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Theranostics 2019; 9(2):424-435. doi:10.7150/thno.29698 This issue Cite

Research Paper

Low Levels of Sox2 are required for Melanoma Tumor-Repopulating Cell Dormancy

Qiong Jia^1*, Fang Yang^1*, Wei Huang², Yao Zhang¹, Binghao Bao³, Ke Li¹, Fuxiang Wei¹, Cunyu Zhang¹, Haibo Jia^3✉

1. Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomechanical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
2. National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
3. Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
*These authors contributed equally to the study.

✉ Corresponding author: Dr. Haibo Jia, Phone/fax: (+86) 2787792072; Email: haibo.jiaedu.cn

Abstract

Tumorigenic cells, when facing a hostile environment, may enter a dormant state, leading to long-term tumor survival, relapse, and metastasis. To date, the molecular mechanism of tumor cell dormancy remains poorly understood.

Methods: A soft, 3-dimentional (3D) fibrin gel culture system was used to mechanically select and grow highly malignant and tumorigenic melanoma tumor-repopulating cells (TRCs). We cultured control melanoma TRCs, TRCs with Sox2 knockdown, TRCs with Sox2 knockout, and a 2D control for in vitro and in vivo experiments. Western blotting, immunofluorescence, and flow cytometry analysis were performed to examine TRC dormancy and exit from dormancy.

Results: Under a low-expression condition, we show that Sox2, a stemness molecule participates in dormancy regulation of highly tumorigenic cells that can repopulate a tumor (TRCs). Intriguingly, complete depletion of Sox2 via knockout results in dormancy exit and growth resumption of melanoma TRCs in culture and elevation of melanoma TRC apoptosis. Mice that are injected subcutaneously with Sox2-depleted melanoma TRCs do not form tumors and survive much longer than those injected with melanoma TRCs. We found that complete depletion of Sox2 promotes nuclear translocation of phosphorylated STAT3, where it binds to the p53 gene promoter, thus activating the p53-caspase3 cascade.

Conclusion: These findings provide a novel insight into the role of the Sox2 gene in tumor cell stemness, tumor dormancy, and apoptosis.

Keywords: dormancy, TRCs (tumor-repopulating cells), Sox2 gene, apoptosis, stemness

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