Basic Medical Institute, Hongqiao International Institute of Medicine, Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Department of Laboratory Medicine, Shanghai General Hospital Jiading Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Basic Medical Institute, Hongqiao International Institute of Medicine, Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Cancer Lett. 2021 Oct 28;519:150-160. doi: 10.1016/j.canlet.2021.07.017. Epub 2021 Jul 13.
Calcium channel TRPV6 upregulation is associated with poor prognosis of breast cancer by promoting invasion and metastasis, and TRPV6 is a potential target for breast cancer therapy. However, the mechanism by which TRPV6 promotes breast metastasis remains unclear. Here, we report that TRPV6 expression is upregulated in metastatic breast cancers and that TRPV6 overexpression or upregulation accelerates primary breast cancer cell migration. In contrast, TRPV6 suppression decreases cell migration. Mechanistically, TRPV6 activates NFATC2 by increasing NFATC2IP phosphorylation at Ser204, and CDK5 is a candidate kinase that may perform this phosphorylation. Consequently, activated NFATC2 increases breast cancer metastasis by upregulating ADAMTS6 expression. These observations suggest that TRPV6 increases NFATC2 transcriptional activity by increasing NFATC2IP phosphorylation, which consequently upregulates ADAMTS6 expression to promote breast cancer metastasis.
钙通道 TRPV6 的上调与乳腺癌不良预后相关，通过促进侵袭和转移，TRPV6 是乳腺癌治疗的潜在靶点。然而，TRPV6 促进乳腺癌转移的机制尚不清楚。在这里，我们报告 TRPV6 的表达在转移性乳腺癌中上调，并且 TRPV6 的过表达或上调加速了原发性乳腺癌细胞的迁移。相比之下，TRPV6 的抑制降低了细胞迁移。在机制上，TRPV6 通过增加 NFATC2IP 在 Ser204 处的磷酸化来激活 NFATC2，而 CDK5 是可能执行这种磷酸化的候选激酶。因此，激活的 NFATC2 通过上调 ADAMTS6 的表达来增加乳腺癌的转移。这些观察结果表明，TRPV6 通过增加 NFATC2IP 的磷酸化来增加 NFATC2 的转录活性，从而上调 ADAMTS6 的表达以促进乳腺癌转移。
