The Therapeutic Potential of ADAMTS8 in Lung Adenocarcinoma without Targetable Therapy

Abstract

Lung cancer is well known for its high mortality worldwide. The treatment for advanced lung cancer needs more attention to improve its survival time. A disintegrin and metallopeptidase with thrombospondin motifs 8 (ADAMTS8) has been linked to several cancer types. However, its role in lung cancer is worthy of deep investigation to promote novel drug development. This study took advantage of RNA-seq and bioinformatics to verify the role that ADAMTS8 plays in lung cancer. The functional assays suggested that ADAMTS8 mediates invasion and metastasis when expressed at a low level, contributing to poor overall survival (OS). The expression of ADAMTS8 was under the regulation of GATA Binding Protein 1 (GATA1) and executed its pathologic role through Thrombospondin Type 1 Domain Containing 1 (THSD1) and ADAMTS Like 2 (ADAMTSL2). To define the impact of ADAMTS8 in the lung cancer treatment strategy, this study further grouped lung cancer patients in the TCGA database into mutated epidermal growth factor receptor (EGFR)/wild-type EGFR and programmed death ligand 1 (PD-L1) high/low groups. Importantly, the expression of ADAMTS8 was correlated positively with the recruitment of anticancer NKT cells and negatively with the infiltration of immunosuppressive Treg and exhausted T cells. The results indicated that lung cancer patients with higher ADAMTS8 levels among wild-type EGFR or low PD-L1 groups survive longer than those with lower levels do. This study indicates that ADAMTS8 might be a treatment option for patients with lung adenocarcinoma who lack efficient targeted or immunotherapies.

ADAMTS1 induces epithelial-mesenchymal transition pathway in non-small cell lung cancer by regulating TGF-β

“…For example, ADAMTS5 was upregulated in NSCLC tissues and enhances the migration and invasion of lung cancer cells [ 33 ]. ADAMTS8 is an unfavorable predictor of lung cancer patients, and it mediates invasion and metastasis when expressed at a low level [ 34 ]. In higher stages and advanced NSCLC patients, enhanced VWF/ADAMTS-13 ratio and downregulated ADAMTS-13 were observed.…”

Function and prognostic value of basement membrane -related genes in lung adenocarcinoma

“…The upregulated proteins may inhibit cell proliferation and promote apoptosis by suppressing VEGFA. Lee et al (2022) found that ADAMTS8 expression was positively correlated with the recruitment of anti-cancer NKT cells, patients with higher ADAMTS8 levels in wild-type EGFR or low PD-L1 groups survived longer than with low levels of LUAD, suggesting that ADAMTS8 may be a treatment option for patients with lung adenoma who lack effective targeted or immunotherapy. ADAMTS8 acts as a secretory protease to inhibit the EGFR signaling pathway, while phosphorylating MEK and ERK levels are reduced.…”

ADAMTS Proteases: Their Multifaceted Role in the Regulation of Cancer Metastasis

“…In addition, ADAMTS8 expression was reported to be regulated by the transcription factor GATA1. GATA1 expression was found significantly downregulated in LC samples compared to healthy tissues and this correlated with reduction in ADAMTS8 levels [ 32 ] .…”