Department of Medical Laboratory Science, The Fifth People's Hospital of Wuxi, The Medical School of Jiangnan University Wuxi, Wuxi, Jiangsu, 214005, China.
Department of Pathology, The Fifth People's Hospital of Wuxi, Nanjing Medical University, Wuxi, Jiangsu, 214005, China.
Sci Rep. 2017 Aug 29;7(1):9687. doi: 10.1038/s41598-017-10468-x.
5-FU-based combinatory chemotherapeutic regimens have been routinely used for many years for the treatment of breast cancer patients. Recurrence and chemotherapeutic drug resistance are two of the most prominent factors that underpin the high mortality rates associated with most breast cancers (BC). Increasing evidence indicates that overexpression of ADAMs could correlate with cancer progression. However, the role of ADAMs in the chemoresistance of cancer cells has rarely been reported. In this study, we observed that 5-FU induces expression of the ADAM12 isoform ADAM12-L but not ADAM12-S in BC cells and in recurrent BC tissues. The overexpression of ADAM12-L in BC cells following 5-FU treatment results in the acquisition of resistance to 5-FU. ADAM12-L overexoression also resulted in increased levels of p-Akt but not p-ERK. These alterations enhanced BC cell growth and invasive abilities. Conversely, ADAM12 knockdown attenuated the levels of p-Akt and restored 5-FU sensitivity in 5-FU-resistant BC cells. ADAM12 knockdown also reduced BC cell survival and invasive abilities. These findings suggest that ADAM12-L mediates chemoresistance to 5-FU and 5-FU-induced recurrence of BC by enhancing PI3K/Akt signaling. The results of this study suggest that specific ADAM12-L inhibition could optimize 5-FU-based chemotherapy of BC, thereby preventing BC recurrence in patients.
5-FU 为基础的联合化疗方案已被常规使用多年，用于治疗乳腺癌患者。复发和化疗耐药性是导致大多数乳腺癌（BC）高死亡率的两个最突出的因素。越来越多的证据表明，ADAMs 的过度表达可能与癌症的进展有关。然而，ADAMs 在癌细胞的化疗耐药性中的作用很少有报道。在这项研究中，我们观察到 5-FU 诱导 BC 细胞和复发性 BC 组织中 ADAM12 同工型 ADAM12-L 的表达，但不诱导 ADAM12-S 的表达。5-FU 处理后，BC 细胞中 ADAM12-L 的过表达导致对 5-FU 的耐药性。ADAM12-L 的过表达也导致 p-Akt 水平增加，但 p-ERK 水平没有增加。这些改变增强了 BC 细胞的生长和侵袭能力。相反，ADAM12 敲低降低了 p-Akt 的水平，并恢复了 5-FU 耐药性 BC 细胞对 5-FU 的敏感性。ADAM12 敲低也降低了 BC 细胞的存活和侵袭能力。这些发现表明，ADAM12-L 通过增强 PI3K/Akt 信号通路介导对 5-FU 的化疗耐药性和 5-FU 诱导的 BC 复发。本研究的结果表明，特异性 ADAM12-L 抑制可能优化基于 5-FU 的 BC 化疗，从而防止患者的 BC 复发。
