Phosphatase POPX2 secretome SILAC

Cancer metastasis is a complex mechanism involving multiple processes. In an earlier study, we reported that the levels of serine/threonine phosphatase POPX2 were positively correlated with cancer cell motility through modulating MAPK signaling. Surprisingly, here we found that POPX2 knockdown cells induced more numerous and larger tumor nodules in lungs in longer term animal studies, suggesting that lower levels of POPX2 may favor tumor progression in later stages of metastasis. We hypothesize that POPX2 may do so by modulation of angiogenesis. Secretome analysis of POPX2-knockdown MDA-MB-231 cells using SILAC-mass spectrometry and cytokine array showed that silencing of POPX2 leads to increased secretion of exosomes, which may in turn induce multiple pro-angiogenic cytokines. This study, combined with our earlier findings, suggests that a single ubiquitously expressed phosphatase POPX2 influences cancer metastasis via modulating multiple biological processes including MAPK signaling and exosome-cytokine secretion.

癌症转移（cancer metastasis）是一种涉及多重进程的复杂生物学机制。在既往研究中，我们曾报道丝氨酸/苏氨酸磷酸酶POPX2（serine/threonine phosphatase POPX2）的表达水平可通过调控丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）信号通路，与癌细胞的运动能力呈正相关。令人意外的是，本研究发现，在长期动物实验中，POPX2基因敲低的细胞可在肺部形成更多、体积更大的肿瘤结节，这提示POPX2低表达或许会促进转移晚期阶段的肿瘤进展。我们推测，POPX2或通过调控血管生成（angiogenesis）实现这一作用。通过稳定同位素标记氨基酸细胞培养质谱（stable isotope labeling with amino acids in cell culture-mass spectrometry, SILAC-MS）与细胞因子芯片，对POPX2基因敲低的MDA-MB-231细胞开展分泌组分析，结果显示：沉默POPX2可促进外泌体（exosomes）的分泌，而外泌体又可诱导多种促血管生成细胞因子的产生。本研究结合既往研究结果表明，作为一种泛表达的磷酸酶，POPX2可通过调控包括MAPK信号通路与外泌体-细胞因子分泌在内的多重生物学过程，进而影响癌症转移。