Human mesenchymal stem cells promote tumor growth via MAPK pathway and metastasis by epithelial mesenchymal transition and integrin α5 in hepatocellular carcinoma
Human mesenchymal stem cells promote tumor growth via MAPK pathway and metastasis by epithelial mesenchymal transition and integrin α5 in hepatocellular carcinoma
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人间充质干细胞通过MAPK途径促进肝细胞癌中的肿瘤生长并通过上皮间质转化和整合素α5促进转移
DOI：
10.1038/s41419-019-1622-1
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发表时间：
2019-05-29
影响因子：
9
通讯作者：
Lin, Hui
中科院分区：
文献类型：
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作者：
Chen, Jiang;Ji, Tong;Lin, Hui
间充质干细胞（MSCs）由于其出色的肿瘤趋向性能力，似乎是抗癌药物的一种潜在载体。然而，间充质干细胞与肝细胞癌（HCC）之间的相互作用颇具争议，其潜在机制也不明确。在这项研究中，对人源间充质干细胞（hMSCs）在异种移植和原位模型中对肿瘤增殖和转移的影响进行了研究。研究发现，hMSCs在体内可通过激活丝裂原活化蛋白激酶（MAPK）信号通路促进肿瘤生长，并通过上皮 - 间质转化（EMT）促进转移。为了测试hMSCs是否能诱导免疫抑制效应，通过免疫组织化学染色检测自然杀伤（NK）细胞标志物CD56的表达，并通过实时定量逆转录聚合酶链反应（qRT - PCR）检测白细胞介素 - 6（IL - 6）和肿瘤坏死因子 - α（TNF - α）的表达。结果发现，在hMSCs处理的组织中，CD56表达显著降低，而TNF - α和IL - 6表达增加。从机制上讲，进行了RNA测序，结果发现整合素α5（ITGA5）在hMSCs处理的HCC中过度表达。ITGA5小干扰RNA阻断了hMSCs诱导的HCC迁移和侵袭，而ITGA5的过表达促进了HCC - hMSCs的迁移和侵袭能力，这表明ITGA5的表达与hMSCs诱导的肿瘤转移有关。这些发现表明，hMSCs可能在HCC增殖和转移中起重要作用，并可被确定为HCC的一个潜在治疗靶点。
Mesenchymal stem cells (MSCs) appear to be a potential vehicle for anticancer drugs due to their excellent tumor tropism ability. However, the interactions between MSCs and hepatocellular carcinoma (HCC) are quite controversial and the underlying mechanisms are ambiguous. In this study, an investigation was conducted into the effect of human MSCs (hMSCs) on tumor proliferation and metastasis both in xenograft and orthotopic models. It was discovered that hMSCs could promote tumor growth though activating mitogen-activated protein kinase (MAPK) signaling pathway and promote metastasis by epithelial mesenchymal transition (EMT) in vivo. To test whether hMSCs could induce immunosuppressive effects, the expression of the Natural killer (NK) cell marker CD56 was measured by immunohistochemical staining and the expression of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured by qRT-PCR. It was found out that CD56 expression significantly decreased, while TNF-alpha and IL-6 expression increased in the hMSCs-treated tissues. Mechanistically, RNA sequencing was performed, which led to a discovery that integrin alpha 5 (ITGA5) was over-expressed in hMSCs-treated HCC. ITGA5 siRNAs blocked the hMSCs-induced migration and invasion of HCC, while over-expression of ITGA5 promoted the migration and invasion ability in HCC-hMSCs, indicating that the expression of ITGA5 is associated with hMSCs-induced tumor metastasis. These findings suggest that hMSCs may play a vital role in HCC proliferation and metastasis and could be identified as a putative therapeutic target in HCC.