Theranostics 2021; 11(5):2297-2317. doi:10.7150/thno.51000 This issue Cite

Research Paper

CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3β/β-catenin/OCT4 axis

Wenzhi Shen1,2,✉, Xiaoyuan Zhang1,2, Jiaping Tang3, Zhixin Zhang4, Renle Du5, Dehong Luo6, Xiaoran Liu1, Yong Xia1, Yanping Li1, Shanshan Wang1, Siyuan Yan1, Wancai Yang1, Rong Xiang5, Na Luo3, Yunping Luo7, Jianjun Li2

1. Dept. of Pathology and Institute of Precision Medicine, Jining Medical University, Jining 272067, China.
2. Institute of Breast Research, Jining Medical University, Jining 272067, China.
3. Dept. of Anatomy and Histology, School of Medicine, Nankai University, Tianjin 300071, China.
4. Dept. of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining 272029, China.
5. Dept. of Immunology, School of Medicine, Nankai University, Tianjin 300071, China.
6. The First People's Hospital of Zunyi, Zunyi, 563002, China.
7. Dept. of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.

Citation:
Shen W, Zhang X, Tang J, Zhang Z, Du R, Luo D, Liu X, Xia Y, Li Y, Wang S, Yan S, Yang W, Xiang R, Luo N, Luo Y, Li J. CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3β/β-catenin/OCT4 axis. Theranostics 2021; 11(5):2297-2317. doi:10.7150/thno.51000. https://www.thno.org/v11p2297.htm
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Abstract

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Rationale: Considerable evidence suggests that breast cancer metastasis and recurrence occur due to emergence of cancer stem cells (CSCs). In our previous study, we designed a high-throughput siRNA screening platform that identifies inflammation genes involved in the regulation of cancer cell stemness. We reported that CCL16 protein decreases OCT4 expression and reduces the ALDH+ subpopulation. However, the mechanism by which CCL16 maintains stem cell-like properties remains unclear.

Methods: Tissue microarrays were used to evaluate CCL16 expression. Cancer stemness assays were performed in CCL16 knockdown and overexpressing cells in vitro and in a xenograft model in vivo. Human phosphokinase array, immunofluorescence and chromatin immunoprecipitation assays were performed to explore the underlying mechanism.

Results: We report that CCL16 was overexpressed in breast tumors and significantly correlated with clinical progression. We found that silencing CCL16 in MDA-MB-231 and BT549 cells diminished CSC properties including ALDH+ subpopulation, side population, chemo-resistance, and sphere formation. Furthermore, mice bearing CCL16-silenced MDA-MB-231 xenografts had lower tumorigenic frequency and developed smaller tumors. Exploration of the underlying mechanism found that CCL16 selects CCR2 to activate p-AKT/GSK3β signaling and facilitate β-catenin nuclear translocation. Further, CCL16 binds to the OCT4 promoter and promotes OCT4 expression. In addition, shRNAs targeting CCR2 and XAV939 targeting β-catenin abolished CCL16-mediated cancer stemness. Upstream, IL10 mediates STAT3 activation, which binds to the CCL16 promoter and enhances its expression. The STAT3-targeted inhibitor Stattic suppressed CCL16 expression in vitro and restrained tumor progression in vivo.

Conclusions: We identified a potential CSC regulator and suggest a novel mechanism for how CCL16 governs cancer cell stemness. We propose that CCL16 could be an effective target for breast cancer therapy.

Keywords: CCL16, CSCs, CCR2, β-catenin, OCT4, breast cancer


Citation styles

APA
Shen, W., Zhang, X., Tang, J., Zhang, Z., Du, R., Luo, D., Liu, X., Xia, Y., Li, Y., Wang, S., Yan, S., Yang, W., Xiang, R., Luo, N., Luo, Y., Li, J. (2021). CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3β/β-catenin/OCT4 axis. Theranostics, 11(5), 2297-2317. https://doi.org/10.7150/thno.51000.

ACS
Shen, W.; Zhang, X.; Tang, J.; Zhang, Z.; Du, R.; Luo, D.; Liu, X.; Xia, Y.; Li, Y.; Wang, S.; Yan, S.; Yang, W.; Xiang, R.; Luo, N.; Luo, Y.; Li, J. CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3β/β-catenin/OCT4 axis. Theranostics 2021, 11 (5), 2297-2317. DOI: 10.7150/thno.51000.

NLM
Shen W, Zhang X, Tang J, Zhang Z, Du R, Luo D, Liu X, Xia Y, Li Y, Wang S, Yan S, Yang W, Xiang R, Luo N, Luo Y, Li J. CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3β/β-catenin/OCT4 axis. Theranostics 2021; 11(5):2297-2317. doi:10.7150/thno.51000. https://www.thno.org/v11p2297.htm

CSE
Shen W, Zhang X, Tang J, Zhang Z, Du R, Luo D, Liu X, Xia Y, Li Y, Wang S, Yan S, Yang W, Xiang R, Luo N, Luo Y, Li J. 2021. CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3β/β-catenin/OCT4 axis. Theranostics. 11(5):2297-2317.

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