Lundberg Ida V, Löfgren Burström Anna, Edin Sofia, Eklöf Vincy, Öberg Åke, Stenling Roger, Palmqvist Richard, Wikberg Maria L
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden.
PLoS One. 2014 Jul 10;9(7):e101957. doi: 10.1371/journal.pone.0101957. eCollection 2014.
Sporadic colorectal cancer (CRC) is a common malignancy and also one of the main causes of cancer deaths worldwide. Aberrant expression of the transcription factor SOX2 has recently been observed in several cancer types, but its role in CRC has not been fully elucidated. Here we studied the expression of SOX2 in 441 CRC patients by immunohistochemistry and related the expression to clinicopathological and molecular variables and patient prognosis. SOX2 was expressed in 11% of the tumors and was significantly associated to BRAFV600E mutation, but not to KRAS mutations (codon 12 and 13). SOX2 positivity was correlated to poor patient survival, especially in BRAFV600E mutated cases. In vitro studies showed that cells expressing the constitutively active BRAFV600E had increased SOX2 expression, a finding not found in cells expressing KRASG12V. Furthermore, blocking downstream BRAF signalling using a MEK-inhibitor resulted in a decreased expression of SOX2. Since SOX2 overexpression has been correlated to increased migration and invasion, we investigated the SOX2 expression in human CRC liver metastasis and found that a SOX2 positive primary CRC also had SOX2 expression in corresponding liver metastases. Finally we found that cells overexpressing SOX2 in vitro showed enhanced expression of FGFR1, which has been reported to correlate with liver metastasis in CRC. Our novel findings suggest that SOX2 expression is partly regulated by BRAF signalling, and an increased SOX2 expression may promote CRC metastasis and mediate a poor patient prognosis.
散发性结直肠癌（CRC）是一种常见的恶性肿瘤，也是全球癌症死亡的主要原因之一。转录因子SOX2的异常表达最近在几种癌症类型中被观察到，但其在CRC中的作用尚未完全阐明。在此，我们通过免疫组织化学研究了441例CRC患者中SOX2的表达，并将该表达与临床病理和分子变量以及患者预后相关联。SOX2在11%的肿瘤中表达，并且与BRAFV600E突变显著相关，但与KRAS突变（密码子12和13）无关。SOX2阳性与患者生存率低相关，尤其是在BRAFV600E突变的病例中。体外研究表明，表达组成型活性BRAFV600E的细胞中SOX2表达增加，而在表达KRASG12V的细胞中未发现此现象。此外，使用MEK抑制剂阻断BRAF下游信号传导导致SOX2表达降低。由于SOX2过表达与迁移和侵袭增加相关，我们研究了人CRC肝转移中SOX2的表达，发现SOX2阳性的原发性CRC在相应的肝转移中也有SOX2表达。最后，我们发现体外过表达SOX2的细胞中FGFR1表达增强，据报道FGFR1与CRC肝转移相关。我们的新发现表明，SOX2表达部分受BRAF信号传导调节，SOX2表达增加可能促进CRC转移并导致患者预后不良。
