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Common molecular pathways involved in human CD133+/CD34+ progenitor cell expansion and cancer.

Okamoto OK, Carvalho AC, Marti LC, Vêncio RZ, Moreira-Filho CA - Cancer Cell Int. (2007)

Bottom Line: Several genes and signaling pathways not previously associated with ex vivo expansion of CD133+/CD34+ cells were identified, most of which associated with cancer.Regulation of MEK/ERK and Hedgehog signaling genes in addition to numerous proto-oncogenes was detected during conditions of enhanced progenitor cell expansion.Quantitative real-time PCR analysis confirmed down-regulation of several newly described cancer-associated genes in CD133+/CD34+ cells, including DOCK4 and SPARCL1 tumor suppressors, and parallel results were verified when comparing their expression in cells from chronic myeloid leukemia patients Our findings reveal potential molecular targets for oncogenic transformation in CD133+/CD34+ cells and strengthen the link between deregulation of stem/progenitor cell expansion and the malignant process.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo - Escola Paulista de Medicina, São Paulo, Brazil. keith.nexp@epm.br

ABSTRACT

Background: Uncovering the molecular mechanism underlying expansion of hematopoietic stem and progenitor cells is critical to extend current therapeutic applications and to understand how its deregulation relates to leukemia. The characterization of genes commonly relevant to stem/progenitor cell expansion and tumor development should facilitate the identification of novel therapeutic targets in cancer.

Methods: CD34+/CD133+ progenitor cells were purified from human umbilical cord blood and expanded in vitro. Correlated molecular changes were analyzed by gene expression profiling using microarrays covering up to 55,000 transcripts. Genes regulated during progenitor cell expansion were identified and functionally classified. Aberrant expression of such genes in cancer was indicated by in silico SAGE. Differential expression of selected genes was assessed by real-time PCR in hematopoietic cells from chronic myeloid leukemia patients and healthy individuals.

Results: Several genes and signaling pathways not previously associated with ex vivo expansion of CD133+/CD34+ cells were identified, most of which associated with cancer. Regulation of MEK/ERK and Hedgehog signaling genes in addition to numerous proto-oncogenes was detected during conditions of enhanced progenitor cell expansion. Quantitative real-time PCR analysis confirmed down-regulation of several newly described cancer-associated genes in CD133+/CD34+ cells, including DOCK4 and SPARCL1 tumor suppressors, and parallel results were verified when comparing their expression in cells from chronic myeloid leukemia patients

Conclusion: Our findings reveal potential molecular targets for oncogenic transformation in CD133+/CD34+ cells and strengthen the link between deregulation of stem/progenitor cell expansion and the malignant process.

No MeSH data available.


Related in: MedlinePlus

Expression levels of DOCK4, SPARCL1, BCL10, GLI2, MS4A6A, and FNBP3 genes in healthy individuals (control) and chronic myeloid leukemia patients. Total RNA was extracted from purified mononuclear cells from peripheral blood samples. Transcript levels were quantified by real-time PCR and results are given as normalized gene expression. Horizontal bars indicate median expression values. Statistical significance: P < 0.001 for DOCK4; P < 0.01 for SPARCL1, BCL10, and GLI2; P < 0.05 for MS4A6A and FNBP3.
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Figure 4: Expression levels of DOCK4, SPARCL1, BCL10, GLI2, MS4A6A, and FNBP3 genes in healthy individuals (control) and chronic myeloid leukemia patients. Total RNA was extracted from purified mononuclear cells from peripheral blood samples. Transcript levels were quantified by real-time PCR and results are given as normalized gene expression. Horizontal bars indicate median expression values. Statistical significance: P < 0.001 for DOCK4; P < 0.01 for SPARCL1, BCL10, and GLI2; P < 0.05 for MS4A6A and FNBP3.

Mentions: Several of these cancer-associated genes identified as being regulated during CD133+/CD34+ cell expansion are new and still not fully functionally characterized in the literature, such as MS4A6A, FNBP3, DOCK4, and SPARCL1. Differential expression of these genes, in addition to other identified early E2-regulated genes displaying aberrant expression in tumors was confirmed in CD133+/CD34+ cells by quantitative real-time PCR (Fig.3), validating the microarray data. To further examine a possible connection with tumorigenesis, differential expression of the abovementioned genes was examined in the mononuclear cell fraction of healthy volunteers and chronic myeloid leukemia (CML) patients. Significant differences in expression were found for DOCK4, GLI2, BCL10, SPARCL1, MS4A6A, and FNBP3 (Fig.4).


