Zhuang Sujing, Li Li, Zang Yuwei, Li Guangfeng, Wang Feng
Department of Neurology, Linyi Central Hospital, Linyi, Shandong 276499, P.R. China.
Department of Radiology, Yishui People's Hospital, Linyi, Shandong 276499, P.R. China.
Oncol Lett. 2020 Apr;19(4):3349-3355. doi: 10.3892/ol.2020.11428. Epub 2020 Mar 3.
Breast cancer is the second leading primary cause for cancer-related mortality among women and metastasis to the brain is a disastrous event for patients with increasing incidence. A previous study confirmed the critical function of RRM2 in breast cancer cell growth. Unfortunately, the role and fundamental molecular mechanism of RRM2 in breast cancer metastasis remains elusive. In the current study, higher RRM2 expression was validated in breast cancer tissues, especially in the brain metastasis group. Simultaneously, the expression of RRM2 was increased in breast cancer cells relative to the normal breast epithelial cell line MCF-10A, concomitant with higher levels of RRM2 in the highly metastatic MDA-MB-231 cell line relative to the weakly metastatic MCF-7 cell line. Knockdown of RRM2 by small interfering-RRM2 transfection notably suppressed the malignant metastatic behavior of breast cancer cells, including invasion and migration. Simultaneously, RRM2 downregulation also restrained the transcription and release of vascular endothelial growth factor (VEGF) in breast cancer cells. Moreover, inhibition of RRM2 dampened the activation of phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signaling by decreasing phosphorylated-AKT and downstream matrix metalloproteinases-2 expression. Intriguingly, reactivation of the PI3K/AKT pathway with its agonist insulin-like growth factor-1 reversed the adverse effects of RRM2 suppression on cancer cell invasion, migration and VEGF expression. Together, these findings suggest that RRM2 may act as a pro-metastatic factor to facilitate breast cancer metastasis by evoking cell invasion, migration and VEGF expression through the PI3K/AKT signaling pathway. This study may provide an attractive target for metastatic intervention in breast cancer.
乳腺癌是女性癌症相关死亡的第二大主要原发性原因，而脑转移对发病率不断上升的患者来说是灾难性事件。先前的一项研究证实了RRM2在乳腺癌细胞生长中的关键作用。不幸的是，RRM2在乳腺癌转移中的作用和基本分子机制仍不清楚。在本研究中，证实乳腺癌组织中RRM2表达较高，尤其是在脑转移组。同时，与正常乳腺上皮细胞系MCF-10A相比，乳腺癌细胞中RRM2的表达增加，且与高转移性MDA-MB-231细胞系相比，低转移性MCF-7细胞系中RRM2水平更高。通过小干扰RNA-RRM2转染敲低RRM2可显著抑制乳腺癌细胞的恶性转移行为，包括侵袭和迁移。同时，RRM2下调也抑制了乳腺癌细胞中血管内皮生长因子（VEGF）的转录和释放。此外，抑制RRM2可通过降低磷酸化AKT和下游基质金属蛋白酶-2的表达来减弱磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）信号通路的激活。有趣的是，用其激动剂胰岛素样生长因子-1重新激活PI3K/AKT通路可逆转RRM2抑制对癌细胞侵袭、迁移和VEGF表达的不利影响。总之，这些发现表明RRM2可能作为一种促转移因子，通过PI3K/AKT信号通路引发细胞侵袭、迁移和VEGF表达来促进乳腺癌转移。本研究可能为乳腺癌转移干预提供一个有吸引力的靶点。
