The role of tumor cells in synthesizing pro-inflammatory molecules is still controversial. Here we report that hypoxic treatment of the MCF-7 human mammary adenocarcinoma cell line induced activation of hypoxia-inducible factor 1α (HIF-1α) and nuclear factor-kappa B (NF-κB). Importantly, hypoxia regulated expression of alarmin receptors such as the receptor for advanced glycation end products (RAGE) and the purinoreceptor (P2X7R), and up-regulated inflammatory response (IR) genes such as the inducible enzymes nitric oxide synthase (NOS2), cycloxygenase (COX2), and the acute-phase protein pentraxin-3 (PTX3). Hypoxia also stimulated chemokine (C-X-C motif) receptor 4 (CXCR4) mRNA synthesis. In fact, the CXCR4 ligand stromal-derived factor-1α (SDF-1α) increased invasion and migration of hypoxic MCF-7 cells. Inhibition of HIF-1α by chetomin and NF-κB by parthenolide reduced mRNA and protein expression of the studied molecules and prevented invasion of hypoxic MCF-7 cells. Moreover, solid invasive mammary tumor microenvironment was analyzed after laser-capture microdissection (LCMD) comparing tumor versus host normal tissue. Nuclear translocation of HIF-1α and NF-κB and up-regulation of IR, CXCR4, estrogen receptor α (ERα), and epithelial growth factor receptor (EGFR) was observed in tumor but not in host normal tissue in the absence of a local inflammatory leukocyte infiltrate. We conclude that under hypoxic conditions MCF-7 cells acquire a pro-inflammatory phenotype, and that solid human mammary carcinoma evidenced a similar activation of HIF-1α, NF-κB, and IR genes in malignant tumor cells as compared to the normal host tissues. We suggest a role for IR activation in the malignant progression of transformed cells. © 2010 Japanese Cancer Association.

Tafani, M., Russo, A., Di Vito, M., Sale, P., Pellegrini, L., Schito, L., Gentileschi, S., Bracaglia, R., Marandino, F., Garaci, E., Russo, M. A., Up-regulation of pro-inflammatory genes as adaptation to hypoxia in MCF-7 cells and in human mammary invasive carcinoma microenvironment, <<CANCER SCIENCE>>, 2010; 101 (4): 1014-1023. [doi:10.1111/j.1349-7006.2010.01493.x] [http://hdl.handle.net/10807/133994]

Up-regulation of pro-inflammatory genes as adaptation to hypoxia in MCF-7 cells and in human mammary invasive carcinoma microenvironment

Di Vito, Maura;Gentileschi, Stefano;Bracaglia, Roberto;
2010

Abstract

The role of tumor cells in synthesizing pro-inflammatory molecules is still controversial. Here we report that hypoxic treatment of the MCF-7 human mammary adenocarcinoma cell line induced activation of hypoxia-inducible factor 1α (HIF-1α) and nuclear factor-kappa B (NF-κB). Importantly, hypoxia regulated expression of alarmin receptors such as the receptor for advanced glycation end products (RAGE) and the purinoreceptor (P2X7R), and up-regulated inflammatory response (IR) genes such as the inducible enzymes nitric oxide synthase (NOS2), cycloxygenase (COX2), and the acute-phase protein pentraxin-3 (PTX3). Hypoxia also stimulated chemokine (C-X-C motif) receptor 4 (CXCR4) mRNA synthesis. In fact, the CXCR4 ligand stromal-derived factor-1α (SDF-1α) increased invasion and migration of hypoxic MCF-7 cells. Inhibition of HIF-1α by chetomin and NF-κB by parthenolide reduced mRNA and protein expression of the studied molecules and prevented invasion of hypoxic MCF-7 cells. Moreover, solid invasive mammary tumor microenvironment was analyzed after laser-capture microdissection (LCMD) comparing tumor versus host normal tissue. Nuclear translocation of HIF-1α and NF-κB and up-regulation of IR, CXCR4, estrogen receptor α (ERα), and epithelial growth factor receptor (EGFR) was observed in tumor but not in host normal tissue in the absence of a local inflammatory leukocyte infiltrate. We conclude that under hypoxic conditions MCF-7 cells acquire a pro-inflammatory phenotype, and that solid human mammary carcinoma evidenced a similar activation of HIF-1α, NF-κB, and IR genes in malignant tumor cells as compared to the normal host tissues. We suggest a role for IR activation in the malignant progression of transformed cells. © 2010 Japanese Cancer Association.
Inglese
Tafani, M., Russo, A., Di Vito, M., Sale, P., Pellegrini, L., Schito, L., Gentileschi, S., Bracaglia, R., Marandino, F., Garaci, E., Russo, M. A., Up-regulation of pro-inflammatory genes as adaptation to hypoxia in MCF-7 cells and in human mammary invasive carcinoma microenvironment, <<CANCER SCIENCE>>, 2010; 101 (4): 1014-1023. [doi:10.1111/j.1349-7006.2010.01493.x] [http://hdl.handle.net/10807/133994]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/133994
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