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

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.

Pleomorphic Adenoma of the Salivary Glands and Epithelial–Mesenchymal Transition

“…The most crucial step in controlling gene expression is RNA transcription, which depends on the balance of positive and negative TFs. Negative TF suppresses positive TF when cartilage-specific genes such as δEF1 , AP-2α , SNAIL , SLUG , Twist1 , and C/EBPβ [ 48 , 69 , 70 , 71 , 72 ] are not expressed. Among these genes, δEF1 , AP-2α , and Twist1 are expressed by chondrocyte progenitor cells and can remain undifferentiated [ 58 , 69 , 71 , 72 ].…”

“…Negative TF suppresses positive TF when cartilage-specific genes such as δEF1 , AP-2α , SNAIL , SLUG , Twist1 , and C/EBPβ [ 48 , 69 , 70 , 71 , 72 ] are not expressed. Among these genes, δEF1 , AP-2α , and Twist1 are expressed by chondrocyte progenitor cells and can remain undifferentiated [ 58 , 69 , 71 , 72 ]. Therefore, their expression in salivary glands was compared to that in PA.…”

“…Twist1 , a member of the TF’s basic helix-loop-helix family, is essential for the development of tissues of mesoderm origin, emphasizing its function in EMT and metastasis [ 73 ]. Twist1 has also been identified as a downstream mediator of standard Wnt signaling, known to suppress cartilage cell differentiation in cartilage [ 72 ]. Furthermore, ectopic expression of Twist1 suppressed the expression of chondrocyte marker genes such as type II collagen and aggrecan in mouse chondrocyte progenitor cells.…”

“…Furthermore, ectopic expression of Twist1 suppressed the expression of chondrocyte marker genes such as type II collagen and aggrecan in mouse chondrocyte progenitor cells. In contrast, Twist1 depletion enhanced the expression of these genes [ 72 ]. Twist1 can directly or indirectly regulate the expression of the target gene.…”

The importance of Ras in drug resistance in cancer

“…Although the incidence of Ras mutations in cancer stem cells is relatively low, Ras‐mediated pathways have been implicated (Corces‐Zimmerman et al, 2014). In addition to the aforementioned β‐catenin‐mediated stabilisation of Ras, stabilised OCT4 and SOX2 expression has also been shown in response to AKT activation, by extracellular biochemical and radiation stresses (Maiuthed et al, 2018; Park et al, 2021). Indeed, activation of the MAPK pathway through the Ras–Raf interaction promotes increased expression of SOX2 and NANOG (Chan et al, 2018; Du et al, 2019).…”