Integrin α6β4 drives triple-negative breast cancer (TNBC) aggressiveness through the transcriptional regulation of key genes. Here, we investigated how integrin α6β4 regulates protein tyrosine phosphatase receptor type Z1 (PTPRZ1). Using stable re-expression of integrin β4 (ITGB4) in cells naturally devoid of integrin α6β4 or knockdown or knockout (KO) of ITGB4, we found that integrin α6β4 regulates PTPRZ1 expression. To gain mechanistic insight, we focused on Hif-1α due to the impact of integrin α6β4 on a hypoxia-associated signature. We found that nuclear localization of Hif-1α, but not Hif-2α, was substantially enhanced with integrin α6β4 signaling. Hif-1α knockdown by shRNA or chemical inhibition decreased PTPRZ1 expression, while chemical activation of Hif-1α increased it. Upstream of Hif-1α, integrin α6β4 upregulates UCHL1 to stabilize Hif-1α and ultimately regulate PTPRZ1. Inhibition of UCHL1 and PTPRZ1 dramatically decreases integrin α6β4-mediated cell migration and three-dimensional invasive growth. Finally, public breast cancer database analyses demonstrated that ITGB4 correlates with PTPRZ1 and that high expression of ITGB4, UCHL1, HIF1A, and PTPRZ1 associated with decreased overall survival, distant metastasis free survival, post progression survival, and relapse-free survival. In summary, these findings provide a novel function of integrin α6β4 in promoting tumor invasive phenotypes through UCHL1-Hif-1α-mediated regulation of PTPRZ1.
整合素α6β4通过调控关键基因的转录驱动三阴性乳腺癌（TNBC）的侵袭性。本研究探讨了整合素α6β4如何调控蛋白酪氨酸磷酸酶受体Z1型（PTPRZ1）。通过在天然缺乏整合素α6β4的细胞中稳定重新表达整合素β4（ITGB4），或对ITGB4进行敲低或敲除（KO），我们发现整合素α6β4调控PTPRZ1的表达。为探究其机制，鉴于整合素α6β4对缺氧相关特征的影响，我们聚焦于Hif-1α。研究发现，整合素α6β4信号传导显著增强了Hif-1α（而非Hif-2α）的核定位。通过shRNA敲低或化学抑制Hif-1α可降低PTPRZ1表达，而化学激活Hif-1α则增加其表达。在Hif-1α上游，整合素α6β4上调UCHL1以稳定Hif-1α，最终调控PTPRZ1。抑制UCHL1和PTPRZ1显著降低了整合素α6β4介导的细胞迁移和三维侵袭性生长。最后，对公共乳腺癌数据库的分析表明，ITGB4与PTPRZ1相关，且ITGB4、UCHL1、HIF1A和PTPRZ1的高表达与总生存期、无远处转移生存期、进展后生存期和无复发生存期的降低相关。总之，这些发现揭示了整合素α6β4通过UCHL1-Hif-1α介导的PTPRZ1调控促进肿瘤侵袭表型的新功能。
肿瘤(癌症)患者之家