Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
J Mol Med (Berl). 2019 Feb;97(2):243-255. doi: 10.1007/s00109-018-1731-9. Epub 2018 Dec 18.
Cancer stem cells (CSCs), which support tumor progress in hepatocellular carcinoma (HCC) developed in fibrotic or cirrhotic livers, are regulated by the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are the major component of the tumor stroma in HCC; however, the mechanisms by which CAFs contribute to stemness maintenance remain largely unknown. Here, we found that the expression of CD24 was high in HCC tissues compared with adjacent normal liver tissues, and positively correlated with the poor prognosis and α-SMA expression in CAFs. CD24 cells isolated from HCC cell lines exhibited stemness properties of self-renewal, chemotherapy resistance, metastasis, and tumorigenicity in NOD/SCID mice. Moreover, CAF-derived HGF and IL6 enhanced the stemness properties of CD24 cells via activating STAT3 Tyr705 phosphorylation. Blockade of HGF/c-Met or IL6/IL6R signaling significantly abolished the effect of CAFs on stemness properties, which compromised the activation of STAT3 pathway in CD24 cells. Meanwhile, knockdown of STAT3 in CD24 cells notably attenuated CAF-induced stemness characteristics of CD24 cells. Furthermore, in HCC patients, higher expression of phospho-STAT3 was also demonstrated to be positively correlated with poor clinical outcomes. In summary, HGF and IL6 secreted by CAFs promoted the stemness properties of CD24 cells through the phosphorylation of STAT3 signaling, and targeting the paracrine pathways may provide a new therapeutic strategy for HCC. KEY MESSAGES: CD24, identified as a marker for HCC CSCs, was positively correlated with the poor prognosis and α-SMA expression in CAFs. CAFs promoted self-renewal, chemotherapy resistance, metastasis, and tumorigenicity of CD24 HCC cells. HGF and IL6 secreted by CAFs promoted the stemness properties of CD24 HCC cells through the phosphorylation of STAT3.
癌症干细胞（CSCs）在纤维变性或肝硬化中发展的肝细胞癌（HCC）中支持肿瘤进展，受肿瘤微环境调节。癌症相关成纤维细胞（CAFs）是 HCC 肿瘤基质的主要成分；然而，CAFs 促进干细胞维持的机制在很大程度上仍不清楚。在这里，我们发现与相邻正常肝组织相比，HCC 组织中 CD24 的表达较高，并且与 CAF 中的不良预后和 α-SMA 表达呈正相关。从 HCC 细胞系中分离出的 CD24 细胞在 NOD/SCID 小鼠中表现出自我更新、化疗耐药、转移和致瘤性的干细胞特性。此外，CAF 衍生的 HGF 和 IL6 通过激活 STAT3 Tyr705 磷酸化增强了 CD24 细胞的干细胞特性。阻断 HGF/c-Met 或 IL6/IL6R 信号显著消除了 CAFs 对干细胞特性的影响，从而使 CD24 细胞中 STAT3 途径的激活受到影响。同时，CD24 细胞中 STAT3 的敲低显著减弱了 CAF 诱导的 CD24 细胞的干细胞特征。此外，在 HCC 患者中，磷酸化 STAT3 的高表达也被证明与不良临床结局呈正相关。总之，CAFs 分泌的 HGF 和 IL6 通过 STAT3 信号的磷酸化促进了 CD24 细胞的干细胞特性，靶向旁分泌途径可能为 HCC 提供一种新的治疗策略。
CD24 被鉴定为 HCC CSCs 的标志物，与 CAF 中的不良预后和 α-SMA 表达呈正相关。CAFs 促进 CD24 HCC 细胞的自我更新、化疗耐药、转移和致瘤性。CAFs 分泌的 HGF 和 IL6 通过 STAT3 磷酸化促进 CD24 HCC 细胞的干细胞特性。
