Abstract
Recent studies have demonstrated the involvement of colorectal cancer (CRC) stem cells (CSC) in transformation, cancer progression and metastasis. The main goal of this paper was to examine the molecular mechanisms by which SATB2 induced malignant transformation of colorectal epithelial cells. SATB2 induced malignant transformation and these transformed cells gained the characteristics of CSCs by expressing stem cell markers (CD44, CD133, LGR5 and DCLK1) and transcription factors (c-Myc, Nanog and Sox2). Overexpression of SATB2 in normal colorectal epithelial cells increased cell motility, migration and invasion, which were associated with an increase in N-cadherin and Zeb1, and decrease in E-cadherin expression. SATB2 overexpression also upregulated XIAP and cyclin D1, suggesting its role in cell survival and cell cycle. Furthermore, the expression of SATB2 was positively correlated with β-catenin expression in CRC. In contrary, depletion of SATB2 inhibited cell proliferation, colony formation, cell motility and expression of β-catenin, Snail, Slug, Zeb1 and N-cadherin, and upregulated E-cadherin. Furthermore, SATB2 silencing inhibited the expression of stem cell markers, pluripotency maintaining transcription factors, cell cycle and cell proliferation/survival genes and TCF/LEF targets. Finally, β-catenin/TCF-LEF pathway mediated the biological effects of SATB2 in CSCs. These studies support the role of SATB2/β-catenin/TCF-LEF pathway in transformation and carcinogenesis.
Highlights
Colorectal cancer (CRC) is the third most common malignancy worldwide, and accounts for nearly 1 million newly diagnosed cases and half a million deaths each year[1]
Since SATB2 is not expressed in human normal colon epithelial cells, but highly expressed in transformed cells, CSCs and colorectal cancer (CRC) cell lines, it can be used as a diagnostic biomarker for CRC
SATB2 is not expressed in human normal colon epithelial cells, but it is highly expressed in colorectal cancer cell lines
Summary
Colorectal cancer (CRC) is the third most common malignancy worldwide, and accounts for nearly 1 million newly diagnosed cases and half a million deaths each year[1]. SATB2 is over expressed in 85% of CRC tumors, suggesting its use as a diagnostic marker for colon cancer[19]. During embryonic development Wnt/β-catenin signaling pathway plays a crucial role in regulating cell proliferation and differentiation, whereas in adults it regulates tissue homeostasis and injury repair through generation of stem cells[22,23,24]. Wnt ligands activate signaling pathway leading to β-catenin stabilization, nuclear translocation, TCF/LEF transcription and induction of β-catenin/TCF target genes[25, 26]. Some of the targets of TCF/LEF includes pluripotency maintaining factors (c-Myc, Sox-2, Oct-4, Nanog), stem cell marker (CD44), cell cycle and cell survival genes (Cyclin D1 and Survivin), EMT- and metastasis-related genes (Twist, E-cadherin, MMP2, MMP7 and MMP9), and angiogenesis regulator (VEGF)[34]. The regulation Wnt/β-catenin signaling pathway by SATB2 has not been examined
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