Wu Yun, Niu Yuxu, Wu Yue, Chen Xiaoyu, Shen Xiaoyong, Gao Wen
Department of Thoracic Surgery, Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated with Fudan University, Shanghai, China.
J Thorac Dis. 2021 Jan;13(1):189-201. doi: 10.21037/jtd-20-1889.
The sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) has been specifically linked to lung cancer. However, the underlying mechanisms in regulating lung adenocarcinoma (LAC) are unclear. The aim of this study was to assess the specific regulation between SAMHD1 and LAC.
We retrospectively reviewed 238 patients who underwent surgery for LAC between January 2018 and December 2019. The expression of SAMHD1 was detected by quantitative reverse-transcription polymerase chain reaction (RT-qPCR) in tumors and paired adjacent tissues. A lentivirus was used to overexpress SAMHD1 and stimulator of interferon genes (STING) in A549 cells; and RT-qPCR and western blot analysis were performed to verify their levels. Cell proliferation was evaluated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Celigo imaging cytometry. Cell apoptosis was detected by Annexin V staining. Overexpressed SAMHD1 suppressed LAC progression in a xenograft model. The DNA damage response inhibitor (DDRi) was used to assess the cell proliferation and apoptosis rate in SAMHD1-overexpressing A549 cells and the control group. A rescue experiment was carried out to evaluate the potential influence of SAMHD1 and STING.
A low expression of SAMHD1 was associated with advanced disease. Overexpression of SAMHD1 decreased cell proliferation and invasion in A549 cells, and the apoptosis rate was significantly higher in the overexpressed SAMHD1 cells than those in the control group. The overexpression of SAMHD1 inhibited tumor progression in the xenograft model. The expression of STING was lower in SAMHD1-overexpressing A549 cells than those in the wild-type group. Furthermore, the inhibited cellular behaviors of LAC cells resulting from the stable SAMHD1 expression were partially reversed after STING overexpression. Treatment with DDRi could inhibit cancer cell progression.
Upregulation of SAMHD1 could suppress the progression of LAC and through the negative regulation of STING.
含无菌α基序（SAM）结构域和组氨酸-天冬氨酸（HD）结构域蛋白1（SAMHD1）与肺癌存在特定关联。然而，其调控肺腺癌（LAC）的潜在机制尚不清楚。本研究旨在评估SAMHD1与LAC之间的具体调控关系。
我们回顾性分析了2018年1月至2019年12月期间接受LAC手术的238例患者。通过定量逆转录聚合酶链反应（RT-qPCR）检测肿瘤组织及配对的癌旁组织中SAMHD1的表达。利用慢病毒在A549细胞中过表达SAMHD1和干扰素基因刺激因子（STING）；并进行RT-qPCR和蛋白质印迹分析以验证其水平。通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法和Celigo成像细胞术评估细胞增殖。通过膜联蛋白V染色检测细胞凋亡。过表达的SAMHD1在异种移植模型中抑制LAC进展。使用DNA损伤反应抑制剂（DDRi）评估过表达SAMHD1的A549细胞和对照组中的细胞增殖和凋亡率。进行了一项挽救实验以评估SAMHD1和STING的潜在影响。
SAMHD1低表达与疾病进展相关。SAMHD1过表达降低了A549细胞的增殖和侵袭能力，且过表达SAMHD1的细胞凋亡率显著高于对照组。SAMHD1过表达抑制了异种移植模型中的肿瘤进展。过表达SAMHD1的A549细胞中STING的表达低于野生型组。此外，STING过表达后部分逆转了稳定表达SAMHD1导致的LAC细胞行为抑制。DDRi处理可抑制癌细胞进展。
SAMHD1上调可抑制LAC进展，并通过对STING的负调控发挥作用。
