Glutathione S-transferase omega 2 (GSTO2) lacks any appreciable GST activity but presents thioltransferase activity and therefore plays an important role in regulating the glutathione redox balance. In addition, GSTO2 polymorphisms are strongly associated with lung function and the risk of chronic obstructive pulmonary disease. We recently reported that GSTO2 is exclusively expressed in airway basal cells, Clara cells, and type II alveolar cells, which have self-renewal capacity in the lungs. In this study, we examined the expression of GSTO2 in non-small cell lung cancer (NSCLC) and analyzed the relationship between GSTO2 expression and clinicopathological features. We enrolled 233 patients who were diagnosed with NSCLC and underwent surgery, and immunohistochemically evaluated the expression of GSTO2 using formalin-fixed, paraffin-embedded sections of surgical specimens. While all 94 squamous cell carcinoma samples showed no GSTO2 expression, 58 of 139 lung adenocarcinoma (LAC) samples exhibited GSTO2 expression. The expression of GSTO2 in LAC samples was significantly associated with never or light (Brinkman Index < 400) smoking history (P=0.0027) and histological subtypes (lepidic 85/110, 77%; acinar 30/68, 44%; papillary 18/64, 22%; micropapillary 1/6, 16.7%; solid 3/31, 9.6%; P<0.0001). There were no significant differences between the groups with respect to pN, pM, EGFR mutation, ALK fusion, and ROS-1 fusion. However, GSTO2 expression in LAC significantly associated with pT1 (P<0.0001), early stage (P<0.0001), and absence of PD-L1 expression (P=0.0027). Moreover, patients with GSTO2-negative LAC had a significantly lower disease-free survival rate than those with GSTO2-positve LAC (P=0.028). To examine whether GSTO2 expression affects PD-L1 expression, we prepared GSTO2-transfected and mock-transfected NSCLC cell lines (A549, PC-9, and H520). However, there was no difference in PD-L1 transcription between the GSTO2 and mock transfectants. Previous studies have reported that PD-L1 protein expression is induced via the mitogen-activated protein kinase (MAPK) signaling pathways in lung cancer, glioblastoma, and hepatocellular carcinoma. Our prior finding that GSTO2 accelerates the phosphorylation of p38, a key protein of MAPK signaling (Cancer Science, 2022), suggests that GSTO2 may be involved in PD-L1 expression as a post-transcriptional regulator. In summary, our study indicates that GSTO2 loss contributes to LAC progression partially through the induction of PD-L1 expression. Citation Format: Ryusuke Sumiya, Hiroto Hatano, Teruki Hagiwara, Satoshi Nagasaka, Hiromu Suzuki, Kazuhiko Yamada, Norihiro Kokudo, Yuki I. Kawamura. Loss of glutathione S-Transferase omega 2 is associated with PD-L1 expression and poor prognosis in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2602.
Glutathione S-transferase omega 2 (GSTO2) is one of regulators of GSH/GSSG balance, and its polymorphism showed strong associations with lung functions as well as the risk of chronic obstructive pulmonary disease. Recently, we found that GSTO2 was exclusively expressed in airway basal cells, Clara cells and type II alveolar cells, which have self-renewal capacity in the lungs; however, its expression was lost in lung squamous cell carcinoma (LSCC). In the present study, we restored GSTO2 expression in LSCC cell lines (LK-2 and H520) to clarify the significance of GSTO2 loss in LSCC. In both LSCC cell lines used, GSTO2 overexpression significantly inhibited cell growth and colony formation in vitro. In a subcutaneous xenograft model, GSTO2-transfected LK-2 cells formed smaller tumors in nude mice than mock-transfected cells. Upon intravenous injection into nude mice, the incidence of liver metastasis was lower in mice injected with GSTO2-transfected LK-2 cells than in those injected with mock-transfected cells. Metabolomic analyses using the XF96 extracellular flux analyzer revealed that GSTO2 overexpression suppressed mitochondrial oxidative phosphorylation but did not affect glycolysis. Upon JC-1 dye staining, GSTO2-transfected cells showed decreased mitochondrial membrane potential compared with mock-transfected cells. Since β-catenin has been reported as a novel regulator of the OXPHOS in hepatocytes, we next examined the effect of GSTO2 expression on β-catenin expression in LSCC and found that GSTO2 overexpression suppressed the expression of β-catenin. Because p38 phosphorylation was accelerated in both GSTO2-transfected cells, we examined the involvement of the p38 signaling pathway in the GSTO2-mediated downregulation of β-catenin as well as mitochondrial membrane potential in LSCC.When GSTO2-transfected cells were treated with SB203580, a specific inhibitor of p38 MAPK, β-catenin expression and mitochondrial membrane potentialwere restored. Finally, we examine whether DNA methylation of the GSTO2 could explain the loss of GSTO2 expression in LSCC. When human LSCC cell lines were treated with 5-aza-2′-deoxycytidine, a DNA-methyltransferase inhibitor, GSTO2 transcription was induced. Bisulfite sequencing showed that the promoter region of the GSTO2 was frequently methylated in LSCC tissues than that of normal tissue. Our study indicated that the loss of GSTO2 via DNA hypermethylation contributes to the cell growth and progression of LSCC, probably by modulating oxidative phosphorylation in mitochondria via the p38/β-catenin signaling pathway. Citation Format: Ryusuke Sumiya, Masayoshi Terayama, Teruki Hagiwara, Kazuaki Nakata, Satoshi Nagasaka, Kazuhiko Yamada, Norihiro Kokudo, Hiromu Suzuki, Kawamura I. Yuki. GSTO2, a novel tumor suppressor gene of lung squamous cell carcinoma, regulates mitochondria function via the p38/β-catenin signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3783.
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