Zhang Ping, Liu Lei, Zhang Lu, He Xiaogan, Xu Xiaojun, Lu Yaojuan, Li Feifei
Department of Pathophysiology, Basic Medical School, Anhui Medical University Hefei 230032, Anhui, China.
Department of Laboratory Medicine, Zhoupu Hospital Affiliated to Shanghai University of Medicine & Health Sciences Shanghai, China.
Am J Transl Res. 2020 May 15;12(5):2305-2318. eCollection 2020.
Runx2, a master regulator of osteogenesis, is abnormally expressed in advanced breast cancer. Here we addressed Runx2 contribution to breast cancer cell growth and metastasis. We found that CD44 and Runx2 were both elevated in breast cancer tissues compared with the adjacent normal tissues in breast cancer patients. Runx2 expression was significantly correlated with tumor TNM stage, metastasis and poor prognosis. We then screened several breast cancer cell lines and found that Runx2 expression level was positively related to the malignant level of the cells screened. Knockdown of Runx2 in high metastatic cell line MDA-MB-231 could inhibit breast cancer cell vitality, invasion and clone formation capacity, while overexpression of Runx2 in low metastatic cell line MCF-7 could increase those malignant behaviors. The mechanism might be due to Runx2 positively regulating cancer stem cell properties, as CD44 expression level and CD44/CD24 breast cancer stem cell population were both significantly decreased in Runx2 knockdown cells. Cancer stem cell renewal ability such as soft agar clone formation, mammospheres formation and tumor formation ability in null mice were all decreased after knockdown of Runx2. On the contrary, overexpression of Runx2 could enhance all above stem cell renewal ability. Lastly, we explored how Runx2 changes cancer stem cell population. We found it could affect epithelial mesenchymal transition (EMT). Runx2 could regulate mesenchymal marker and epithelial marker expression and affect activation of Wnt/β-catenin signaling pathway. These results together strongly suggest that Runx2 can promote CD44/CD24 breast cancer stem cell properties and breast cancer tumorigenesis through EMT process.
Runx2是成骨的主要调节因子，在晚期乳腺癌中异常表达。在此，我们探讨了Runx2对乳腺癌细胞生长和转移的作用。我们发现，与乳腺癌患者的癌旁正常组织相比，CD44和Runx2在乳腺癌组织中均升高。Runx2表达与肿瘤TNM分期、转移及预后不良显著相关。然后，我们筛选了几种乳腺癌细胞系，发现Runx2表达水平与所筛选细胞的恶性程度呈正相关。在高转移细胞系MDA-MB-231中敲低Runx2可抑制乳腺癌细胞活力、侵袭及克隆形成能力，而在低转移细胞系MCF-7中过表达Runx2可增加这些恶性行为。其机制可能是Runx2正向调节癌症干细胞特性，因为在敲低Runx2的细胞中，CD44表达水平及CD44/CD24乳腺癌干细胞群体均显著降低。敲低Runx2后，癌症干细胞的更新能力如软琼脂克隆形成、乳腺球形成及在裸鼠中的成瘤能力均下降。相反，过表达Runx2可增强上述所有干细胞更新能力。最后，我们探究了Runx2如何改变癌症干细胞群体。我们发现它可影响上皮-间质转化（EMT）。Runx2可调节间质标志物和上皮标志物的表达，并影响Wnt/β-连环蛋白信号通路的激活。这些结果共同强烈表明，Runx2可通过EMT过程促进CD44/CD24乳腺癌干细胞特性及乳腺癌肿瘤发生。
