**1. Introduction**

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 [3–7]. For the identification of CSCs, several putative markers such as transmembrane glycoprotein (CD133) and the cell-surface glycoprotein

**Citation:** Park, J.-H.; Kim, Y.-H.; Shim, S.; Kim, A.; Jang, H.; Lee, S.-J.; Park, S.; Seo, S.; Jang, W.I.; Lee, S.B.; et al. Radiation-Activated PI3K/AKT Pathway Promotes the Induction of Cancer Stem-Like Cells via the Upregulation of SOX2 in Colorectal Cancer. *Cells* **2021**, *10*, 135. https:// doi.org/10.3390/cells10010135

Received: 30 November 2020 Accepted: 8 January 2021 Published: 12 January 2021

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(CD44) were reported to be expressed in colorectal cancer and correlated with high-risk cases and a poorer survival rate of colorectal cancer patients [8,9]. However, the molecular subclassification of CSCs based on their cancer-promotion property in colorectal cancer needs to be understood.

The stemness program is involved in maintaining the properties of CSCs, such as selfrenewal and cancer-initiation, which are the hallmarks of cancer cells. SOX2 is a member of the SRY-related HMG-box (SOX) gene family and play an essential role in the maintenance of a pluripotent state in stem cells and cell-fate determination during developmental processes [10,11]. SOX2 is one of the key molecules driving CSC properties. SOX2-expressing cancer cells, such as those in skin and bladder carcinomas, express high levels of CSC markers, depending on tissue origin, and reveal enhanced tumorigenicity [12,13]. Recent studies have shown that SOX2 is aberrantly expressed and involved in the maintenance of CSCs. The properties of CSCs, including spheroid-like growth and metastatic potential, were observed in SOX2-positive colorectal cancer with an increased expression of CSC markers such as CD44 [14,15]. Moreover, Ghisolfi et al. recently showed that environmental stresses such as radiation induced the expression of both mRNA and protein of SOX2 and regulated CSCs in hepatocellular carcinoma cells [16]. However, the induction and the signaling pathways of SOX2 upon environmental stress in colorectal CSCs remain unclear.

In this study, we investigated the induction and regulatory role of SOX2 in colorectal CSCs following radiation exposure in both radioresistant and radiosensitive colorectal cancer cell lines.
