Abstract
BackgroundTo improve current treatment strategies for patients with aggressive colorectal cancer (CRC), the molecular understanding of subgroups of CRC with poor prognosis is of vast importance. SOX2 positive tumors have been associated with a poor patient outcome, but the functional role of SOX2 in CRC patient prognosis is still unclear.MethodsAn in vitro cell culture model expressing SOX2 was used to investigate the functional role of SOX2 in CRC. In vitro findings were verified using RNA from fresh frozen tumor tissue or immunohistochemistry on formalin fixed paraffin embedded (FFPE) tumor tissue from a cohort of 445 CRC patients.ResultsUsing our in vitro model, we found that SOX2 expressing cells displayed several characteristics of cancer stem cells; such as a decreased proliferative rate, a spheroid growth pattern, and increased expression of stem cell markers CD24 and CD44. Cells expressing SOX2 also showed down-regulated expression of the intestinal epithelial marker CDX2. We next evaluated CDX2 expression in our patient cohort. CDX2 down-regulation was more often found in right sided tumors of high grade and high stage. Furthermore, a decreased expression of CDX2 was closely linked to MSI, CIMP-high as well as BRAF mutated tumors. A decreased expression of CDX2 was also, in a stepwise manner, strongly correlated to a poor patient prognosis. When looking at SOX2 expression in relation to CDX2, we found that SOX2 expressing tumors more often displayed a down-regulated expression of CDX2. In addition, SOX2 expressing tumors with a down-regulated CDX2 expression had a worse patient prognosis compared to those with retained CDX2 expression.ConclusionsOur results indicate that SOX2 expression induces a cellular stem cell state in human CRC with a decreased expression of CDX2. Furthermore, a down-regulated expression of CDX2 results in a poor patient prognosis in CRC and at least part of the prognostic importance of SOX2 is mediated through CDX2 down-regulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2509-5) contains supplementary material, which is available to authorized users.
Highlights
To improve current treatment strategies for patients with aggressive colorectal cancer (CRC), the molecular understanding of subgroups of CRC with poor prognosis is of vast importance
In a cohort of CRC patients, we further demonstrate that SOX2 expression is significantly associated with down-regulated expression of Caudal type homeobox 2 (CDX2) and at least part of the prognostic importance of SOX2 is mediated through CDX2 downregulation
We investigated the expression of several matrix metalloproteinases (MMPs) to examine possible effects on the extracellular matrix, caused by SOX2 expression
Summary
To improve current treatment strategies for patients with aggressive colorectal cancer (CRC), the molecular understanding of subgroups of CRC with poor prognosis is of vast importance. SOX2 positive tumors have been associated with a poor patient outcome, but the functional role of SOX2 in CRC patient prognosis is still unclear. CRC is often detected at late stages contributing to the high mortality rate seen in this disease. Most patients receive a similar stage specific treatment strategy, not all benefit from. It is known that SOX2 plays essential roles in cell fate determination, thereby regulating developmental processes [2]. Aberrant expression of SOX2 has been reported in CRC as well as several other types of cancers [3,4,5,6]. According to our previous study, Lundberg et al BMC Cancer (2016) 16:471
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