Journal Article

The JAK2/STAT3/CCND2 Axis promotes colorectal Cancer stem cell persistence and radioresistance

Choi, Jang-Hyun, Kim, Jee-Heun, Nam, Jeong-Seok, Park, So-Yeon, Lee, Choong-Jae, Kim, Ji-Won, Kim, Ji-Young

2019

Overview

Background Radiotherapy (RT) is a highly effective multimodal nonsurgical treatment that is essential for patients with advanced colorectal cancer (CRC). Nevertheless, cell subpopulations displaying intrinsic radioresistance survive after RT. The reactivation of their proliferation and successful colonization at local or distant sites may increase the risk of poor clinical outcomes. Recently, radioresistant cancer cells surviving RT were reported to exhibit a more aggressive phenotype than parental cells, although the underlying mechanisms remain unclear. Methods By investigating public databases containing CRC patient data, we explored potential radioresistance-associated signaling pathways. Then, their mechanistic roles in radioresistance were investigated through multiple validation steps using patient-derived primary CRC cells, human CRC cell lines, and CRC xenografts. Results Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling was activated in radioresistant CRC tissues in correlation with local and distant metastases. JAK2 was preferentially overexpressed in the CRC stem cell subpopulation, which was accompanied by the phosphorylation of STAT proteins, especially STAT3. JAK2/STAT3 signaling played an essential role in promoting tumor initiation and radioresistance by limiting apoptosis and enhancing clonogenic potential. Mechanistically, the direct binding of STAT3 to the cyclin D2 (CCND2) promoter increased CCND2 transcription. CCND2 expression was required for persistent cancer stem cell (CSC) growth via the maintenance of an intact cell cycle and proliferation with low levels of DNA damage accumulation. Conclusion Herein, we first identified JAK2/STAT3/CCND2 signaling as a resistance mechanism for the persistent growth of CSCs after RT, suggesting potential biomarkers and regimens for improving outcomes among CRC patients.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Apoptosis / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer stem cells (CSCs) / Care and treatment / Cell cycle / Cell Line, Tumor / Colorectal cancer / Colorectal cancer (CRC) / Colorectal Neoplasms - genetics / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - radiotherapy / Cyclin D2 (CCND2) / Cyclin D2 - metabolism / Diagnosis / Gene Knockout Techniques / Genetic aspects / Genetic transcription / Humans / Hyaluronan Receptors - metabolism / Immunology / Janus kinase 2 (JAK2) / Janus Kinase 2 - metabolism / Kinases / Models, Biological / Neoplastic Stem Cells - metabolism / Oncology / Radiation Tolerance - genetics / Radioresistance / Radiotherapy / Signal transducer and activator of transcription 3 (STAT3) / Signal Transduction / STAT3 Transcription Factor - metabolism / Stem cells