Hou Jing, Zhao Naping, Zhu Pengxi, Chang Jun, Du Yan, Shen Wei
GCP Office, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092 People's Republic of China.
Department of Pharmacy, Changhai Hospital, Naval Military Medical University, 168 Changhai Road, Shanghai, 200433 China.
Cell Biosci. 2020 Aug 3;10:93. doi: 10.1186/s13578-020-00449-5. eCollection 2020.
Cancer stem cells are the main reason of relapse, metastasis and resistance to anti-cancer therapies of Hepatocellular carcinoma (HCC). Mesenchymal stem cells (MSCs) are an important part of the tumor microenvironment. MSCs have been demonstrated to be involved in drug resistance in tumor. How MSCs contribute to radiotherapy resistance of HCC is still indistinct.
Flow cytometry analysis was performed to isolate CD133+ cells from HCC cell lines Huh7 and PLC. The stemness of Huh7-CD133 and PLC-CD133 those were co-cultured with IR-MSCs were investigated by Colony formation assay. Tumor formation in nude mice was used to explore the tumorigenicity of CD133+ cancer cells. The activating Wnt/β-catenin signaling pathway in CSCs were also detected by RT-PCR and Western blotting.
We report that irradiated MSCs (IR-MSCs) could increase the ratio of CD133 cells in hepatocellular carcinoma cells. IR-MSCs could promote stemness maintenance of HCC stem cells. After co-cultured with IR-MSCs, liver cancer stem cells (CSCs) presented increased colony formation ability and tumor formation ability. We also found IR-MSCs promoted Wnt expression of CSCs. Reverse suppression experiment showed that when Wnt inhibitor was added into the culture medium, the effect of IR-MSCs on stemness maintenance was counteracted.
These data showed that IR-MSCs could support stemness maintenance of CSCs by activating Wnt/β-catenin signaling pathway.
癌症干细胞是肝细胞癌（HCC）复发、转移及对抗癌治疗产生耐药性的主要原因。间充质干细胞（MSCs）是肿瘤微环境的重要组成部分。已证实MSCs参与肿瘤的耐药过程。然而，MSCs如何导致HCC放疗抵抗仍不清楚。
采用流式细胞术分析从肝癌细胞系Huh7和PLC中分离CD133+细胞。通过集落形成试验研究与照射后的MSCs（IR-MSCs）共培养的Huh7-CD133和PLC-CD133的干性。利用裸鼠体内肿瘤形成实验探究CD133+癌细胞的致瘤性。还通过逆转录聚合酶链反应（RT-PCR）和蛋白质免疫印迹法检测癌症干细胞中Wnt/β-连环蛋白信号通路的激活情况。
我们发现照射后的MSCs（IR-MSCs）可增加肝癌细胞中CD133细胞的比例。IR-MSCs可促进肝癌干细胞干性的维持。与IR-MSCs共培养后，肝癌干细胞（CSCs）的集落形成能力和肿瘤形成能力增强。我们还发现IR-MSCs可促进CSCs中Wnt的表达。反向抑制实验表明，当向培养基中加入Wnt抑制剂时，IR-MSCs对干性维持的作用被抵消。
这些数据表明，IR-MSCs可通过激活Wnt/β-连环蛋白信号通路来支持CSCs干性的维持。
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