基质-肿瘤扩增的 STC1-Notch1 前馈信号促进肝癌的干细胞特性。
The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma.
机构信息
Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
出版信息
J Transl Med. 2023 Mar 31;21(1):236. doi: 10.1186/s12967-023-04085-8.
BACKGROUND
Cancer-associated fibroblasts (CAFs), an important component of the tumor microenvironment (TME), play crucial roles in tumor stemness. It has been shown in various cancer studies that stanniocalcin-1 (STC1) is secreted by CAFs, however, its function in HCC is still not clear.
METHODS
The serum concentration and intracellular expression level of STC1 were quantified by ELISA and western blotting, respectively. The role of CAF-derived STC1 in HCC stemness was investigated by sphere formation, sorafenib resistance, colony formation, and transwell migration and invasion assays in vitro and in an orthotopic liver xenograft model in vivo. An HCC tissue microarray containing 72 samples was used to evaluate the expression of STC1 and Notch1 in HCC tissues. Coimmunoprecipitation (CoIP) and dual-luciferase reporter assays were performed to further explore the underlying mechanisms. ELISAs were used to measure the serum concentration of STC1 in HCC patients.
RESULTS
We demonstrated that CAFs were the main source of STC1 in HCC and that CAF-derived STC1 promoted HCC stemness through activation of the Notch signaling pathway. In HCC patients, the expression of STC1 was positively correlated with Notch1 expression and poor prognosis. The co-IP assay showed that STC1 directly bound to Notch1 receptors to activate the Notch signaling pathway, thereby promoting the stemness of HCC cells. Our data further demonstrated that STC1 was a direct transcriptional target of CSL in HCC cells. Furthermore, ELISA revealed that the serum STC1 concentration was higher in patients with advanced liver cancer than in patients with early liver cancer.
CONCLUSIONS
CAF-derived STC1 promoted HCC stemness via the Notch1 signaling pathway. STC1 might serve as a potential biomarker for the prognostic assessment of HCC, and the stromal-tumor amplifying STC1-Notch1 feedforward signal could constitute an effective therapeutic target for HCC patients.
背景
癌症相关成纤维细胞（CAFs）是肿瘤微环境（TME）的重要组成部分，在肿瘤干性中发挥关键作用。在各种癌症研究中已经表明，斯钙素-1（STC1）由 CAFs 分泌，然而，其在 HCC 中的功能尚不清楚。
方法
通过 ELISA 和 Western blot 分别定量检测 STC1 的血清浓度和细胞内表达水平。通过体外球体形成、索拉非尼耐药、集落形成、Transwell 迁移和侵袭实验以及体内原位肝异种移植模型研究 CAF 衍生的 STC1 在 HCC 干性中的作用。使用包含 72 个样本的 HCC 组织微阵列评估 HCC 组织中 STC1 和 Notch1 的表达。进行免疫共沉淀（CoIP）和双荧光素酶报告基因检测以进一步探讨潜在机制。ELISA 用于测量 HCC 患者的血清 STC1 浓度。
结果
我们证明 CAFs 是 HCC 中 STC1 的主要来源，CAF 衍生的 STC1 通过激活 Notch 信号通路促进 HCC 干性。在 HCC 患者中，STC1 的表达与 Notch1 表达呈正相关，且与预后不良相关。CoIP 实验表明，STC1 直接与 Notch1 受体结合以激活 Notch 信号通路，从而促进 HCC 细胞的干性。我们的数据进一步表明，STC1 是 HCC 细胞中 CSL 的直接转录靶标。此外，ELISA 显示晚期肝癌患者的血清 STC1 浓度高于早期肝癌患者。
结论
CAF 衍生的 STC1 通过 Notch1 信号通路促进 HCC 干性。STC1 可能作为 HCC 预后评估的潜在生物标志物，基质-肿瘤放大的 STC1-Notch1 正反馈信号可能成为 HCC 患者的有效治疗靶点。
Zotero 插件