Downregulated ADAMTS1 Incorporating A2M Contributes to Tumorigenesis and Alters Tumor Immune Microenvironment in Lung Adenocarcinoma

Abstract

Lung adenocarcinoma (LUAD) still holds the most dreadful clinical outcomes worldwide. Despite advanced treatment strategies, there are still some unmet needs. Next-generation sequencing of large-scale cancer genomics discovery projects combined with bioinformatics provides the opportunity to take a step forward in meeting clinical conditions. Based on in-house and The Cancer Genome Atlas (TCGA) cohorts, the results showed decreased levels of ADAMTS1 conferred poor survival compared with normal parts. Gene set enrichment analyses (GSEA) indicated the negative correlation between ADAMTS1 and the potential roles of epithelial–mesenchymal transition (EMT), metastasis, and poor prognosis in LUAD patients. With the knockdown of ADAMTS1, A549 lung cancer cells exhibited more aggressive behaviors such as EMT and increased migration, resulting in cancer metastasis in a mouse model. The pathway interaction network disclosed the linkage of downregulated α2-macroglobulin (A2M), which regulates EMT and metastasis. Furthermore, immune components analysis indicated a positive relationship between ADAMTS1 and the infiltrating levels of multiple immune cells, especially anticancer CD4+ T cells in LUAD. Notably, ADAMTS1 expression was also inversely correlated with the accumulation of immunosuppressive myeloid-derived suppressor cells and regulatory T cells, implying the downregulated ADAMTS1 mediated immune adjustment to fit the tumor survival disadvantages in LUAD patients. In conclusion, our study indicates that ADAMTS1 interacts with A2M in regulating EMT and metastasis in LUAD. Additionally, ADAMTS1 contributes to poor prognosis and immune infiltration in LUAD patients

Proteomic Analyses Reveal the Role of Alpha-2-Macroglobulin in Canine Osteosarcoma Cell Migration

“…According to the authors, HCCP (characterised by the increased expression of A2M) had significant anti-migration efficacy and may be considered a novel therapeutic agent for cancer treatment [34]. In both in vitro and in vivo studies, Lee et al [35] showed that the downregulation of A2M and decreased A2M protein expression levels were positively correlated with decreased ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1). Moreover, bioinformatics analyses suggest that both A2M and ADAMTS1 expressions are correlated with more aggressive phenotypes of lung adenocarcinoma.…”

“…A2M was shown to play a role in activating the epithelial-mesenchymal transition (EMT) and promoting metastasis in lung adenocarcinoma. A2M expression was negatively correlated with patients' overall survival [35]. Zhang and collaborators described A2M downregulation in intrahepatic cholangiocarcinoma (ICC) compared to normal bile duct tissue, suggesting this gene's potential utility as an adverse prognostic factor [25].…”

Construction and validation of a prognostic model for predicting clear cell renal cell carcinoma based on complement-related genes

“…In various tumor tissues, these five complement-related genes were produced by different cells and ultimately affect tumor progression. For example, the overexpression of DOCK4 has been shown to promote migration and invasion in prostate cancer cells ( 39 ), APOBEC3G has been shown to promote colorectal liver cancer metastasis by suppressing mir-29-mediated matrix metalloproteinase-2 inhibition ( 40 ), ADAMTS1 and A2M downregulation has been shown that activating epithelial-mesenchymal transition and altering the immune microenvironment to promote lung adenocarcinoma metastasis ( 41 ), NOTCH4 has been shown to have pro-proliferative, anti-apoptotic, and pro-migratory effects on lung adenocarcinoma cells ( 42 ), and COL4A2 has been shown to activate the RhoA/ROCK pathway to promote the invasion and migration of chicken hepatocellular carcinoma cell line (LMH) cells ( 43 ). These previous studies validate the reliability of our established model to some extent.…”