Common molecular pathways involved in human CD133+/CD34+ progenitor cell expansion and cancer.

Okamoto OK, Carvalho AC, Marti LC, Vêncio RZ, Moreira-Filho CA - Cancer Cell Int. (2007)

Expression levels of DOCK4, SPARCL1, BCL10, GLI2, MS4A6A, and FNBP3 genes in healthy individuals (control) and chronic myeloid leukemia patients. Total RNA was extracted from purified mononuclear cells from peripheral blood samples. Transcript levels were quantified by real-time PCR and results are given as normalized gene expression. Horizontal bars indicate median expression values. Statistical significance: P < 0.001 for DOCK4; P < 0.01 for SPARCL1, BCL10, and GLI2; P < 0.05 for MS4A6A and FNBP3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1904434&req=5

Figure 4: Expression levels of DOCK4, SPARCL1, BCL10, GLI2, MS4A6A, and FNBP3 genes in healthy individuals (control) and chronic myeloid leukemia patients. Total RNA was extracted from purified mononuclear cells from peripheral blood samples. Transcript levels were quantified by real-time PCR and results are given as normalized gene expression. Horizontal bars indicate median expression values. Statistical significance: P < 0.001 for DOCK4; P < 0.01 for SPARCL1, BCL10, and GLI2; P < 0.05 for MS4A6A and FNBP3.
Mentions: Several of these cancer-associated genes identified as being regulated during CD133+/CD34+ cell expansion are new and still not fully functionally characterized in the literature, such as MS4A6A, FNBP3, DOCK4, and SPARCL1. Differential expression of these genes, in addition to other identified early E2-regulated genes displaying aberrant expression in tumors was confirmed in CD133+/CD34+ cells by quantitative real-time PCR (Fig.3), validating the microarray data. To further examine a possible connection with tumorigenesis, differential expression of the abovementioned genes was examined in the mononuclear cell fraction of healthy volunteers and chronic myeloid leukemia (CML) patients. Significant differences in expression were found for DOCK4, GLI2, BCL10, SPARCL1, MS4A6A, and FNBP3 (Fig.4).

Bottom Line: Several genes and signaling pathways not previously associated with ex vivo expansion of CD133+/CD34+ cells were identified, most of which associated with cancer.Regulation of MEK/ERK and Hedgehog signaling genes in addition to numerous proto-oncogenes was detected during conditions of enhanced progenitor cell expansion.Quantitative real-time PCR analysis confirmed down-regulation of several newly described cancer-associated genes in CD133+/CD34+ cells, including DOCK4 and SPARCL1 tumor suppressors, and parallel results were verified when comparing their expression in cells from chronic myeloid leukemia patients Our findings reveal potential molecular targets for oncogenic transformation in CD133+/CD34+ cells and strengthen the link between deregulation of stem/progenitor cell expansion and the malignant process.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo - Escola Paulista de Medicina, São Paulo, Brazil. keith.nexp@epm.br

ABSTRACT

Background: Uncovering the molecular mechanism underlying expansion of hematopoietic stem and progenitor cells is critical to extend current therapeutic applications and to understand how its deregulation relates to leukemia. The characterization of genes commonly relevant to stem/progenitor cell expansion and tumor development should facilitate the identification of novel therapeutic targets in cancer.

Methods: CD34+/CD133+ progenitor cells were purified from human umbilical cord blood and expanded in vitro. Correlated molecular changes were analyzed by gene expression profiling using microarrays covering up to 55,000 transcripts. Genes regulated during progenitor cell expansion were identified and functionally classified. Aberrant expression of such genes in cancer was indicated by in silico SAGE. Differential expression of selected genes was assessed by real-time PCR in hematopoietic cells from chronic myeloid leukemia patients and healthy individuals.

Results: Several genes and signaling pathways not previously associated with ex vivo expansion of CD133+/CD34+ cells were identified, most of which associated with cancer. Regulation of MEK/ERK and Hedgehog signaling genes in addition to numerous proto-oncogenes was detected during conditions of enhanced progenitor cell expansion. Quantitative real-time PCR analysis confirmed down-regulation of several newly described cancer-associated genes in CD133+/CD34+ cells, including DOCK4 and SPARCL1 tumor suppressors, and parallel results were verified when comparing their expression in cells from chronic myeloid leukemia patients

Conclusion: Our findings reveal potential molecular targets for oncogenic transformation in CD133+/CD34+ cells and strengthen the link between deregulation of stem/progenitor cell expansion and the malignant process.

No MeSH data available.


Related in: MedlinePlus