Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, PR China.
Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, PR China.
Cell Death Dis. 2022 Sep 22;13(9):812. doi: 10.1038/s41419-022-05174-0.
Distant metastasis is the main cause of mortality in breast cancer patients. Using the breast cancer genomic data from The Cancer Genome Atlas (TCGA), we identified brain specific Ca2.2 as a critical regulator of metastasis. Ca2.2 expression is significantly upregulated in breast cancer and its higher expression is inversely correlated with survival suggesting a previously unappreciated role of Ca2.2 in breast cancer. Ca2.2 is required for breast cancer migration, invasion, and metastasis. Interestingly, Ca2.2 promotes invadopodia formation and extracellular matrix (ECM) degradation through the stabilization of invadopodia component cortactin in a proteosome-dependent manner. Moreover, deubiquitinating enzyme USP43 mediated the functions of Ca2.2 in cortactin stabilization, invadopodia formation, ECM degradation, and metastasis. Interestingly, Ca2.2 upregulates USP43 expression through NFAT2 dephosphorylation and nuclear localization. Our study uncovered a novel pathway that regulates cortactin expression and invadopodia formation in breast cancer metastasis.
远处转移是乳腺癌患者死亡的主要原因。我们利用癌症基因组图谱（TCGA）的乳腺癌基因组数据，鉴定出脑特异性 Ca2.2 是转移的关键调节因子。Ca2.2 在乳腺癌中表达显著上调，其高表达与生存率呈负相关，提示 Ca2.2 在乳腺癌中具有以前未被认识到的作用。Ca2.2 是乳腺癌迁移、侵袭和转移所必需的。有趣的是，Ca2.2 通过依赖蛋白酶体的方式稳定侵袭小体成分 cortactin，促进侵袭小体的形成和细胞外基质（ECM）的降解。此外，去泛素化酶 USP43 通过 NFAT2 去磷酸化和核定位介导 Ca2.2 在 cortactin 稳定、侵袭小体形成、ECM 降解和转移中的作用。有趣的是，Ca2.2 通过 NFAT2 去磷酸化和核定位上调 USP43 的表达。我们的研究揭示了一条调节乳腺癌转移中 cortactin 表达和侵袭小体形成的新途径。
