Negative regulation of MHC class II gene expression by CXCR4

Carol Sheridan, Miral Sadaria, Poornima Bhat-Nakshatri, Robert Goulet, Howard Edenberg, Brian P. McCarthy, Cheong Hee Chang, Edward Srour, Harikrishna Nakshatri

Research output: Contribution to journalArticle

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Abstract

Objective: CXCR4 is overexpressed in 23 types of cancers of both hematopoietic and nonhematopoietic origin. Based on the known role of CXCR4 and its ligand CXCL12 in homing of hematopoietic cells, CXCR4 is likely to play a role in metastasis. We have initiated a study aimed at dissecting additional functions of CXCR4 in cancer cells, particularly in relation to the immune system. Materials and Methods: RNA from CXCR4+ and CXCR4- subpopulations of MDA-MB-231 breast cancer cells was subjected to microarray analysis. Cell surface expression of CXCR4 and MHC class II proteins were determined by flow cytometry. Real-time PCR was used for measuring mRNA levels of MHC class II and CIITA, the master regulator of MHC class II gene expression. Results: 1988 genes were differentially expressed (p < 0.001) between CXCR4+ and CXCR4- cells. The expression of class II genes HLA-DPα1, HLA-DQβ1, HLA-DRα, HLA-DRβ1, HLA-DRβ3, and CD74 was lower by 2.6-fold to eightfold in CXCR4+ cells compared to CXCR4- cells. Basal and IFN-γ-inducible HLA-DR mRNA and protein levels were lower in CXCR4+ cells than in CXCR4- cells. HLA-DR mRNA expression in both cell types was reduced by CXCL12; the ability of CXCL12 to reduce HLA-DR was lower in cells expressing short interfering RNA against CXCR4. PKA inhibitor H89 and the SRC kinase inhibitor PP2 increased HLA-DR expression in CXCR4+ cells. The basal but not IFN-γ-inducible expression of CIITA was 2.5-fold higher in CXCR4- cells compared to CXCR4+ cells. CD34+/CD38- hematopoietic cells from the human bone marrow contain a distinct CXCR4+/HLA-DR- subpopulation of cells. Conclusion: CXCR4 may influence the immune system under physiologic and pathologic conditions through negative regulation of MHC class II expression, possibly through PKA and SRC kinase.

Original languageEnglish
Pages (from-to)1085-1092
Number of pages8
JournalExperimental Hematology
Volume34
Issue number8
DOIs
StatePublished - Aug 2006

Fingerprint

MHC Class II Genes
Gene Expression
HLA-DR Antigens
Messenger RNA
Immune System
Phosphotransferases
HLA-DR1 Antigen
HLA-DR3 Antigen
Microarray Analysis
Bone Marrow Cells

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Negative regulation of MHC class II gene expression by CXCR4. / Sheridan, Carol; Sadaria, Miral; Bhat-Nakshatri, Poornima; Goulet, Robert; Edenberg, Howard; McCarthy, Brian P.; Chang, Cheong Hee; Srour, Edward; Nakshatri, Harikrishna.

In: Experimental Hematology, Vol. 34, No. 8, 08.2006, p. 1085-1092.

Research output: Contribution to journalArticle

Sheridan, C, Sadaria, M, Bhat-Nakshatri, P, Goulet, R, Edenberg, H, McCarthy, BP, Chang, CH, Srour, E & Nakshatri, H 2006, 'Negative regulation of MHC class II gene expression by CXCR4', Experimental Hematology, vol. 34, no. 8, pp. 1085-1092. https://doi.org/10.1016/j.exphem.2006.03.013
Sheridan C, Sadaria M, Bhat-Nakshatri P, Goulet R, Edenberg H, McCarthy BP et al. Negative regulation of MHC class II gene expression by CXCR4. Experimental Hematology. 2006 Aug;34(8):1085-1092. https://doi.org/10.1016/j.exphem.2006.03.013
Sheridan, Carol ; Sadaria, Miral ; Bhat-Nakshatri, Poornima ; Goulet, Robert ; Edenberg, Howard ; McCarthy, Brian P. ; Chang, Cheong Hee ; Srour, Edward ; Nakshatri, Harikrishna. / Negative regulation of MHC class II gene expression by CXCR4. In: Experimental Hematology. 2006 ; Vol. 34, No. 8. pp. 1085-1092.
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abstract = "Objective: CXCR4 is overexpressed in 23 types of cancers of both hematopoietic and nonhematopoietic origin. Based on the known role of CXCR4 and its ligand CXCL12 in homing of hematopoietic cells, CXCR4 is likely to play a role in metastasis. We have initiated a study aimed at dissecting additional functions of CXCR4 in cancer cells, particularly in relation to the immune system. Materials and Methods: RNA from CXCR4+ and CXCR4- subpopulations of MDA-MB-231 breast cancer cells was subjected to microarray analysis. Cell surface expression of CXCR4 and MHC class II proteins were determined by flow cytometry. Real-time PCR was used for measuring mRNA levels of MHC class II and CIITA, the master regulator of MHC class II gene expression. Results: 1988 genes were differentially expressed (p < 0.001) between CXCR4+ and CXCR4- cells. The expression of class II genes HLA-DPα1, HLA-DQβ1, HLA-DRα, HLA-DRβ1, HLA-DRβ3, and CD74 was lower by 2.6-fold to eightfold in CXCR4+ cells compared to CXCR4- cells. Basal and IFN-γ-inducible HLA-DR mRNA and protein levels were lower in CXCR4+ cells than in CXCR4- cells. HLA-DR mRNA expression in both cell types was reduced by CXCL12; the ability of CXCL12 to reduce HLA-DR was lower in cells expressing short interfering RNA against CXCR4. PKA inhibitor H89 and the SRC kinase inhibitor PP2 increased HLA-DR expression in CXCR4+ cells. The basal but not IFN-γ-inducible expression of CIITA was 2.5-fold higher in CXCR4- cells compared to CXCR4+ cells. CD34+/CD38- hematopoietic cells from the human bone marrow contain a distinct CXCR4+/HLA-DR- subpopulation of cells. Conclusion: CXCR4 may influence the immune system under physiologic and pathologic conditions through negative regulation of MHC class II expression, possibly through PKA and SRC kinase.",
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AU - Sadaria, Miral

