IGF/STAT3/NANOG/Slug Signaling Axis Simultaneously Controls Epithelial-Mesenchymal Transition and Stemness Maintenance in Colorectal Cancer

Abstract

Discovery of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are two milestones in people exploring the nature of malignant tumor in recent decades. Although some studies have presented the potential connections between them, the link details, underneath their superficial correlation, are largely unknown. In this study, we identified a small subpopulation of NANOG-positive colorectal cancer (CRC) cells, and demonstrated that they exhibited characteristics of CSCs and EMT traits simultaneously. Furthermore, we found that NANOG was a core factor in regulating both of EMT and stemness in CRC cells, NANOG modulate EMT and metastasis by binding to Slug promoter and transcriptionally regulate Slug expression. For the first time, we demonstrated that NANOG was regulated by extracellular IGF signaling pathway via STAT3 phosphorylation in CRC. This coincides with that IGF receptor IGF-1R is often increasing expressed in malignant metastasis colon cancer. Taken together, our data define the crucial functions of IGF/STAT3/NANOG/Slug signaling axis in the progression of CRC by operating EMT and CSCs properties, which make them served as potential therapeutic targets for treatment of CRC. STEM CELLS 2016;34:820-831 SIGNIFICANCE STATEMENTNANOG, a core multipotential transcription factor was described as a stemness maintainer and EMT facilitator, but the knowledge of tumor-environmental triggering signal of NANOG is limited. Here we show that IGF signaling, an important tumor promoting signal and a poor prognosis indicator of CRC, drive the expression of NANOG by cytoplasmic mediator STAT3. Besides the role as a stemness maintainer, NANOG promotes EMT through activating Slug at transcriptional level directly. The evidence of IGF/STAT3/NANOG/Slug axis as a causative mechanism of NANOG-mediated EMT and self-renewal of CSCs contributes to uncover the yet incompletely understood process of tumor initiation and metastasis.

PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer

“…Once the cancer cells obtain mesenchymal phenotypes, they gain the ability to migrate into the stroma or migrate to distant sites and organs, and finally contribute to tumor metastasis and recurrence [42,43]. In addition, numerous studies have also indicated that cancer cells undergoing EMT attain certain characteristics of cancer stem cells, which leads to chemo/radio resistance and tumor immune escape [44]. It is noteworthy that PD-L1 has been considered as an important mediator of EMT in certain human cancer tissues, such as lung cancer, colorectal cancer, and head and neck cancer [21].…”

Sterol regulatory element-binding protein 1 cooperates with c-Myc to promote epithelial-mesenchymal transition in colorectal cancer

“…Metastasis is the primary cause of mortality in patients with CRC, the mechanism of which remains to be fully elucidated (3,18). Further investigation into the underlying mechanisms of CRC metastasis is required.…”

“…Metabolic reprogramming is one of the key features of cancer cells (18). SREBP1 has become an area of interest in cancer biology because it is a key regulator of lipid metabolism (19).…”

Steering of carcinoma progression by the YIN/YANG interaction of STAT1/STAT3

“…Patients with gain-of-function (GOF) mutations in STAT3 shape the cancer gene expression landscape of inflammatory liver adenomas or of mature T cell neoplasia (26,27). Importantly, STAT3 regulates also stem cell to tissue fate and invasive processes through epithelial to mesenchymal transitions or mesenchymal to epithelial transitions during embryo or cancer progression (28). Thus, STAT3 can control key differentiation processes under physiologic or malignant conditions.…”