CMAR_A_331222 8887..8900

*These authors contributed equally to this work Purpose: Lung cancer is one of the most commonly diagnosed cancer as well as the leading cause of cancer-related mortality worldwide, among which lung adenocarcinoma (LUAD) is the most frequent form of lung cancer. Previous studies have shown that 15hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of prostaglandins to reduce their biological activities and behaves as a tumor suppressor in various cancers. Thus, we aimed to systematically examine the effects of 15-PGDH overexpression on cellular processes in lung adenocarcinoma cells. Methods: The stable 15-PGDH-overexpressing A549 cell line was constructed using lentivirus particles. CCK-8 assay was used to determine the cell proliferation rate and sensitivity to cisplatin. Tandem mass tag (TMT)-based quantitative proteomic analysis was used to identify differentially expressed proteins between control and 15-PGDH-overexpression cells. The cell cycle was determined by a flow cytometer. The expression levels of mesenchymal and epithelial markers were measured using Western blotting. Wound healing and transwell assays were used to detect the cell migration and cell invasion ability, respectively. Results: Analysis of datasets in The Cancer Genome Atlas revealed that the PGDH gene expression level in the lung adenocarcinoma tissues was significantly lower than that in the pericarcinous tissues. 15-PGDH overexpression in A549 cells reduced cell proliferation rate. Quantitative proteomics revealed that 15-PGDH overexpression inhibited PI3K/AKT/mTOR signaling pathway, which is a signaling pathway driving tumor cell growth and epithelialmesenchymal transition (EMT) process. In addition, both cell cycle and DNA repair-related proteins were down-regulated in 15-PGDH overexpressed cells. 15-PGDH overexpression induced G1/S cell cycle arrest and increased susceptibility to DNA damaging reagent cisplatin. Importantly, overexpression of 15-PGDH inhibited EMT process with the downregulation of β-catenin and Snail-1 as well as upregulation of E-cadherin and ZO-1. Conclusion: 15-PGDH is a tumor suppressor in lung cancer and may serve as a potential therapeutic target to prevent lung adenocarcinoma.

[1]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[2]  Yiping Wei,et al.  KIAA0101 as a new diagnostic and prognostic marker, and its correlation with gene regulatory networks and immune infiltrates in lung adenocarcinoma , 2020, Aging.

[3]  B. Broom,et al.  Downregulation of 15-hydroxyprostaglandin dehydrogenase during acquired tamoxifen resistance and association with poor prognosis in ERα-positive breast cancer , 2020, Exploration of targeted anti-tumor therapy.

[4]  Junjie Li,et al.  15-PGDH Expression in Gastric Cancer: A Potential Role in Anti-Tumor Immunity , 2020, Cancer management and research.

[5]  Zun-yi Zhang,et al.  EXO1 Plays a Carcinogenic Role in Hepatocellular Carcinoma and is related to the regulation of FOXP3 , 2020, Journal of Cancer.

[6]  Xing Lin,et al.  TRIM2 directly deubiquitinates and stabilizes Snail1 protein, mediating proliferation and metastasis of lung adenocarcinoma , 2020, Cancer Cell International.

[7]  Dongyun He,et al.  Exonuclease 1 (Exo1) Participates in Mammalian Non-Homologous End Joining and Contributes to Drug Resistance in Ovarian Cancer , 2020, Medical science monitor : international medical journal of experimental and clinical research.

[8]  A. Alzahrani.  PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. , 2019, Seminars in cancer biology.

[9]  M. Soukhtanloo,et al.  Role of AKT and mTOR Signaling Pathways in the Induction of Epithelial-Mesenchymal Transition (EMT) Process. , 2019, Biochimie.

[10]  Damian Szklarczyk,et al.  STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets , 2018, Nucleic Acids Res..

[11]  Qing Deng,et al.  EXO1 overexpression is associated with poor prognosis of hepatocellular carcinoma patients , 2018, Cell cycle.

[12]  Chong Geng,et al.  KIAA0101 inhibition suppresses cell proliferation and cell cycle progression by promoting the interaction between p53 and Sp1 in breast cancer. , 2018, Biochemical and biophysical research communications.

[13]  M. Kris,et al.  The Impact of Smoking and TP53 Mutations in Lung Adenocarcinoma Patients with Targetable Mutations—The Lung Cancer Mutation Consortium (LCMC2) , 2017, Clinical Cancer Research.

[14]  T. Thompson,et al.  Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions. , 2017, Current medicinal chemistry.

[15]  Cheng Li,et al.  GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses , 2017, Nucleic Acids Res..

