Abstract
The current treatment strategy for patients with aggressive colorectal cancer has been hampered by resistance to radiotherapy and chemotherapy due to the existence of cancer stem-like cells (CSCs). Recent studies have shown that SOX2 expression plays an important role in the maintenance of CSC properties in colorectal cancer. In this study, we investigated the induction and regulatory role of SOX2 following the irradiation of radioresistant and radiosensitive colorectal cancer cells. We used FACS and western blotting to analyze SOX2 expression in cells. Among the markers of colorectal CSCs, the expression of CD44 increased upon irradiation in radioresistant cells. Further analysis revealed the retention of CSC properties with an upregulation of SOX2 as shown by enhanced resistance to radiation and metastatic potential in vitro. Interestingly, both the knockdown and overexpression of SOX2 led to increase in CD44+ population and induction of CSC properties in colorectal cancer following irradiation. Furthermore, selective genetic and pharmacological inhibition of the PI3K/AKT pathway, but not the MAPK pathway, attenuated SOX2-dependent CD44 expression and metastatic potential upon irradiation in vitro. Our findings suggested that SOX2 regulated by radiation-induced activation of PI3K/AKT pathway contributes to the induction of colorectal CSCs, thereby highlighting its potential as a therapeutic target.
Highlights
Given the evidence that SOX2 was aberrantly expressed and involved in the maintenance of cancer stem-like cells (CSCs) in colorectal cancer [14,15], these results indicated the possibility of a functional relationship between SOX2 expression and CD44-mediated CSC property in radioresistant cells upon radiation exposure
Recent studies have shown that SOX2 is aberrantly expressed and involved in the maintenance of properties of colorectal CSCs, including spheroid-like growth and metastatic potential [14,15]
We extended these studies to demonstrate that SOX2 is regulated by the phosphatidylinositol 3-kinase (PI3K)/AKT pathway and contributes to the induction of colorectal CSCs in response to radiation
Summary
Colorectal cancer is one of the most common malignancies and the fourth leading cause of cancer death in the world. The current treatment strategy for patients with aggressive colorectal cancer has been hampered by their resistance to radiotherapy and chemotherapy [1,2]. Growing evidence indicates that the existence of a small population of cancer cells known as cancer stem-like cells (CSCs) is responsible for tumor recurrence and is the main cause of treatment resistance in many cancers, including glioma, breast, oral, and colorectal cancer. CSCs further exhibit diverse cancer-initiating properties such as self-renewal and metastatic potential [3,4,5,6,7]. The molecular subclassification of CSCs based on their cancer-promotion property in colorectal cancer needs to be understood
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