PINCH-1 interacts with myoferlin to promote breast cancer progression and metastasis
PINCH-1 interacts with myoferlin to promote breast cancer progression and metastasis
复制标题
PINCH-1与肌铁蛋白相互作用促进乳腺癌进展和转移
DOI：
10.1038/s41388-019-1135-5
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发表时间：
2020-03-01
期刊：
影响因子：
8
通讯作者：
Sun, Ying
中科院分区：
文献类型：
--
作者：
Qian, Tao;Liu, Chengmin;Sun, Ying
PINCH-1是细胞-细胞外基质（ECM）粘附机器的细胞质组分，其经常在癌症中过表达。然而，PINCH-1在癌症中的功能和机制仍有待确定。在这里，我们表明PINCH-1与myoferlin相互作用，myoferlin是一种对癌症进展至关重要的跨膜蛋白。PINCH-1和myoferlin两者的高表达与人类乳腺癌患者的不良临床结果相关。从乳腺癌细胞中消融PINCH-1降低了肌铁蛋白水平，并在体外抑制了乳腺癌细胞增殖、迁移和内皮细胞管形成，在体内抑制了乳腺肿瘤生长、血管生成和转移。机械地，PINCH-1通过其与肌钙蛋白的相互作用以及其泛素化和蛋白酶体依赖性降解的调节来控制肌钙蛋白水平。在功能上，PINCH-1的重新表达，而不是肌钙蛋白结合缺陷型Δ LIM 2突变体的重新表达，有效地逆转了PINCH-1缺失引起的肌钙蛋白表达抑制和乳腺癌进展。最后，肌铁蛋白表达的恢复足以逆转PINCH-1缺陷诱导的对乳腺癌进展的抑制。这些结果揭示了PINCH-1-myoferlin信号传导轴对乳腺癌进展至关重要，并提出了乳腺癌治疗控制的新策略。
PINCH-1 is a cytoplasmic component of the cell-extracellular matrix (ECM) adhesion machine that is frequently overexpressed in cancer. The functions and mechanism of PINCH-1 in cancer, however, remain to be determined. Here, we show that PINCH-1 interacts with myoferlin, a transmembrane protein that is critical for cancer progression. High expression of both PINCH-1 and myoferlin correlates with poor clinical outcome in human breast cancer patients. Ablation of PINCH-1 from breast cancer cells diminished myoferlin level and suppressed breast cancer cell proliferation, migration, and endothelial cell tube formation in vitro and breast tumor growth, angiogenesis and metastasis in vivo. Mechanistically, PINCH-1 controls myoferlin level through its interaction with myoferlin and regulation of its ubiquitination and proteasome-dependent degradation. Functionally, re-expression of PINCH-1, but not that of a myoferlin-binding defectiveΔLIM2 mutant, effectively reversed the inhibition of myoferlin expression and breast cancer progression induced by loss of PINCH-1. Finally, restoration of myoferlin expression was sufficient to reverse PINCH-1-deficiency induced inhibition on breast cancer progression. These results reveal a PINCH-1-myoferlin signaling axis that is critical for breast cancer progression and suggest a new strategy for therapeutic control of breast cancer.