Interestingly in HCC cell lines

Interestingly, in HCC cell lines the overexpression of SOX2 correlated with an increased cell invasion and sphere formation ability (Sun et al., 2013), suggesting a connection to an EMT and CSC phenotype. In HCC patients, SOX2 expression predicted poor overall survival and prognosis even after hepatectomy (Sun et al., 2013; Yin et al., 2013). Investigating SOX2 expression levels in colorectal cancer (CRC) patients, Lundberg et al. detected expression in 11% of patients (n=441 CRC tissue samples) (Lundberg et al., 2014), and demonstrated that the expression level correlated with liver and lymph-node metastasis and predicts poor patient survival (Saiki et al., 2009; Lundberg et al., 2014). Furthermore, they discovered an association with BRAFV600E mutations (Lundberg et al., 2014), which was linked to poor prognosis. Interestingly, no correlation was found regarding KRAS mutations (codon 12 and 13). SOX2 is not expressed in normal pancreatic acinar or ductal cells of the pancreas, but was detected in 19.3% out of 217 human PDAC samples. As in colorectal cancer, the overexpression of SOX2 resulted in enhanced cell proliferation, de-differentiation, and an EMT phenotype (Herreros-Villanueva et al., 2013.) Interestingly, SOX2 levels increased during PanIN (pancreatic intraepithelial neoplasia) progression, suggesting a role of SOX2 during early pancreatic tumorigenesis. SOX2 expression is also common (57.1%) in invasive and poorly differentiated PDACs, corroborating an important role of SOX2 also in the maintenance of carcinogenesis (Sanada et al., 2006).
KLF4 Krüppel-like-factor 4 (KLF4) is a zinc finger type transcription factor known to be highly expressed in various human tissues, including epithelial cells of the gastrointestinal-tract (Chen et al., 2003). KLF4 is able to bi-directionally regulate genes that are controlling Saracatinib regulation, epithelial differentiation, EMT, and apoptosis. On the one hand, KLF4 is able to induce a p21-dependent cell cycle arrest, thus acting as a tumor suppressor, whereas on the other hand, in the presence of pro-oncogenic signals, such as oncogenic RAS, KLF4 is able to inhibit apoptosis by inhibition of the Bax/p53-tumorsupressor complex. These two antithetic effects might explain the apparently divergent roles of KLF4 in different tumor types, depending on the presence of additional oncogenic factors. In the intestine epithelial KLF4 exerts an important role in epithelial proliferation and differentiation. Here, KLF4 displays an identical expression pattern as the negative regulator of WNT, APC (adenomatous polyposis gene) (Chen et al., 2003; Jenkins et al., 1998; Katz et al., 2005). However, there is further evidence of KLF4 as a driver of carcinogenesis in gastrointestinal-cancers: thus, as a tumor suppressor, the biological role of KLF4 is very distinct from SOX2 and OCT4. KLF4 is commonly decreased or lost in gastrointestinal cancers (Yang et al., 2005; Wei et al., 2005; Zhang et al., 2012a; Zhang et al., 2012b; Choi et al., 2006; Patel et al., 2010; Li et al., 2012), and the loss of KLF4 expression is associated with poor clinical outcome (Wei et al., 2006). KLF4 is known to be down-regulated during tumor initiation, and consecutively lost during tumor progression. In order to determine the expression level of KLF4 as well as its prognostic relevance, Ma et al. examined 98 ESCC patient samples. KLF4 expression was significantly higher in corresponding normal esophageal tissue (82.7% positive) as compared to tumor tissue (43.8% positive), and correlated with the differentiation grade of the tumor. Overall survival was significantly better in the KLF4 expression group as compared to the KLF4 negative group (median OS of 55 vs. 26months; 5-year OS 48.8% vs. 25.5%) (Ma et al., 2014). Concerning gastric cancer, clinicopathological examination of patient samples revealed a significantly higher overall survival rate in patients with high cytoplasmic KLF4 expression as compared to low expression (Hsu et al., 2013). A genetically engineered KLF4 knockout mouse model led to increased stomach cell proliferation and triggered the formation of precancerous lesions (Katz et al., 2005). In gastric cancer a frequent abnormal activation of β-catenin was linked to increased tumor growth, invasion, and metastasis (Conacci-Sorrell et al., 2003). In human gastric cancer cell lines KLF4 inhibited β-catenin expression, thus regulating β-catenin-mediated functions in gastric cancer cells (Zhang et al., 2012b).