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- Title
SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1-Negative Lung Adenocarcinomas.
- Authors
Tanaka, Ichidai; Dayde, Delphine; Tai, Mei Chee; Mori, Haruki; Solis, Luisa M; Tripathi, Satyendra C; Fahrmann, Johannes F; Unver, Nese; Parhy, Gargy; Jain, Rekha; Parra, Edwin R; Murakami, Yoshiko; Aguilar-Bonavides, Clemente; Mino, Barbara; Celiktas, Muge; Dhillon, Dilsher; Casabar, Julian Phillip; Nakatochi, Masahiro; Stingo, Francesco; Baladandayuthapani, Veera
- Abstract
<bold>Background: </bold>Approximately 20% of lung adenocarcinoma (LUAD) is negative for the lineage-specific oncogene Thyroid transcription factor 1 (TTF-1) and exhibits worse clinical outcome with a low frequency of actionable genomic alterations. To identify molecular features associated with TTF-1-negative LUAD, we compared the transcriptomic and proteomic profiles of LUAD cell lines. SRGN , a chondroitin sulfate proteoglycan Serglycin, was identified as a markedly overexpressed gene in TTF-1-negative LUAD. We therefore investigated the roles and regulation of SRGN in TTF-1-negative LUAD.<bold>Methods: </bold>Proteomic and metabolomic analyses of 41 LUAD cell lines were done using mass spectrometry. The function of SRGN was investigated in 3 TTF-1-negative and 4 TTF-1-positive LUAD cell lines and in a syngeneic mouse model (n = 5 to 8 mice per group). Expression of SRGN was evaluated in 94 and 105 surgically resected LUAD tumor specimens using immunohistochemistry. All statistical tests were 2-sided.<bold>Results: </bold>SRGN was markedly overexpressed at mRNA and protein levels in TTF-1-negative LUAD cell lines (P < .001 for both mRNA and protein levels). Expression of SRGN in LUAD tumor tissue was associated with poor outcome (hazard ratio = 4.22, 95% confidence interval = 1.12 to 15.86, likelihood ratio test, P = .03), and with higher expression of Programmed cell death 1 ligand 1 (PD-L1) in tumor cells and higher infiltration of Programmed cell death protein 1-positive lymphocytes. SRGN regulated expression of PD-L1 as well as proinflammatory cytokines, including Interleukin-6, Interleukin-8, and C-X-C motif chemokine 1 in LUAD cell lines; increased migratory and invasive properties of LUAD cells and fibroblasts; and enhanced angiogenesis. SRGN was induced by DNA demethylation resulting from Nicotinamide N-methyltransferase-mediated impairment of methionine metabolism.<bold>Conclusions: </bold>Our findings suggest that SRGN plays a pivotal role in tumor-stromal interaction and reprogramming into an aggressive and immunosuppressive tumor microenvironment in TTF-1-negative LUAD.
- Subjects
RESEARCH; ANIMAL experimentation; LUNG tumors; CELL physiology; PROTEOMICS; COMPARATIVE studies; RESEARCH funding; MICE; PHENOTYPES
- Publication
JNCI: Journal of the National Cancer Institute, 2022, Vol 114, Issue 2, p290
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djab183