Zfra activates memory Hyal-2+ CD3- CD19- spleen cells to block cancer growth, stemness, and metastasis in vivo
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Ming-Hui Lee1,*, Wan-Pei Su1,*, Wan-Jen Wang1,*, Sing-Ru Lin1,*, Chen-Yu Lu1,*, Yu-An Chen1,*, Jean-Yun Chang1, Shenq-Shyang Huang1, Pei-Yi Chou1, Siou-Ru Ye1, Szu-Jung Chen1, Huan He1, Ting-Hsiu Liu1, Ying-Tsen Chou2, Li-Jin Hsu3,4,*, Feng-Jie Lai5, Shean-Jen Chen6, Hoong-Chien Lee7, David Kakhniashvili8, Steven R. Goodman8, Nan-Shan Chang1,2,4,6,9
1Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan, ROC
2Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan, ROC
3Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University Medical College, Tainan, Taiwan, ROC
4Center of Infectious Disease and Signal Research, National Cheng Kung University, Tainan, Taiwan, ROC
5Department of Dermatology, Chi-Mei Medical Center, Tainan, Taiwan, ROC
6Advanced Optoelectronic Technology Center, National Cheng Kung University Medical College, Tainan, Taiwan, ROC
7Graduate Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, Taiwan, ROC
8Institute of Biomedical Sciences and Technology, Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
9Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA
*These authors have contributed equally to this work
Nan-Shan Chang, e-mail: [email protected]
Keywords: Zfra, skin cancer, melanoma, metastasis, stemness
Received: September 18, 2014 Accepted: December 11, 2014 Published: February 20, 2015
Zfra is a 31-amino-acid zinc finger-like protein, which participates in the tumor necrosis factor signaling. Here, we determined that when nude mice and BALB/c mice were pre-injected with nanogram levels of a synthetic Zfra1–31 or truncated Zfra4–10 peptide via tail veins, these mice became resistant to the growth, metastasis and stemness of melanoma cells, and many malignant cancer cells. The synthetic peptides underwent self-polymerization in phosphate-buffered saline. Alteration of the Ser8 phosphorylation site to Gly8 abolished Zfra aggregation and its-mediated cancer suppression in vivo. Injected Zfra peptide autofluoresced due to polymerization and was trapped mainly in the spleen. Transfer of Zfra-stimulated spleen cells to naïve mice conferred resistance to cancer growth. Zfra-binding cells, designated Hyal-2+ CD3- CD19- Z cells, are approximately 25–30% in the normal spleen, but are significantly downregulated (near 0–3%) in tumor-growing mice. Zfra prevented the loss of Z cells caused by tumors. In vitro stimulation or education of naïve spleen cells with Zfra allowed generation of activated Z cells to confer a memory anticancer response in naïve or cancer-growing mice. In particular, Z cells are abundant in nude and NOD-SCID mice, and can be readily activated by Zfra to mount against cancer growth.
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