Department of Pharmacology, Case Western Reserve University Cleveland, Cleveland, OH, USA.
Oncogene. 2013 Aug 15;32(33):3829-39. doi: 10.1038/onc.2012.405. Epub 2012 Sep 10.
We report on the role of hexamethylene-bis-acetamide-inducible protein 1 (HEXIM1) as an inhibitor of metastasis. HEXIM1 expression is decreased in human metastatic breast cancers when compared with matched primary breast tumors. Similarly we observed decreased expression of HEXIM1 in lung metastasis when compared with primary mammary tumors in a mouse model of metastatic breast cancer, the polyoma middle T antigen (PyMT) transgenic mouse. Re-expression of HEXIM1 (through transgene expression or localized delivery of a small molecule inducer of HEXIM1 expression, hexamethylene-bis-acetamide) in PyMT mice resulted in inhibition of metastasis to the lung. Our present studies indicate that HEXIM1 downregulation of HIF(-)1α protein allows not only for inhibition of vascular endothelial growth factor-regulated angiogenesis, but also for inhibition of compensatory pro-angiogenic pathways and recruitment of bone marrow-derived cells (BMDCs). Another novel finding is that HEXIM1 inhibits cell migration and invasion that can be partly attributed to decreased membrane localization of the 67 kDa laminin receptor, 67LR, and inhibition of the functional interaction of 67LR with laminin. Thus, HEXIM1 re-expression in breast cancer has therapeutic advantages by simultaneously targeting more than one pathway involved in angiogenesis and metastasis. Our results also support the potential for HEXIM1 to indirectly act on multiple cell types to suppress metastatic cancer.
我们报告了六亚甲基双乙酰胺诱导蛋白 1（HEXIM1）作为转移抑制剂的作用。与匹配的原发性乳腺癌相比，人类转移性乳腺癌中 HEXIM1 的表达降低。同样，我们在转移性乳腺癌的小鼠模型——多瘤病毒中期 T 抗原（PyMT）转基因小鼠中观察到，与原发性乳腺肿瘤相比，肺转移中 HEXIM1 的表达降低。在 PyMT 小鼠中通过转基因组表达或局部递送来诱导 HEXIM1 表达的小分子（己二酰双乙酰胺）重新表达 HEXIM1，可抑制肺转移。我们目前的研究表明，HEXIM1 下调 HIF(-)1α 蛋白不仅可以抑制血管内皮生长因子调节的血管生成，还可以抑制代偿性促血管生成途径和骨髓源性细胞（BMDCs）的募集。另一个新发现是 HEXIM1 抑制细胞迁移和侵袭，这部分归因于 67LR（67kDa 层粘连蛋白受体）的膜定位减少和 67LR 与层粘连蛋白的功能相互作用的抑制。因此，乳腺癌中 HEXIM1 的重新表达通过同时靶向血管生成和转移中涉及的多个途径具有治疗优势。我们的结果还支持 HEXIM1 间接作用于多种细胞类型以抑制转移性癌症的潜力。
