Abstract
Sox2 (sex-determining region Y-Box) is one of the master transcriptional factors that are important in maintaining the pluripotency of embryonic stem cells (ESCs). In line with this function, Sox2 expression is largely restricted to ESCs and somatic stem cells. We report that Sox2 is expressed in cell lines and tumor samples derived from ALK-positive anaplastic large cell lymphoma (ALK+ALCL), for which the normal cellular counterpart is believed to be mature T-cells. The expression of Sox2 in ALK+ALCL can be attributed to nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), the oncogenic fusion protein carrying a central pathogenetic role in these tumors. By confocal microscopy, Sox2 protein was detectable in virtually all cells in ALK+ALCL cell lines. However, the transcriptional activity of Sox2, as assessed using a Sox2-responsive reporter construct, was detectable only in a small proportion of cells. Importantly, downregulation of Sox2 using short interfering RNA in isolated Sox2active cells, but not Sox2inactive cells, resulted in a significant decrease in cell growth, invasiveness and tumorigenicity. To conclude, ALK+ALCL represents the first example of a hematologic malignancy that aberrantly expresses Sox2, which represents a novel mechanism by which NPM-ALK mediates tumorigenesis. We also found that the transcriptional activity and oncogenic effects of Sox2 can be heterogeneous in cancer cells.
Highlights
We found that protein expression was detectable in virtually all cells in both cell downregulation of signal transducer and activator of transcription 3 (STAT3) or nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expression was followed by lines (Figures 1d and e)
In support that the expression of green fluorescence protein (GFP) is specific for Sox[2], and d, we found evidence that the expression of Sox[2] was we found that the GFP expression in isolated Sox2active cells dependent on STAT3, as knockdown of STAT3 using siRNA decreased dramatically when Sox[2] was downregulated using resulted in a dramatic downregulation of Sox[2]
It has been reported that Sox[2] is expressed in CD34 þ hematopoietic stem cells.[41,42]. These observations suggest that the expression of Sox[2] in ALK þ ALCL cells represents an aberrant event
Summary
The biological importance of Sox[2] is highlighted by the observations that Sox[2] homozygous-null mouse embryos die soon after implantation,[5] and mutations of the Sox[2] gene have been linked to optic nerve hypoplasia and syndromic microphthalmia in humans.[6] Sox[2] is believed to work in concert with other ESC proteins, Oct[4], to maintain self-renewal and the pluripotency of ESCs.[5] Similar to the other Sox family members, Sox[2] binds to DNA in a highly sequence-specific manner.[3] Genes that are transcriptionally regulated by Sox[2] often contain a contiguous composite Sox-Oct cis-regulatory element to which Sox[2] and Oct[4] bind synergistically.[7,8] On the basis of results of chromatin immunoprecipitation-on-chip studies, it appears that the Sox2–Oct[4] regulatory complex upregulates a large number of genes important for the maintenance of the pluripotency of ESCs and downregulates genes responsible for the initiation of differentiation.[9,10] Recent studies have implicated Sox[2] in cancer biology. Sox[2] has been reported to be highly expressed in a number of solid tumors, including cancers of the prostate,[11] stomach,[12,13] breast,[14] colorectum,[15] brain[16,17] and testicles,[18] and most of these reports focus on the correlation between
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