of Runx2/Cbfa1 protein in human myeloma cells has also been demonstrated. Moreover, using small interfering RNA (siRNA) to silent Runx2 in myeloma cells, we suppressed OPN mRNA and protein expression. OPN production in myeloma cells was stimulated by growth factors as IL-6 and IFG-1 and in turn OPN stimulated myeloma cell proliferation. In an 'in vitro' angiogenesis system we showed that OPN production by myeloma cells is critical for the proangiogenic effect of myeloma cells. The expression of OPN by purified bone marrow (BM) CD138 þ cells has also been investigated in 60 newly diagnosed multiple myeloma (MM) patients, finding that 40% of MM patients tested expressed OPN. Higher OPN levels have been detected in the BM plasma of MM patients positive for OPN as compared to controls. Moreover, significantly higher BM angiogenesis has been observed in MM patients positive for OPN as compared to those negative. Our data highlight that human myeloma cells with active Runx2/Cbfa1 protein directly produce OPN that is involved in the pathophysiology of MM-induced angiogenesis.

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Autocrine stimulation by osteopontin plays a pivotal role in the expression of the mitogenic and invasive phenotype of RET/PTC-transformed thyroid cells

Cited by 42 publications

References 37 publications

CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells

CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells

Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene

Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients

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