脂肪间充质干细胞通过 TRPC3/NF-κB 轴诱导 MT-CAFs 表型促进结肠癌的进展。
Mesenchymal stem cells derived from adipose accelerate the progression of colon cancer by inducing a MT-CAFs phenotype via TRPC3/NF-KB axis.
机构信息
Beijing Key Laboratory (No.BZO38 1), Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No. 1 Shuaifuyuan Hutong, Dongcheng District, Beijing, 100730, People's Republic of China.
Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, No. 1 Shuaifuyuan Hutong, Dongcheng District, Beijing, 100730, People's Republic of China.
出版信息
Stem Cell Res Ther. 2022 Jul 23;13(1):335. doi: 10.1186/s13287-022-03017-5.
BACKGROUND
There is increasing evidence that mesenchymal stem cells (MSCs) help shape the tumor microenvironment and promote tumor progression, and ion channels might play a critical role in this process. The objective of the present study was to explore the function and mechanism of MT-CAFs on progression of colon cancer.
METHODS
Here, a gene chip was used for a general analysis of gene expression changes in MSC-transformed CAF cells (MT-CAFs). Bioinformatic tool and western blot screened out the ion channel protein TRPC3 with significantly increased expression, and identify the function through two-photon microscope. The progression of cancer was detected via MTS, transwell and Wound Healing. ELISA deected the secretion of inflammation factors. TRPC3/NF-KB axis was identified by western blot and immunofluorescence.
RESULTS
TRPC3 can caused calcium influx, which further activated the NF-KB signaling pathway. Knockdown or inhibition of TRPC3 in MSCs significantly reduced the activation of NF-KB, and decreased the growth, migration, and invasion of MT-CAFs. After TRPC3 knockdown, the ability of MT- CAFs to promote tumor migration and invasion was impaired. Conversely, the upregulation of TRPC3 expression in MT-CAFs had the opposite effect. In vivo, TRPC3 expressed on MSCs also contributed to the tumorigenesis and progression of cancer cells. In addition, the Oncomine and GEPIA databases showed that TRPC3 expression is higher in colon cancer tissues compared with normal colon tissues, and was positively correlated with the expression of the CAF genes alpha-smooth muscle (α-SMA/ACTA2) and fibroblast activation protein Alpha. The disease-free survival of patients with positive TRPC3 expression in MSCs was significantly shorter than those with negative expression.
CONCLUSIONS
These results indicate that TRPC3 expressed on MT-CAFs plays a critical role in tumor progression via the NF-KB signaling pathway, and is correlated with poor prognosis in colon cancer patients. Therefore, TRPC3 may be a novel therapeutic target for the treatment of colon cancer.
背景
越来越多的证据表明间充质干细胞（MSCs）有助于塑造肿瘤微环境并促进肿瘤进展，而离子通道可能在这一过程中发挥关键作用。本研究旨在探讨 MSC 转化的 CAF 细胞（MT-CAFs）在结肠癌进展中的作用和机制。
方法
本研究使用基因芯片对 MSC 转化的 CAF 细胞（MT-CAFs）中的基因表达变化进行了全面分析。生物信息学工具和 Western blot 筛选出表达明显增加的离子通道蛋白 TRPC3，并通过双光子显微镜鉴定其功能。通过 MTS、transwell 和划痕愈合实验检测癌症的进展。ELISA 检测炎症因子的分泌。通过 Western blot 和免疫荧光鉴定 TRPC3/NF-KB 轴。
结果
TRPC3 可引起钙内流，进而激活 NF-KB 信号通路。在 MSCs 中敲低或抑制 TRPC3 可显著降低 NF-KB 的激活，并减少 MT-CAFs 的生长、迁移和侵袭。TRPC3 敲低后，MT-CAFs 促进肿瘤迁移和侵袭的能力受损。相反，上调 MT-CAFs 中的 TRPC3 表达则有相反的效果。体内实验表明，MSC 上表达的 TRPC3 也有助于肿瘤细胞的发生和进展。此外，Oncomine 和 GEPIA 数据库显示，与正常结肠组织相比，结肠癌组织中 TRPC3 的表达更高，并且与 CAF 基因α-平滑肌肌动蛋白（α-SMA/ACTA2）和成纤维细胞激活蛋白 Alpha 的表达呈正相关。在 MSCs 中表达阳性的 TRPC3 的患者的无病生存期明显短于表达阴性的患者。
结论
这些结果表明，MT-CAFs 上表达的 TRPC3 通过 NF-KB 信号通路在肿瘤进展中发挥关键作用，并与结肠癌患者的不良预后相关。因此，TRPC3 可能成为治疗结肠癌的新靶点。
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