Proliferation and bone marrow engraftment of AML blasts is dependent on β‐catenin signalling

Siapati, Elena K.; Papadaki, M.; Kozaou, Zoi; Rouka, Erasmia; Michali, Evridiki; Savvidou, Ioanna; Gogos, Dimitrios; Kyriakou, Despina; Anagnostopoulos, N.I.; Vassilopoulos, George

doi:10.1111/j.1365-2141.2010.08471.x

Cited by 42 publications

(35 citation statements)

References 29 publications

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“…It has been reported that β-catenin is expressed and activated in LSCs and that it is required for self-renewal (37,38). Thus, we postulated that SPARC expression may be higher in less differentiated hematopoietic cell subpopulations.…”

Section: Sparc Overexpression Ismentioning

confidence: 80%

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SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome

et al. 2014

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Aberrant expression of the secreted protein, acidic, cysteine-rich (osteonectin) (SPARC) gene, which encodes a matricellular protein that participates in normal tissue remodeling, is associated with a variety of diseases including cancer, but the contribution of SPARC to malignant growth remains controversial. We previously reported that SPARC was among the most upregulated genes in cytogenetically normal acute myeloid leukemia (CN-AML) patients with gene-expression profiles predictive of unfavorable outcome, such as mutations in isocitrate dehydrogenase 2 (IDH2-R172) and overexpression of the oncogenes brain and acute leukemia, cytoplasmic (BAALC) and v-ets erythroblastosis virus E26 oncogene homolog (ERG). In contrast, SPARC was downregulated in CN-AML patients harboring mutations in nucleophosmin (NPM1) that are associated with favorable prognosis. Based on these observations, we hypothesized that SPARC expression is clinically relevant in AML. Here, we found that SPARC overexpression is associated with adverse outcome in CN-AML patients and promotes aggressive leukemia growth in murine models of AML. In leukemia cells, SPARC expression was mediated by the SP1/NF-κB transactivation complex. Furthermore, secreted SPARC activated the integrinlinked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent β-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-κB complex resulted in SPARC downregulation and leukemia growth inhibition. Together, our data indicate that evaluation of SPARC expression has prognosticative value and SPARC is a potential therapeutic target for AML.

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Section: Sparc Overexpression Ismentioning

confidence: 80%

“…Thus, the net result of the SPARC/integrin/ILK interplay is enhanced β-catenin. The latter is required for self-renewal of leukemia stem cells (LSCs) (37)(38)(39)(40)(41). Thus, we hypothesized that SPARC overexpression leads to aberrant β-catenin activation in AML.…”

Section: Sparc Overexpression Ismentioning

confidence: 99%

SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome

et al. 2014

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“…Certain studies have suggested that HIF-1α activation regulates the Wnt/β-catenin signaling pathway, which activates the expression of target genes and contributes to the enhanced invasion of hypoxic gastric cancer cells (35)(36)(37). CD44 is a target gene of the Wnt/β-catenin signaling pathway (38); therefore, the mechanism by which HIF-1α regulates CD44 may be associated with the Wnt/β-catenin signaling pathway in gastric cancer. Further studies are required to investigate these underlying mechanisms in gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia regulates CD44 expression via hypoxia-inducible factor-1α in human gastric cancer cells

Liang

et al. 2016

Oncology Letters

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Abstract. Hypoxia induces proliferation and invasion in cancer cells via hypoxia-inducible factor (HIF)-1α. The cell adhesion molecule cluster of differentiation (CD) 44 has been associated with increased cell invasion and metastasis. Whether hypoxia regulates the expression of CD44 in gastric cancer cells remains to be established. In the current study, the effects of hypoxia on HIF-1α and CD44 expression levels in human gastric cell lines SGC-7901 and BGC-823 were evaluated. The cells were cultured in 1% O 2 for 1 week and then treated with 20 nM rapamycin for 72 h. Cell viability was evaluated using the Cell Counting kit-8 assay, and cell invasion was detected by the Transwell invasion assay. The protein and messenger (m) RNA expression levels of HIF-1α and CD44 were detected using western blotting and reverse transcription-quantitative polymerase chain reaction, respectively. The results revealed that cell viability and invasion increased under hypoxic conditions, but decreased following rapamycin treatment in SGC-7901 and BGC-823 cells. Hypoxia also increased the protein and mRNA expression levels of HIF-1α and CD44 in these two cell lines. However, this hypoxia-induced increase in HIF-1α and CD44 protein and mRNA expression levels was inhibited by rapamycin. These findings suggest that hypoxia induced the proliferation and invasion of SGC-7901 and BGC-823 cells. Furthermore, CD44 expression levels were potentially associated with HIF-1α expression levels. Therefore, in gastric cancer cells, hypoxia may regulate CD44 expression via HIF-1α in order to promote cell proliferation and invasion.

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“…10,11 To test whether inhibiting WNT signaling affected survival or differentiation of primary AML blasts with different levels of nuclear β-catenin, we used a compound (iCRT3) that inhibits WNT signaling by blocking the interaction between β-catenin and TCF family transcription factors.…”

Section: Letters To the Editormentioning

confidence: 99%