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SAMHD1 can suppress lung adenocarcinoma progression through the negative regulation of STING
1Department of Thoracic Surgery, Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated with Fudan University, Shanghai, China.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
Upregulation of SAMHD1 could suppress the progression of LAC in vivo and in vitro through the negative regulation of STING.
Insights
Upregulating sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) suppresses lung adenocarcinoma (LAC) progression by inhibiting stimulator of interferon genes (STING). This finding offers new therapeutic targets for LAC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Lung adenocarcinoma (LAC) progression mechanisms are not fully understood.
- Sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is implicated in lung cancer.
- The specific role of SAMHD1 in LAC requires elucidation.
Purpose of the Study:
- To investigate the regulatory role of SAMHD1 in lung adenocarcinoma (LAC).
- To assess the relationship between SAMHD1 expression and LAC progression.
- To explore the underlying molecular mechanisms involving SAMHD1 in LAC.
Main Methods:
- Retrospective analysis of 238 LAC patients.
- Quantitative reverse-transcription polymerase chain reaction (RT-qPCR) to measure SAMHD1 expression.
- Lentiviral overexpression of SAMHD1 and stimulator of interferon genes (STING) in A549 cells.
- Cell proliferation assays (MTT, Celigo) and apoptosis detection (Annexin V staining).
- In vivo xenograft model and DNA damage response inhibitor (DDRi) treatment.
Main Results:
- Low SAMHD1 expression correlated with advanced LAC.
- SAMHD1 overexpression reduced cell proliferation and invasion, and increased apoptosis in LAC cells.
- SAMHD1 overexpression inhibited tumor growth in a xenograft model.
- STING expression was downregulated by SAMHD1, and STING overexpression partially reversed SAMHD1's inhibitory effects.
- DNA damage response inhibitors showed efficacy in inhibiting cancer cell progression.
Conclusions:
- SAMHD1 upregulation suppresses LAC progression both in vitro and in vivo.
- This suppression is mediated through the negative regulation of STING.
- Targeting SAMHD1 and STING pathways may offer novel therapeutic strategies for LAC.
