Upregulation of MGP by HOXC8 promotes the proliferation, migration, and EMT processes of triple-negative breast cancer
Upregulation of MGP by HOXC8 promotes the proliferation, migration, and EMT processes of triple-negative breast cancer
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HOXC8上调MGP促进三阴性乳腺癌的增殖、迁移和EMT过程
DOI：
10.1002/mc.23079
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发表时间：
2019-07-01
影响因子：
4.6
通讯作者：
Li, Yong
中科院分区：
文献类型：
--
作者：
Gong, Chen;Zou, Jin;Li, Yong
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，占所有乳腺癌病例的15%-20%。由于缺乏靶向治疗，TNBC的管理仍然是一个挑战。此前，我们报道了同源盒C8 （HOXC8）参与乳腺癌细胞的转移和迁移。通过染色质免疫沉淀和荧光素酶检测，我们发现HOXC8作为转录因子激活基质Gla蛋白（MGP）基因的转录，导致TNBC细胞的增殖、非锚定生长和迁移增加。我们进一步证明，MGP表达促进了TNBC细胞的上皮-间质转化（epithelial-mesenchymal transition， EMT）过程，而对其他乳腺癌亚型没有促进作用，这表明MGP诱导EMT促进了TNBC细胞的增殖和迁移。此外，我们发现，与正常乳腺组织相比，MGP在临床乳腺标本中的表达上调，MGP的高表达与TNBC患者较差的无复发生存率有统计学关联，这表明MGP可能是TNBC患者的一种新的生物标志物或治疗靶点。总之，我们的研究结果表明，HOXC8-MGP轴在TNBC的肿瘤发生中发挥了重要作用，可能是TNBC治疗的一个有希望的治疗靶点。
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype which accounts for 15%-20% of all breast cancer cases. The management of TNBC has remained a challenge due to its lack of targeted therapy. Previously, we reported that homeobox C8 (HOXC8) was involved in metastasis and migration of breast cancer cells. By chromatin immunoprecipitation and luciferase assays, we found that HOXC8 functioned as a transcription factor to activate the transcription of matrix Gla protein (MGP) gene, leading to an increase in the proliferation, anchorage-independent growth, and migration of TNBC cells. We further demonstrated that MGP expression promoted the epithelial-mesenchymal transition (EMT) process of TNBC cells, but not the other subtypes of breast cancer, suggesting that MGP induced EMT to promote proliferation and migration of TNBC cells. Moreover, we found that MGP was upregulated in clinical breast specimens compared to normal breast tissues and high MGP expression was statistically associated with poor, relapse-free survival for TNBC patients, indicating that MGP is probably a novel biomarker or therapeutic target for TNBC patients. Together, our results showed that the HOXC8-MGP axis played an important role in the tumorigenesis of TNBC and might be a promising therapeutic target for TNBC treatment.