TY - JOUR
T1 - SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1-Negative Lung Adenocarcinomas
AU - Tanaka, Ichidai
AU - Dayde, Delphine
AU - Tai, Mei Chee
AU - Mori, Haruki
AU - Solis, Luisa M.
AU - Tripathi, Satyendra C.
AU - Fahrmann, Johannes F.
AU - Unver, Nese
AU - Parhy, Gargy
AU - Jain, Rekha
AU - Parra, Edwin R.
AU - Murakami, Yoshiko
AU - Aguilar-Bonavides, Clemente
AU - Mino, Barbara
AU - Celiktas, Muge
AU - Dhillon, Dilsher
AU - Casabar, Julian Phillip
AU - Nakatochi, Masahiro
AU - Stingo, Francesco
AU - Baladandayuthapani, Veera
AU - Wang, Hong
AU - Katayama, Hiroyuki
AU - Dennison, Jennifer B.
AU - Lorenzi, Philip L.
AU - Do, Kim Anh
AU - Fujimoto, Junya
AU - Behrens, Carmen
AU - Ostrin, Edwin J.
AU - Rodriguez-Canales, Jaime
AU - Hase, Tetsunari
AU - Fukui, Takayuki
AU - Kajino, Taisuke
AU - Kato, Seiichi
AU - Yatabe, Yasushi
AU - Hosoda, Waki
AU - Kawaguchi, Koji
AU - Yokoi, Kohei
AU - Chen-Yoshikawa, Toyofumi F.
AU - Hasegawa, Yoshinori
AU - Gazdar, Adi F.
AU - Wistuba, Ignacio I.
AU - Hanash, Samir
AU - Taguchi, Ayumu
N1 - Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press. All rights reserved.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.
AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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.
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U2 - 10.1093/jnci/djab183
DO - 10.1093/jnci/djab183
M3 - Article
C2 - 34524427
AN - SCOPUS:85124434223
SN - 0027-8874
VL - 114
SP - 290
EP - 301
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 2
ER -