Dysregulated JAK2 expression by TrkC promotes metastasis potential, and EMT program of metastatic breast cancer.
Dysregulated JAK2 expression by TrkC promotes metastasis potential, and EMT program of metastatic breast cancer.
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DOI：
10.1038/srep33899
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发表时间：
2016-09-22
影响因子：
4.6
通讯作者：
Jin W
中科院分区：
文献类型：
--
作者：
Kim MS;Jeong J;Seo J;Kim HS;Kim SJ;Jin W
转移性乳腺癌是一种侵袭性肿瘤，与高水平的上皮-间质转化（EMT）标志物、il - 6/JAK2/STAT3和PI3K/AKT通路的激活、细胞生长、迁移、侵袭、转移和CSC状态相关。我们发现了一个新的分子和功能网络存在于转移中，调节和协调TrkC。TrkC抑制socs3介导的JAK2降解增加了JAK2/STAT3的总表达，然后通过激活JAK2/STAT3级联导致Twist-1的上调。此外，TrkC增加IL-6的分泌和表达，表明TrkC产生的这种自分泌环通过持续激活JAK2/STAT3级联和上调Twist表达来维持间质状态。此外，TrkC与c-Src/Jak2复合物相互作用，通过调控Jak2 /STAT3激活和Jak2 /STAT3表达增加Twist-1和Twist-2水平。此外，TrkC通过上调Twist-1和Twist-2诱导EMT，从而增强乳腺癌的转移潜力。此外，TrkC显著增强乳腺癌细胞形成肺转移和原发肿瘤形成的能力。出乎意料的是，我们发现TrkC的表达与临床乳腺肿瘤病理表型有显著的相关性。这些发现表明，TrkC在转移性乳腺癌的致瘤性、转移和自我更新特征中起着核心作用。
Metastatic breast cancers are aggressive tumors associated with high levels of epithelial-mesenchymal transition (EMT) markers, activation of IL6/JAK2/STAT3 and PI3K/AKT pathways for cell growth, mobility, invasion, metastasis, and CSC status. We identified a new molecular and functional network present in metastasis that regulates and coordinates with TrkC. Inhibition of SOCS3-mediated JAK2 degradation by TrkC increases total JAK2/STAT3 expression, and then leads to upregulation of Twist-1 through activation of JAK2/STAT3 cascade. Also, TrkC increases secretion and expression of IL-6, suggesting that this autocrine loop generated by TrkC maintains the mesenchymal state by continued activation of the JAK2/STAT3 cascade and upregulation of Twist expression. Moreover, TrkC interacts with the c-Src/Jak2 complex, which increases Twist-1 and Twist-2 levels via regulation of JAK2/STAT3 activation and JAK2/STAT3 expression. Furthermore, TrkC enhances metastatic potential of breast cancer via induction of EMT by upregulating Twist-1 and Twist-2. Additionally, TrkC significantly enhances the ability of breast cancer cells to form pulmonary metastases and primary tumor formation. Unexpectedly, we found that TrkC expression and clinical breast tumor pathological phenotypes show significant correlation. These findings suggest that TrkC plays a central role in tumorigenicity, metastasis, and self-renewal traits of metastatic breast cancer.
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