*Article* **Radiation-Activated PI3K/AKT Pathway Promotes the Induction of Cancer Stem-Like Cells via the Upregulation of SOX2 in Colorectal Cancer**

**Ji-Hye Park 1,†, Young-Heon Kim 1,†, Sehwan Shim <sup>1</sup> , Areumnuri Kim <sup>1</sup> , Hyosun Jang <sup>1</sup> , Su-Jae Lee <sup>2</sup> , Sunhoo Park 1,3, Songwon Seo <sup>4</sup> , Won Il Jang <sup>1</sup> , Seung Bum Lee 1,\* ,‡ and Min-Jung Kim 1,\* ,‡**


**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 stemlike 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.

**Keywords:** colorectal cancer; cancer-stem like cells; radioresistance; SOX2; PI3K/AKT
