Colorectal cancer-associated fibroblasts promote metastasis by up-regulating LRG1 through stromal IL-6/STAT3 signaling.
Colorectal cancer-associated fibroblasts promote metastasis by up-regulating LRG1 through stromal IL-6/STAT3 signaling.
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结直肠癌相关成纤维细胞通过基质 IL-6/STAT3 信号传导上调 LRG1 来促进转移。
DOI：
10.1038/s41419-021-04461-6
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发表时间：
2021-12-20
影响因子：
9
通讯作者：
Wu XJ
中科院分区：
文献类型：
--
作者：
Zhong B;Cheng B;Huang X;Xiao Q;Niu Z;Chen YF;Yu Q;Wang W;Wu XJ
癌症相关成纤维细胞（CAF）已被证明在结直肠癌转移中发挥重要作用，但其潜在机制仍有待充分阐明。使用CRC临床样品以及离体CAFs-CRC共培养模型，我们发现CAF诱导CRC中富含亮氨酸的α-2-糖蛋白1（LRG 1）的表达，其中与原发性肿瘤相比，其在转移性CRC组织中显示出显著更高的表达。我们进一步表明，CAFs诱导的LRG 1促进CRC迁移和侵袭，这是伴随着EMT（上皮-间质转化）诱导。此外，该信号传导轴也已在肝转移小鼠模型中得到证实，该模型显示CAFs诱导的LRG 1显著加速转移。从机制上讲，我们证明CAFs分泌的IL-6（白细胞介素-6）负责CRC中LRG 1的上调，这是通过JAK 2激活后STAT 3的直接反式激活发生的。在临床CRC肿瘤样本中，LRG 1表达与CAFs特异性标志物α-SMA呈正相关，LRG 1表达越高，预测临床结局越差，尤其是无远处转移生存期，支持LRG 1在CRC进展中的作用。总的来说，这项研究为CAFs介导的CRC转移提供了新的见解，并表明CAFs介导的IL-6-STAT 3-LRG 1轴的治疗靶向可能是减轻CRC转移的潜在策略。
Cancer-associated fibroblasts (CAFs) have been shown to play a strong role in colorectal cancer metastasis, yet the underlying mechanism remains to be fully elucidated. Using CRC clinical samples together with ex vivo CAFs-CRC co-culture models, we found that CAFs induce expression of Leucine Rich Alpha-2-Glycoprotein 1(LRG1) in CRC, where it shows markedly higher expression in metastatic CRC tissues compared to primary tumors. We further show that CAFs-induced LRG1 promotes CRC migration and invasion that is concomitant with EMT (epithelial-mesenchymal transition) induction. In addition, this signaling axis has also been confirmed in the liver metastatic mouse model which displayed CAFs-induced LRG1 substantially accelerates metastasis. Mechanistically, we demonstrate that CAFs-secreted IL-6 (interleukin-6) is responsible for LRG1 up-regulation in CRC, which occurs through a direct transactivation by STAT3 following JAK2 activation. In clinical CRC tumor samples, LRG1 expression was positively correlated with CAFs-specific marker, α-SMA, and a higher LRG1 expression predicted poor clinical outcomes especially distant metastasis free survival, supporting the role of LRG1 in CRC progression. Collectively, this study provided a novel insight into CAFs-mediated metastasis in CRC and indicated that therapeutic targeting of CAFs-mediated IL-6-STAT3-LRG1 axis might be a potential strategy to mitigate metastasis in CRC.
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影响因子：
64.5
作者：
Boelens MC;Wu TJ;Nabet BY;Xu B;Qiu Y;Yoon T;Azzam DJ;Twyman-Saint Victor C;Wiemann BZ;Ishwaran H;Ter Brugge PJ;Jonkers J;Slingerland J;Minn AJ
通讯作者：
Minn AJ
影响因子：
8
作者：
Niu, GL;Wright, KL;Yu, H
通讯作者：
Yu, H
影响因子：
3.7
作者：
Lin HX;Qiu HJ;Zeng F;Rao HL;Yang GF;Kung HF;Zhu XF;Zeng YX;Cai MY;Xie D
通讯作者：
Xie D
影响因子：
2.9
作者：
Furukawa, Kenta;Kawamoto, Koichi;Nagano, Hiroaki
通讯作者：
Nagano, Hiroaki
DOI：
10.1515/bchm2.1977.358.1.639
发表时间：
1977-01-01
影响因子：
--
作者：
HAUPT, H;BAUDNER, S
通讯作者：
BAUDNER, S