PMID- 34726807 OWN - NLM STAT- MEDLINE DCOM- 20220112 LR - 20240405 IS - 1349-7006 (Electronic) IS - 1347-9032 (Print) IS - 1347-9032 (Linking) VI - 113 IP - 1 DP - 2022 Jan TI - Loss of GSTO2 contributes to cell growth and mitochondria function via the p38 signaling in lung squamous cell carcinoma. PG - 195-204 LID - 10.1111/cas.15189 [doi] AB - Glutathione S-transferase omega 2 (GSTO2) lacks any appreciable GST activity, but it exhibits thioltransferase activity. The significance of GSTO2 in lung function has been reported; however, the precise expression and molecular function of GSTO2 in the lungs remain unclear. In the present study, we found that GSTO2 is expressed in airway basal cells, non-ciliated, columnar Clara cells, and type II alveolar cells, which have self-renewal capacity in the lungs. Contrastingly, no GSTO2 expression was observed in 94 lung squamous cell carcinoma (LSCC) samples. When human LSCC cell lines were treated with 5-aza-2'-deoxycytidine, a DNA-methyltransferase inhibitor, GSTO2 transcription was induced, suggesting that aberrant GSTO2 hypermethylation in LSCC is the cause of its downregulation. Forced GSTO2 expression in LSCC cell lines inhibited cell growth and colony formation in vitro. In a subcutaneous xenograft model, GSTO2-transfected 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 cells than in those injected with mock-transfected cells. In addition, GSTO2 induction suppressed the expression of beta-catenin and the oxygen consumption rate, but it did not affect the extracellular acidification rate. Furthermore, GSTO2-transfected cells displayed lower mitochondrial membrane potential than mock-transfected cells. When GSTO2-transfected cells were treated with a p38 inhibitor, beta-catenin expression and mitochondrial membrane potential were recovered. Our study indicated that the loss of GSTO2 via DNA hypermethylation contributes to the growth and progression of LSCC, probably by modulating cancer metabolism via the p38/beta-catenin signaling pathway. CI - (c) 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. FAU - Sumiya, Ryusuke AU - Sumiya R AUID- ORCID: 0000-0002-2464-6717 AD - Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan. AD - Department of Thoracic Surgery, National Center for Global Health and Medicine, Tokyo, Japan. AD - Course of Advanced and Specialized Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan. FAU - Terayama, Masayoshi AU - Terayama M AD - Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan. AD - Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan. FAU - Hagiwara, Teruki AU - Hagiwara T AD - Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan. FAU - Nakata, Kazuaki AU - Nakata K AD - Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan. FAU - Sekihara, Keigo AU - Sekihara K AD - Department of Thoracic Surgery, National Center for Global Health and Medicine, Tokyo, Japan. FAU - Nagasaka, Satoshi AU - Nagasaka S AD - Department of Thoracic Surgery, National Center for Global Health and Medicine, Tokyo, Japan. FAU - Miyazaki, Hideki AU - Miyazaki H AD - Pathology Division of Clinical Laboratory, National Center for Global Health and Medicine, Tokyo, Japan. FAU - Igari, Toru AU - Igari T AD - Pathology Division of Clinical Laboratory, National Center for Global Health and Medicine, Tokyo, Japan. FAU - Yamada, Kazuhiko AU - Yamada K AD - Course of Advanced and Specialized Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan. AD - Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan. FAU - Kawamura, Yuki I AU - Kawamura YI AD - Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan. LA - eng GR - 19K08457/Japan Society for the Promotion of Science/ GR - 19K24058/Japan Society for the Promotion of Science/ GR - 19A1021/National Center for Global Health and Medicine/ GR - 20A1017/National Center for Global Health and Medicine/ GR - 20A3002/National Center for Global Health and Medicine/ GR - 29-1019/National Center for Global Health and Medicine/ PT - Journal Article DEP - 20211121 PL - England TA - Cancer Sci JT - Cancer science JID - 101168776 RN - 776B62CQ27 (Decitabine) RN - EC 2.5.1.18 (GSTO2 protein, human) RN - EC 2.5.1.18 (Glutathione Transferase) SB - IM MH - Animals MH - Carcinoma, Squamous Cell/genetics/*pathology MH - Cell Line, Tumor MH - DNA Methylation/drug effects MH - Decitabine/pharmacology MH - *Down-Regulation/drug effects MH - Epigenesis, Genetic MH - Gene Expression Regulation, Neoplastic/drug effects MH - Glutathione Transferase/*genetics MH - Glycolysis MH - Humans MH - Liver Neoplasms/genetics/*pathology/*secondary MH - Lung Neoplasms/genetics/*pathology MH - MAP Kinase Signaling System/drug effects MH - Male MH - Mice MH - Mice, Nude MH - Neoplasm Transplantation MH - Oxidative Phosphorylation PMC - PMC8748250 OTO - NOTNLM OT - GSTO2 OT - LSCC OT - cancer metabolism OT - p38 OT - beta-catenin COIS- The authors have no conflicts of interest to declare. EDAT- 2021/11/03 06:00 MHDA- 2022/01/13 06:00 PMCR- 2022/01/01 CRDT- 2021/11/02 12:27 PHST- 2021/10/28 00:00 [revised] PHST- 2021/08/08 00:00 [received] PHST- 2021/10/29 00:00 [accepted] PHST- 2021/11/03 06:00 [pubmed] PHST- 2022/01/13 06:00 [medline] PHST- 2021/11/02 12:27 [entrez] PHST- 2022/01/01 00:00 [pmc-release] AID - CAS15189 [pii] AID - 10.1111/cas.15189 [doi] PST - ppublish SO - Cancer Sci. 2022 Jan;113(1):195-204. doi: 10.1111/cas.15189. Epub 2021 Nov 21.