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Theranostics 2024; 14(7):3014-3028. doi:10.7150/thno.94207 This issue Cite

Research Paper

Cancer-associated fibroblast-derived periostin promotes papillary thyroid tumor growth through integrin-FAK-STAT3 signaling

Xiaorui Jin^1,2, Qianmei Deng¹, Shuting Ye¹, Shuting Liu¹, Yilong Fu³, Yingfu Liu⁴, Guoyang Wu^3✉, Gaoliang Ouyang^1,2✉, Tiantian Wu^1✉

1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
2. Department of Hematology, the First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China.
3. Department of General Surgery, Zhongshan Hospital Affiliated to Xiamen University, Xiamen 361004, China.
4. Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China.

✉ Corresponding authors: Tiantian Wu, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China. E-mail: wutiantianedu.cn. Gaoliang Ouyang, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China. E-mail: oygldzedu.cn. Guoyang Wu, Department of General Surgery, Zhongshan Hospital Affiliated to Xiamen University, Xiamen 361004, China. E-mail: wuguoyangmailcom. More

Abstract

Background: Periostin (POSTN) is a critical extracellular matrix protein in various tumor microenvironments. However, the function of POSTN in thyroid cancer progression remains largely unknown.

Methods: Postn and Rag1 knock-out mice and orthotopic mouse models were used to determine the role of POSTN on papillary thyroid tumor progression. Immunofluorescence, cell co-culture, fluorescence in situ hybridization, chromatin immunoprecipitation assay, recombinant protein and inhibitor treatment were performed to explore the underlying mechanisms of POSTN-promoted papillary thyroid tumor growth.

Results: POSTN is up-regulated in papillary thyroid tumors and negatively correlates with the overall survival of patients with thyroid cancer. Cancer-associated fibroblast (CAF)-derived POSTN promotes papillary thyroid tumor growth in vivo and in vitro. POSTN deficiency in CAFs significantly impairs CAF-promoted papillary thyroid tumor growth. POSTN promotes papillary thyroid tumor cell proliferation and IL-4 expression through integrin-FAK-STAT3 signaling. In turn, tumor cell-derived IL-4 induces the activation of CAFs and stimulates POSTN expression by activating STAT6. We reveal the crucial role of CAF-derived POSTN and tumor cell-derived IL-4 in driving the development of papillary thyroid tumors through the POSTN-integrin-FAK-STAT3-IL-4 pathway in tumor cells and IL-4-STAT6-POSTN signaling in CAFs.

Conclusion: Our findings underscore the significance of POSTN and IL-4 as critical molecular mediators in the dynamic interplay between CAFs and tumor cells, ultimately supporting the growth of papillary thyroid tumors.

Keywords: periostin, extracellular matrix, papillary thyroid tumor, cancer-associated fibroblast, IL-4

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