AU - Bhat-Nakshatri, Poornima

AU - Goulet, Robert

AU - Edenberg, Howard

AU - McCarthy, Brian P.

AU - Chang, Cheong Hee

AU - Srour, Edward

AU - Nakshatri, Harikrishna

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N2 - Objective: CXCR4 is overexpressed in 23 types of cancers of both hematopoietic and nonhematopoietic origin. Based on the known role of CXCR4 and its ligand CXCL12 in homing of hematopoietic cells, CXCR4 is likely to play a role in metastasis. We have initiated a study aimed at dissecting additional functions of CXCR4 in cancer cells, particularly in relation to the immune system. Materials and Methods: RNA from CXCR4+ and CXCR4- subpopulations of MDA-MB-231 breast cancer cells was subjected to microarray analysis. Cell surface expression of CXCR4 and MHC class II proteins were determined by flow cytometry. Real-time PCR was used for measuring mRNA levels of MHC class II and CIITA, the master regulator of MHC class II gene expression. Results: 1988 genes were differentially expressed (p < 0.001) between CXCR4+ and CXCR4- cells. The expression of class II genes HLA-DPα1, HLA-DQβ1, HLA-DRα, HLA-DRβ1, HLA-DRβ3, and CD74 was lower by 2.6-fold to eightfold in CXCR4+ cells compared to CXCR4- cells. Basal and IFN-γ-inducible HLA-DR mRNA and protein levels were lower in CXCR4+ cells than in CXCR4- cells. HLA-DR mRNA expression in both cell types was reduced by CXCL12; the ability of CXCL12 to reduce HLA-DR was lower in cells expressing short interfering RNA against CXCR4. PKA inhibitor H89 and the SRC kinase inhibitor PP2 increased HLA-DR expression in CXCR4+ cells. The basal but not IFN-γ-inducible expression of CIITA was 2.5-fold higher in CXCR4- cells compared to CXCR4+ cells. CD34+/CD38- hematopoietic cells from the human bone marrow contain a distinct CXCR4+/HLA-DR- subpopulation of cells. Conclusion: CXCR4 may influence the immune system under physiologic and pathologic conditions through negative regulation of MHC class II expression, possibly through PKA and SRC kinase.

AB - Objective: CXCR4 is overexpressed in 23 types of cancers of both hematopoietic and nonhematopoietic origin. Based on the known role of CXCR4 and its ligand CXCL12 in homing of hematopoietic cells, CXCR4 is likely to play a role in metastasis. We have initiated a study aimed at dissecting additional functions of CXCR4 in cancer cells, particularly in relation to the immune system. Materials and Methods: RNA from CXCR4+ and CXCR4- subpopulations of MDA-MB-231 breast cancer cells was subjected to microarray analysis. Cell surface expression of CXCR4 and MHC class II proteins were determined by flow cytometry. Real-time PCR was used for measuring mRNA levels of MHC class II and CIITA, the master regulator of MHC class II gene expression. Results: 1988 genes were differentially expressed (p < 0.001) between CXCR4+ and CXCR4- cells. The expression of class II genes HLA-DPα1, HLA-DQβ1, HLA-DRα, HLA-DRβ1, HLA-DRβ3, and CD74 was lower by 2.6-fold to eightfold in CXCR4+ cells compared to CXCR4- cells. Basal and IFN-γ-inducible HLA-DR mRNA and protein levels were lower in CXCR4+ cells than in CXCR4- cells. HLA-DR mRNA expression in both cell types was reduced by CXCL12; the ability of CXCL12 to reduce HLA-DR was lower in cells expressing short interfering RNA against CXCR4. PKA inhibitor H89 and the SRC kinase inhibitor PP2 increased HLA-DR expression in CXCR4+ cells. The basal but not IFN-γ-inducible expression of CIITA was 2.5-fold higher in CXCR4- cells compared to CXCR4+ cells. CD34+/CD38- hematopoietic cells from the human bone marrow contain a distinct CXCR4+/HLA-DR- subpopulation of cells. Conclusion: CXCR4 may influence the immune system under physiologic and pathologic conditions through negative regulation of MHC class II expression, possibly through PKA and SRC kinase.

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