CAFs 来源的 SCUBE1 通过 Shh/Gli1 通路在肝癌中促进恶性肿瘤和干细胞特性。
CAFs-derived SCUBE1 promotes malignancy and stemness through the Shh/Gli1 pathway in hepatocellular carcinoma.
机构信息
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, Zhejiang, China.
Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
出版信息
J Transl Med. 2022 Nov 8;20(1):520. doi: 10.1186/s12967-022-03689-w.
BACKGROUND
The tumour microenvironment and cirrhotic liver are excellent sources of cancer-associated fibroblasts (CAFs), which participate in carcinogenesis. Thus, it is important to clarify the crosstalk between CAFs and HCC cells and the related mechanism in regulating carcinogenesis.
METHODS
Human hepatocellular carcinoma (HCC) tissues and matched adjacent normal tissues were obtained from HCC patients. Immunohistochemistry, Western blotting (WB) and RT-qPCR were performed to detect the expression of SCUBE1. The roles of SCUBE1 in inducing stemness features in HCC cells were explored and investigated in vitro and in vivo. Student's t tests or Mann-Whitney U tests were used to compare continuous variables, while chi-square tests or Fisher's exact tests were used to compare categorical variables between two groups.
RESULTS
SCUBE1 was confirmed to be highly expressed in CAFs in HCC and had a strong connection with stemness and a poor prognosis. In addition, CAFs were found to secrete SCUBE1 to enhance the malignancy of HCC cells and increase the proportion of CD133-positive cells. Silencing SCUBE1 expression had the opposite effect. The Shh pathway was activated by SCUBE1 stimulation. Inhibition of cyclopamine partially reversed the stimulating effect of SCUBE1 both in vivo and in vitro. Moreover, based on the RT-qPCR, ELISA and WB results, a high SCUBE1 expression level was found in HCC tissue and serum.
CONCLUSION
This study revealed that CAFs-derived SCUBE1 can enhance the malignancy and stemness of HCC cells through the Shh pathway. This study aims to provide new perspectives for future HCC studies and provide new strategies for HCC treatment.
背景
肿瘤微环境和肝硬化是癌相关成纤维细胞（CAFs）的绝佳来源，CAFs 参与了癌症的发生。因此，阐明 CAFs 与 HCC 细胞之间的相互作用及其在调节癌变中的相关机制非常重要。
方法
从 HCC 患者中获取人肝癌（HCC）组织及其配对的相邻正常组织。采用免疫组织化学、Western blot（WB）和 RT-qPCR 检测 SCUBE1 的表达。在体外和体内研究 SCUBE1 诱导 HCC 细胞干性特征的作用及其相关机制。采用 Student's t 检验或 Mann-Whitney U 检验比较两组间连续变量，采用卡方检验或 Fisher 确切概率法比较两组间分类变量。
结果
SCUBE1 在 HCC 中的 CAFs 中高表达，与干性和不良预后有很强的关联。此外，发现 CAFs 分泌 SCUBE1 以增强 HCC 细胞的恶性程度，并增加 CD133 阳性细胞的比例。沉默 SCUBE1 表达则产生相反的效果。SCUBE1 刺激激活了 Shh 通路。在体内和体外，用环巴胺抑制 Shh 通路可以部分逆转 SCUBE1 的刺激作用。此外，基于 RT-qPCR、ELISA 和 WB 结果，发现 HCC 组织和血清中存在高表达的 SCUBE1。
结论
本研究揭示了 CAFs 来源的 SCUBE1 通过 Shh 通路增强 HCC 细胞的恶性程度和干性。本研究旨在为未来的 HCC 研究提供新的视角，并为 HCC 的治疗提供新的策略。
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