State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
Department of Hematology, the First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen 361003, China.
Theranostics. 2024 May 13;14(7):3014-3028. doi: 10.7150/thno.94207. eCollection 2024.
Periostin (POSTN) is a critical extracellular matrix protein in various tumor microenvironments. However, the function of POSTN in thyroid cancer progression remains largely unknown. and 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 hybridization, chromatin immunoprecipitation assay, recombinant protein and inhibitor treatment were performed to explore the underlying mechanisms of POSTN-promoted papillary thyroid tumor growth. 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 and . 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. 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.
纤调蛋白（POSTN）是各种肿瘤微环境中一种关键的细胞外基质蛋白。然而，POSTN 在甲状腺癌进展中的功能仍知之甚少。本研究使用 POSTN 敲除小鼠和原位小鼠模型，以确定 POSTN 对甲状腺乳头状瘤进展的作用。进行免疫荧光、细胞共培养、荧光杂交、染色质免疫沉淀分析、重组蛋白和抑制剂处理，以探索 POSTN 促进甲状腺乳头状瘤生长的潜在机制。POSTN 在甲状腺乳头状瘤中上调，并与甲状腺癌患者的总生存率呈负相关。癌相关成纤维细胞（CAF）衍生的 POSTN 促进甲状腺乳头状瘤生长和转移。CAF 中 POSTN 的缺失显著损害了 CAF 促进的甲状腺乳头状瘤生长。POSTN 通过整合素-FAK-STAT3 信号通路促进甲状腺乳头状瘤细胞增殖和 IL-4 表达。反过来，肿瘤细胞衍生的 IL-4 通过激活 STAT6 激活 CAF 并刺激 POSTN 表达。我们揭示了 CAF 衍生的 POSTN 和肿瘤细胞衍生的 IL-4 通过 POSTN-整合素-FAK-STAT3-IL-4 通路在肿瘤细胞中以及 IL-4-STAT6-POSTN 信号通路在 CAF 中驱动甲状腺乳头状瘤发展的关键作用。我们的研究结果强调了 POSTN 和 IL-4 作为 CAFs 和肿瘤细胞之间动态相互作用的关键分子介质的重要性，最终支持甲状腺乳头状瘤的生长。
