Radiotherapy-induced cell death activates paracrine HMGB1-TLR2 signaling and accelerates pancreatic carcinoma metastasis.
Radiotherapy-induced cell death activates paracrine HMGB1-TLR2 signaling and accelerates pancreatic carcinoma metastasis.
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放疗诱导的细胞死亡激活旁分泌 HMGB1-TLR2 信号并加速胰腺癌转移
DOI：
10.1186/s13046-018-0726-2
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发表时间：
2018-04-03
期刊：
影响因子：
--
通讯作者：
Zhu H
中科院分区：
文献类型：
--
作者：
Chen X;Zhang L;Jiang Y;Song L;Liu Y;Cheng F;Fan X;Cao X;Gong A;Wang D;Zhu H
辐射后死亡的细胞可以促进存活癌细胞的再增殖，导致肿瘤复发。我们的目的是确定死亡细胞在促进胰腺癌细胞放疗后转移中的作用。使用transwell系统作为体外共培养模型，将少量未处理的胰腺癌细胞接种在上室中，而将大量致死处理的胰腺癌细胞接种在下室中。本研究通过一系列的实验研究了死亡细胞来源的HMGB 1在胰腺癌体外侵袭和体内转移中的作用。然后，我们设计了shRNA敲低和Western印迹分析来检测信号活性。我们发现死亡的胰腺癌细胞显著地促进胰腺癌细胞在体外的侵袭和在体内的癌症转移。HMGB 1基因敲除减弱了放射性死亡细胞对活胰腺癌细胞的迁移刺激作用。最后，我们发现死亡细胞衍生的HMGB 1以旁分泌方式影响癌细胞迁移，这依赖于获得上皮-间质转化（EMT）表型和PI 3 K/pAkt激活。这个过程是由TLR 2受体介导的。我们的研究表明，在放射治疗期间，垂死的胰腺癌细胞激活旁分泌信号事件，促进存活肿瘤细胞的移动性。我们建议抑制HMGB 1以预防胰腺癌复发和转移的策略。本文的在线版本（10.1186/s13046-018-0726-2）包含补充材料，可供授权用户使用。
Dying cells after irradiation could promote the repopulation of surviving cancer cells leading to tumor recurrence. We aim to define the role of dying cells in promoting pancreatic cancer cells metastasis following radiotherapy. Using the transwell system as the in vitro co-culture model, a small number of untreated pancreatic cancer cells were seeded in the upper chamber, while a larger number of lethally treated pancreatic cancer cells were seeded in the lower chamber. A series of experiments were conducted to investigate the role of dying-cell-derived HMGB1 on the invasion of pancreatic cancer in vitro and cancer metastasis in vivo. We then designed shRNA knockdown and Western blot assays to detect signaling activity. We found that dying pancreatic cancer cells significantly promote the invasion of pancreatic cancer cells in vitro and cancer metastasis in vivo. HMGB1 gene knockdown attenuated the migration-stimulating effect of irradiated, dying cells on living pancreatic cancer cells. Finally, we showed that dying-cell-derived HMGB1 functions in a paracrine manner to affect cancer-cell migration dependent on acquiring an epithelial-mesenchymal transition (EMT) phenotype and PI3K/pAkt activation. This process is mediated by the receptor for TLR2. Our study indicates that, during radiotherapy, dying pancreatic cancer cells activate paracrine signaling events that promote the mobility of surviving tumor cells. We suggest a strategy to inhibit HMGB1 for preventing pancreatic carcinoma relapse and metastasis. The online version of this article (10.1186/s13046-018-0726-2) contains supplementary material, which is available to authorized users.
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