宫颈癌是全球第4大常见的女性癌症，目前，手术和放疗仍然是治疗非转移性宫颈癌的主要方法，然而，复发性和转移性宫颈癌尚无有效治疗手段。寻找新的更加有效的宫颈癌治疗靶点就显得尤为重要。已知白介素-6(interleukine-6，IL-6)作为肿瘤促进因子在宫颈癌的发展和转移过程中发挥着十分重要的作用。已有报道显示，间充质干细胞在多种肿瘤中发挥抑癌作用，但对于其内在机制的报道较少;且在宫颈癌的发展过程通常伴随着IL-6表达的增加。在IL-6存在的炎症病理条件下，MSCs对于宫颈癌细胞的增殖和迁移是否仍具有抑制作用仍未可知。本研究通过检测人脐带间充质干细胞(human umbilical cord mesenchymal stem cells，HUC-MSCs)对 IL-6 诱导的 HeLa 细胞增殖、迁移、侵袭以及STAT3/Bcl-2、AMPK/mTOR信号通路的调节作用，探讨其对宫颈癌Hela细胞生物活性的影响及其分子机制。集落形成实验、细胞划痕实验以及Transwell侵袭结果证明，炎症因子IL-6显著促进HeLa细胞增殖、迁移和侵袭(P＜0。05)。而20％和50％MSCs条件培养基显著抑制IL-6诱导的HeLa增殖(P＜0。0001)、迁移(P＜0。01)和侵袭能力(P＜0。0001)。进一步的机制研究结果显示，炎症因子IL-6显著上调抗凋亡信号通路中STAT3和Bcl-2的mRNA(P＜0。0001)和蛋白质(P＜0。01)含量;同时下调AMPK、TSC1和TSC2等基因的表达(P＜0。001)，最终上调细胞代谢相关基因mTOR的表达(P＜0。01)和蛋白质磷酸化水平(P＜0。05)。20％MSCs条件培养基显著抑制HeLa细胞中STAT3/Bcl-2信号通路(P＜0。05)。50％MSCs条件培养基显著抑制HeLa细胞中STAT3/Bcl-2信号通路(P＜0。01)同时激活AMPK/mTOR信号通路(P＜0。05)，诱导细胞周期阻滞(P＜0。0001)。综上所述，MSCs条件培养基通过下调STAT3信号通路和上调AMPK信号通路抑制白介素-6诱导的HeLa细胞的增殖、迁移与侵袭。本研究结果有助于进一步阐释IL-6在宫颈癌中发生发展的作用和机制，为寻找宫颈癌治疗的新研究方向提供实验依据。
Human Umbilical Cord Mesenchymal Stem Cells Inhibit the Biological Behavior of HeLa Cells Induced by IL-6 Through STAT3 and AMPK Signaling Pathways
Cervical cancer is the 4th leading cause of female malignancy-associated mortality worldwide.Surgery and radiotherapy are the main methods of treatment for non-metastatic cervical cancer.There is no clinically effective treatment for the recurrent and metastatic cervical cancer.Therefore,it is particu-larly important to find new and more effective therapeutic targets for cervical cancer treatment.Inflamma-tory response is known to participate in different stages of tumor development.Interleukin-6(IL-6),as a tumor promoting factor,plays a very important role in the development and metastasis of cervical cancer.It has been reported that mesenchymal stem cells play an inhibitory role in a variety of tumors,but there are few reports on their internal mechanism.In addition,the development of cervical cancer is usually accompanied by an increase of IL-6.Whether MSCs can inhibit the proliferation and migration of cervical cancer cells induced by IL-6 in inflammatory conditions is still unknown.This study aimed to explore the effects and mechanism of human umbilical cord mesenchymal stem cells(HUC-MSCs)on the biological activity of HeLa cells induced by IL-6.The colony formation experiment,cell scratch assay and Transwell invasion assay demonstrated that IL-6 significantly promoted HeLa cell proliferation,migration and inva-sion(P＜0.05).Results showed that both 20％and 50％MSCs conditioned medium significantly inhib-ited IL-6-induced proliferation(P＜0.0001),migration(P＜0.01)and invasion(P＜0.0001)of HeLa cells,and IL-6 significantly up-regulated the expression of STAT3 and Bcl-2 genes(P＜0.0001)and protein(P＜0.01)in the anti-apoptosis signaling pathway.At the same time,the expression of AMPK,TSC1 and TSC2 genes was down-regulated(P＜0.001),leading to the up-regulation of metabo-lism related mTOR gene(P＜0.01)and protein(P＜0.05).Furthermore,20％MSCs conditioned medium down-regulated the mRNA and protein expression of STAT3 and Bcl-2(P＜0.05).And 50％MSCs conditioned medium down-regulated the STAT3/Bcl-2 signaling pathway(P＜0.01),up-regula-ted the AMPK/mTOR signaling pathway(P＜0.05)and induced cell cycle arrest(P＜0.0001)signif-icantly in HeLa cells.In summary,MSCs conditioned medium inhibited IL-6-induced HeLa cell prolifer-ation,migration and invasion by down-regulating STAT3 signaling pathway and up-regulating AMPK sig-naling pathway.The results of this study are helpful to further elucidate the role and mechanism of IL-6 in the development of cervical cancer,and provide experimental basis for searching for therapeutic targets of cervical cancer.
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维普
