Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas

“…In human ALK þ tumors, we were able to demonstrate for the first time a strong inverse correlation between miR-16 and VEGF expression levels. Nevertheless, as the increase in VEGF mRNA was detected in ALK þ lymphoma cells, that is, in conditional transgenic models as well as ALCL patients, we suggest that VEGF is regulated at both transcriptional, as reported by Marzec et al, 20 and posttranscriptional levels in ALK þ ALCL. Several trials have been opened for ALK þ tumors (http:// www.ClinicalTrials.gov).…”

“…33,34 These mechanisms include activation of several downstream signal-transduction pathways, which regulate cell survival, proliferation, migration and, more recently, hypoxia. 20,24 Although hypoxia has been reported to upregulate HIF-1a and VEGF in ALK-positive (ALK þ ) ALCL, 20 so far no studies have implicated it in angiogenesis in ALK tumor development.…”

“…They found that inhibition of HIF1a expression markedly suppressed cell growth and proliferation and decreased VEGF synthesis in ALCL cell line. 20 As lymphoma tissues are predominantly under hypoxic conditions, it is possible that HIF1a has an important role in the pathogenesis of ALK þ ALCL.…”

Anaplastic lymphoma kinase: Role in cancer and therapy perspective

“…Some of these genes, such as JUNB, YBX1, BCL2A1, HIF1A, have been validated by siRNA analyses. [14][15][16][17] MYCN is identified in neuroblastoma as a transcriptional target of activated full-length ALK. 18 There are reports of ALK signaling involving microRNAs, with miR-135b, miR-29a and miR-16 being downstream of NPM-ALK, and miR-96-mediated regulation of ALK expression.…”

The pathobiology of the oncogenic tyrosine kinase NPM-ALK: a brief update

“…STAT3-mediated epigenetic silencing is also responsible for the loss of T-cell signaling molecules, including CD3ε, ZAP70, LAT and SLP76, all of which are important in determining T-cell identity and T-cell receptor signaling [Ambrogio et al 2009]. A recent paper has revealed that STAT3 binds to the promoter of hypoxia-induced factor 1α (HIF1α) and upregulates HIF1α expression in ALK+ALCL cells [Marzec et al 2011]. This finding suggests that HIF1α could represent an important mechanism by which STAT3 exerts its oncogenic effects in ALK+ALCL, as HIF1α is known to be involved in tumor growth, angiogenesis, invasiveness, metastasis and drug resistance in other types of malignancy [Majmundar et al 2010;Rohwer and Cramer, 2011].…”