Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
Biochem Biophys Res Commun. 2019 May 28;513(2):319-325. doi: 10.1016/j.bbrc.2019.03.198. Epub 2019 Apr 5.
Aberrant expression of sperm-associated antigen 5 (SPAG5) is implicated to play oncogenic roles in several types of cancers. However, the functions of SPAG5 in lung adenocarcinoma remain unclear. In this study, we investigated the role of SPAG5 in lung adenocarcinoma. We found that SPAG5 was upregulated in most of the lung adenocarcinoma cell lines as compared to normal lung epithelial cells. SPAG5 knockdown suppressed proliferation, colony forming, and migration of lung adenocarcinoma A549 cells in vitro and inhibited tumor growth in vivo. These suggest that upregulated SPAG5 promotes lung tumor progression. Importantly, treatment with MDM2 inhibitor, Nutlin-3a, restored p53 and p21 expression and suppressed SPAG5 expression in wild-type p53 lung adenocarcinoma cells, A549 and H460, but not in p53-null lung cancer cells, H1299. This suggests that the p53 signal pathway is essential for SPAG5 suppression. In addition, knocking-down p53 or p21 in A549 and H460 cells attenuated Nutlin-3a-induced repression of SPAG5, which further supports that the p53-p21 axis is required for SPAG5 repression. Thus, SPAG5 can serve as a prognostic marker, and therapeutic strategy targeting the p53-p21-SPAG5 axis may have important clinical implications.
精子相关抗原 5（SPAG5）的异常表达被认为在几种类型的癌症中发挥致癌作用。然而，SPAG5 在肺腺癌中的功能仍不清楚。在本研究中，我们研究了 SPAG5 在肺腺癌中的作用。我们发现与正常肺上皮细胞相比，SPAG5 在大多数肺腺癌细胞系中上调。SPAG5 敲低抑制肺腺癌细胞 A549 的体外增殖、集落形成和迁移，并抑制体内肿瘤生长。这表明上调的 SPAG5 促进肺肿瘤的进展。重要的是，用 MDM2 抑制剂 Nutlin-3a 处理野生型 p53 肺腺癌细胞 A549 和 H460，但不是 p53 缺失的肺癌细胞 H1299，可恢复 p53 和 p21 的表达并抑制 SPAG5 的表达。这表明 p53 信号通路对 SPAG5 的抑制是必需的。此外，在 A549 和 H460 细胞中敲低 p53 或 p21 可减弱 Nutlin-3a 诱导的 SPAG5 抑制，这进一步支持 p53-p21 轴是 SPAG5 抑制所必需的。因此，SPAG5 可作为预后标志物，靶向 p53-p21-SPAG5 轴的治疗策略可能具有重要的临床意义。
