Silencing CTNND1 Mediates Triple-Negative Breast Cancer Bone Metastasis via Upregulating CXCR4/CXCL12 Axis and Neutrophils Infiltration in Bone.
Silencing CTNND1 Mediates Triple-Negative Breast Cancer Bone Metastasis via Upregulating CXCR4/CXCL12 Axis and Neutrophils Infiltration in Bone.
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沉默CTNND1通过上调CXCR4/CXCL12轴和骨中中性粒细胞浸润介导三阴性乳腺癌骨转移
DOI：
10.3390/cancers13225703
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发表时间：
2021-11-15
期刊：
影响因子：
5.2
通讯作者：
Jiang W
中科院分区：
文献类型：
--
作者：
Lin Q;Fang X;Liang G;Luo Q;Cen Y;Shi Y;Jia S;Li J;Yang W;Sanders AJ;Gong C;Jiang W
远处转移，尤其是骨转移，是乳腺癌患者死亡的主要原因。然而，乳腺癌骨转移患者经常因延迟干预而复杂化，因为临床上不能足够早地检测到骨转移。在这里，我们报告CTNND 1在三阴性乳腺癌（TNBC）患者的原发性肿瘤和转移性骨病变中下调。CTNND 1的减少是骨骼归巢和乳腺癌细胞在骨骼微环境中存活的关键内在因素。因此，CTNND 1可能成为早期预测三阴性乳腺癌骨转移的新生物标志物。三阴性乳腺癌（TNBC）的骨转移由于诊断和干预的延迟、缺乏有效的治疗以及更多的与乳腺癌相关的并发症，经常导致比其他类型的乳腺癌更差的预后。在本研究中，我们通过TNBC样品的高通量测序鉴定了CTNND 1作为来自TNBC的转移性骨病变中最减少的分子。体内实验表明，CTNND 1的敲低增强了肿瘤细胞向骨的转移，也增加了骨中的中性粒细胞浸润。在体外，我们证明了CTNND 1的敲除加速了肿瘤细胞的上皮-间充质转化（EMT）及其向骨的募集。CTNND 1通过激活PI 3 K/AKT/HIF-1α通路上调CXCR 4，参与EMT和骨归巢。此外，CTNND 1表达降低的TNBC细胞通过分泌更多的GM-CSF和IL-8加速嗜中性粒细胞浸润而引发细胞毒性T细胞应答。临床上，CTNND 1水平较低的三阴性乳腺癌患者的总生存期（OS）和无远处转移生存期（DMFS）较短。结论：CTNND 1表达下调在促进TNBC骨转移中起重要作用，CTNND 1可能是预测TNBC骨转移风险的潜在生物标志物。
Distant metastasis, especially bone metastasis, is the major cause of death in breast cancer patients. However, breast cancer patients with bone metastasis are frequently complicated by delayed intervention as clinically bone metastasis cannot be detected early enough. Here, we report that CTNND1 is downregulated in both primary tumors and metastatic bone lesions of patients with triple-negative breast cancer (TNBC). Decreased CTNND1 is a crucial intrinsic contributor to homing to the bones and the survival of the breast cancer cells in the bone microenvironment. Thus, CTNND1 may be a novel biomarker for early predicting bone metastasis of triple-negative breast cancer. Bone metastasis from triple-negative breast cancer (TNBC) frequently results in poorer prognosis than other types of breast cancer due to the delay in diagnosis and intervention, lack of effective treatments and more skeletal-related complications. In the present study, we identified CTNND1 as a most reduced molecule in metastatic bone lesion from TNBC by way of high throughput sequencing of TNBC samples. In vivo experiments revealed that knockdown of CTNND1 enhanced tumor cells metastasis to bones and also increased neutrophils infiltration in bones. In vitro, we demonstrated that knockdown of CTNND1 accelerated epithelial–mesenchymal transformation (EMT) of tumor cells and their recruitment to bones. The involvement by CTNND1 in EMT and bone homing was achieved by upregulating CXCR4 via activating the PI3K/AKT/HIF-1αpathway. Moreover, TNBC cells with reduced expression of CTNND1 elicited cytotoxic T-cells responses through accelerating neutrophils infiltration by secreting more GM-CSF and IL-8. Clinically, patients with triple-negative breast cancer and lower level of CTNND1 had shorter overall survival (OS) and distant metastasis-free survival (DMFS). It was concluded that downregulation of CTNND1 played a critical role in facilitating bone metastasis of TNBC and that CTNND1 might be a potential biomarker for predicting the risk of bone metastases in TNBC.
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影响因子：
21.3
作者：
Ilina O;Gritsenko PG;Syga S;Lippoldt J;La Porta CAM;Chepizhko O;Grosser S;Vullings M;Bakker GJ;Starruß J;Bult P;Zapperi S;Käs JA;Deutsch A;Friedl P
通讯作者：
Friedl P
影响因子：
50.3
作者：
Xiao, Yansen;Cong, Min;Hu, Guohong
通讯作者：
Hu, Guohong
影响因子：
4
作者：
Ding, Xiuming;Wang, Xiuqin;Ju, Shumei
通讯作者：
Ju, Shumei
影响因子：
82.9
作者：
Schalper KA;Carleton M;Zhou M;Chen T;Feng Y;Huang SP;Walsh AM;Baxi V;Pandya D;Baradet T;Locke D;Wu Q;Reilly TP;Phillips P;Nagineni V;Gianino N;Gu J;Zhao H;Perez-Gracia JL;Sanmamed MF;Melero I
通讯作者：
Melero I
影响因子：
4
作者：
Kurley, Sarah J.;Tischler, Verena;Reynolds, Albert B.
通讯作者：
Reynolds, Albert B.