Targeting JAK2/STAT3 Signaling Attenuates Radioresistance of Cancer Stem Cells in Colorectal cancer

Abstract

Radiotherapy (RT) is a highly effective nonsurgical treatment essential for patients with advanced colorectal cancer (CRC). Nevertheless, a subpopulation of cancer cells displaying intrinsic radioresistance survives after RT, raising risk of poor clinical outcomes. Here, we investigated the potential radioresistant signaling pathways responsible for aggressive phenotype by performing transcriptional profiling of CRC patient tissues. Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling was elevated in radioresistant CRC tissues as well as metastatic tissues. In multiple CRC cells, activation of JAK2/STAT3 signaling promoted radioresistance by limiting apoptosis and enhancing clonogenic potential, moreover, preferentially hyperactivated in the cancer stem cell (CSC) population. We discovered the direct transcriptional target of STAT3, allowing for persistent growth of CSCs after RT by maintaining an intact cell cycle and proliferation with low accumulation of DNA damage. Herein, we first identify the resistance mechanism for the persistent growth of CSCs after RT, suggesting potential biomarkers and regimens for improving outcomes among CRC patients.