[16]  Yan Li,et al.  β-Catenin promotes cell proliferation, migration, and invasion but induces apoptosis in renal cell carcinoma , 2017, OncoTargets and therapy.

[17]  Walter J Curran,et al.  Lung cancer: current therapies and new targeted treatments , 2017, The Lancet.

[18]  G. Lou,et al.  KIAA0101, a target gene of miR-429, enhances migration and chemoresistance of epithelial ovarian cancer cells , 2016, Cancer Cell International.

[19]  C. Zappa,et al.  Non-small cell lung cancer: current treatment and future advances. , 2016, Translational lung cancer research.

[20]  K. Bae,et al.  Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration , 2015, Science.

[21]  Dan Sun,et al.  Expression of 15-hydroxyprostaglandin dehydrogenase and cyclooxygenase-2 in non-small cell lung cancer: Correlations with angiogenesis and prognosis , 2014, Oncology letters.

[22]  Ting Liu,et al.  FOXM1 Modulates Cisplatin Sensitivity by Regulating EXO1 in Ovarian Cancer , 2014, PloS one.

[23]  H. Zhang,et al.  Expression of KIAA0101 protein is associated with poor survival of esophageal cancer patients and resistance to cisplatin treatment in vitro , 2013, Laboratory Investigation.

[24]  Zhenpeng Qiu,et al.  Variant 1 of KIAA0101, overexpressed in hepatocellular carcinoma, prevents doxorubicin‐induced apoptosis by inhibiting p53 activation , 2012, Hepatology.

[25]  Yingwei Chen,et al.  PI3K: A potential therapeutic target for cancer , 2012, Journal of cellular physiology.

[26]  M. Duncan,et al.  aV integrins and TGF-β-induced EMT: a circle of regulation , 2012, Journal of cellular and molecular medicine.

[27]  A. Maity,et al.  Molecular Neuroscience Review Article , 2011 .

[28]  M. Lopes,et al.  14-3-3 Proteins Regulate Exonuclease 1–Dependent Processing of Stalled Replication Forks , 2011, PLoS genetics.

[29]  Soumya Krishnamurthy,et al.  Cellular Responses to Cisplatin-Induced DNA Damage , 2010, Journal of nucleic acids.

[30]  Matthew A. Titmus,et al.  Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells , 2010, Molecular Cancer.

[31]  T. Hothorn,et al.  Histone macroH2A isoforms predict the risk of lung cancer recurrence , 2009, Oncogene.

[32]  G. Berx,et al.  Snail promotes Wnt target gene expression and interacts with β-catenin , 2008, Oncogene.

[33]  Ping Yang,et al.  Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. , 2008, Mayo Clinic proceedings.

[34]  Steven Piantadosi,et al.  DNA methylation markers and early recurrence in stage I lung cancer. , 2008, The New England journal of medicine.

[35]  T. P. Pretlow,et al.  15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis , 2006, Proceedings of the National Academy of Sciences.

[36]  B. Karlan,et al.  15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer. , 2006, Cancer research.

[37]  H. Tai,et al.  NAD+-linked 15-hydroxyprostaglandin dehydrogenase: structure and biological functions. , 2006, Current pharmaceutical design.

[38]  Li Zhao,et al.  Oncogenic PI3K deregulates transcription and translation , 2005, Nature Reviews Cancer.

[39]  H. Tai,et al.  NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer. , 2004, Carcinogenesis.

[40]  J. Lutterbaugh,et al.  15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-beta-induced suppressor of human gastrointestinal cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[41]  L. Rasmussen,et al.  Characterization of human exonuclease 1 in complex with mismatch repair proteins, subcellular localization and association with PCNA , 2004, Oncogene.

[42]  H. Clevers,et al.  Survivin and molecular pathogenesis of colorectal cancer , 2003, The Lancet.

[43]  Yue Xiong,et al.  p15PAF, a novel PCNA associated factor with increased expression in tumor tissues , 2001, Oncogene.

[44]  Frank McCormick,et al.  β-Catenin regulates expression of cyclin D1 in colon carcinoma cells , 1999, Nature.

[45]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[46]  S. Lippard,et al.  Cisplatin and DNA repair in cancer chemotherapy. , 1995, Trends in biochemical sciences.

[47]  H. Hansen,et al.  Lung cancer. , 1990, Cancer chemotherapy and biological response modifiers.

[48]  A. Gazdar,et al.  The pathology of lung cancer--changing concepts and newer diagnostic techniques. , 1988, Seminars in oncology.