Klotho-mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments
Klotho-mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments
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Klotho 介导的 CCL2 靶向可抑制基质细胞衰老微环境诱导的结直肠癌进展。
DOI：
10.1002/1878-0261.12577
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发表时间：
2019-11-01
影响因子：
6.6
通讯作者：
Wang, Liangjing
中科院分区：
文献类型：
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作者：
Liu, Yangyang;Pan, Jie;Wang, Liangjing
衰老微环境在肿瘤进展中起重要作用。在这里，我们报告阿霉素（DOX）预处理或复制衰老基质细胞（WI-38和HUVEC）促进结直肠癌（CRC）细胞的生长和侵袭在体外和体内。这些促肿瘤发生的作用减弱外源性管理Klotho，抗衰老因子。随后，我们确定了几个衰老相关的分泌表型（SASP）相关的基因，包括CCL 2，这是显着上调两种类型的衰老基质细胞在复制和DNA损伤诱导衰老。重要的是，我们发现衰老基质细胞分泌的CCL 2显著高于非衰老细胞或用Klotho预处理的衰老细胞中所见的CCL 2。值得注意的是，发现CCL 2加速CRC细胞增殖和侵袭，而这种作用可以通过施用特异性CCR 2拮抗剂来阻断。我们进一步表明Klotho可以在DOX诱导的衰老过程中抑制NF-κ B活化，从而阻断CCL 2转录。患者肿瘤组织中Klotho的低表达或CCL 2的高表达与CRC患者的总体生存率差相关。总的来说，我们的研究结果表明，衰老的基质细胞与CRC的进展有关。Klotho可以通过抑制SASP因子（包括CCL 2）的表达来抑制衰老基质细胞相关的CRC进展触发。关键SASP因子如CCL 2的鉴定可能为改善CRC治疗提供潜在的治疗靶点。
Senescent microenvironments play an important role in tumor progression. Here, we report that doxorubicin (DOX)-pretreated or replicative senescent stromal cells (WI-38 and HUVEC) promote colorectal cancer (CRC) cell growth and invasion in vitro and in vivo. These pro-tumorigenic effects were attenuated by exogenous administration of Klotho, an anti-aging factor. We subsequently identified several senescence-associated secretory phenotype (SASP)-associated genes, including CCL2, which were significantly upregulated in both types of senescent stromal cells during replication and DNA damage-induced senescence. Importantly, we found that the secretion of CCL2 by senescent stromal cells was significantly higher than that seen in nonsenescent cells or in senescent cells pretreated with Klotho. Notably, CCL2 was found to accelerate CRC cell proliferation and invasion, while this effect could be blocked by administration of a specific CCR2 antagonist. We further show that Klotho can suppress NF-kappa B activation during DOX-induced senescence and thus block CCL2 transcription. Low expression of Klotho, or high expression of CCL2 in patient tumor tissues, correlated with poor overall survival of CRC patients. Collectively, our findings suggest that senescent stromal cells are linked to progression of CRC. Klotho can suppress the senescent stromal cell-associated triggering of CRC progression by inhibiting the expression of SASP factors including CCL2. The identification of key SASP factors such as CCL2 may provide potential therapeutic targets for improving CRC therapy.