低氧微环境IL-11促进甲状腺未分化癌侵袭转移的作用及机制

Lung metastasis is the major reason of the worse prognosis for the patients with anaplastic thyroid carcinoma(ATC), and tumor microenvironment was reported to have an important role in the development of metastasis of malignant tumors, but the relationship between the tumor microenvironment and lung metastasis of ATC is unclear. We have found the hematopoietic cytokine IL-11 expression in the ATC tissue was positively related to distant metastasis for the patients with ATC. In vitro, we found that ATC cell lines can autocrine IL-11 in a dependent-HIF-1α style treated with CoCl2, a hypoxia mimetic agent. Additionally, IL-11 can induce the expression of p-Akt, p-GSK3β and Snail, a transcription factor which improve the epithelial-to-mesenchymal transition(EMT). On the base of these preliminary studies, we propose that ATC cells autocrine IL-11 in hypoxic microenvironment in a dependent-HIF-1α style, and IL-11induces the EMT of ATC cells through PI3K/Akt/GSK3β/Snail pathway, and ultimately improves the invasive and migratory potentials of ATC cells. Then, we will continue to use ATC cell lines and corresponding lung metastasis animal models as subjects, intervening with knockdown of HIF-1α or IL-11, to detect the changes on the invasive and migratory potentials, EMT of ATC cells, development of lung metastasis in the animal models, and further explore its mechanism. It will be very useful to lower and treat distant metastasis for the patients with ATC by clarifying these mechanisms.

肺转移是甲状腺未分化癌（ATC）预后差的最主要原因，低氧微环境在肿瘤转移过程中发挥了重要作用，但其与ATC肺转移的关系尚不清楚。我们临床研究发现造血细胞因子IL-11与ATC远处转移正相关；体外研究发现低氧模拟剂CoCl2以HIF-1α依赖方式促进ATC细胞自分泌IL-11，进而促进p-Akt、p-GSK3β以及促上皮间质转化（EMT）相关转录因子Snail过表达。据此我们提出低氧微环境诱导ATC细胞自分泌IL-11，后者经PI3K/Akt/GSK3β/Snail通路诱导EMT进而增强ATC侵袭和转移潜力。我们拟用ATC细胞系为研究对象，探索低氧诱导ATC细胞自分泌IL-11，以及敲低HIF-1α（或IL-11）对ATC细胞侵袭与迁移能力、EMT的影响及机制；进一步建立肺转移动物模型，探讨IL-11作为治疗和预防ATC肺转移分子靶点的可行性，该机制的阐明将为改善ATC患者预后提供新思路。

甲状腺未分化癌（anaplastic thyroid carcinoma，ATC）是人类恶性程度最高的肿瘤之一，占全部甲状腺癌的1~5%，但其致死率达全部甲状腺癌的50%，临床研究表明：虽然手术、放疗技术不断提高，化疗药物和方案不断改进和完善，但其确诊后中位生存期一直在3~9个月，1年生存率约20%；研究还发现ATC高致死率与确诊时25~50%的高远处（肺）转移发生率密切相关，因此，探索ATC肺转移发生机制，对于开发新的分子治疗靶点、改善ATC患者预后至关重要。.我们临床研究发现造血细胞因子IL-11与ATC远处转移正相关；体外研究发现低氧模拟剂CoCl2以HIF-1α依赖方式促进ATC细胞自分泌IL-11，进而促进p-Akt、p-GSK3β以及促上皮间质转化（EMT）相关转录因子Snail过表达。据此我们阐明低氧微环境诱导ATC细胞自分泌IL-11，后者经PI3K/Akt/GSK3β/ Snail通路诱导EMT进而增强ATC侵袭和转移潜力。由于IL-11是临床治疗恶性肿瘤化疗后血小板减少的标准治疗药物，而我们发现ATC患者外周血血小板计数与其预后负相关，因此我们推测血小板是否在ATC侵袭转移过程中直接发挥了作用，我们通过体内外实验发现，被肿瘤细胞活化的血小板可分泌趋化因子CCL3，后者通过与其受体CCR5结合发挥作用，并进一步激活NF-κB信号通路上调MMP1蛋白的表达从而参与血小板促ATC侵袭转移过程。.我们通过体内外实验研究发现，促进血小板生成的细胞因子IL-11和血小板本身在促进ATC细胞侵袭与迁移能力提升过程中发挥的重要作用和机制，对我们临床使用IL-11治疗恶性肿瘤化疗后血小板减少的合理性提出了疑问，同时提出将IL-11和血小板作为治疗和预防ATC肺转移靶点的可行性，为不断拓展探索和治疗ATC转移提供了新思路和新方向。