{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPTGS2 (cyclooxygenase‑2) plays a central role in maintaining tissue homeostasis and regulating local inflammatory responses. In normal and injured tissues, PTGS2‐derived prostaglandin E2 (PGE₂) helps preserve fibroblast quiescence and contributes to mucosal repair. For example, increasing tissue stiffness in fibrotic lung injury suppresses PTGS2 expression and PGE₂ synthesis, thereby unleashing fibroblast activation and promoting fibrosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Similarly, PTGS2‐derived PGE₂ has been shown to mediate mucosal healing following colonic injury"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", and experimental models link environmental pollutants to neuroinflammation accompanied by altered PTGS2 expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, in hematopoietic cells, inducible PTGS2 expression is observed during megakaryocytopoiesis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "and PTGS2‐dependent prostanoid synthesis in lung fibroblasts exposed to cigarette smoke further underscores its role in creating a proinflammatory milieu."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in tissue repair, PTGS2 is intricately involved in modulating immune responses. Through its product PGE₂, PTGS2 establishes feedback loops that redirect the differentiation of dendritic cells towards immunosuppressive myeloid-derived suppressor cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, studies investigating functional variants and downstream synthases have provided insights into how PTGS2 activity is finely tuned under both physiologic and pathologic conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant PTGS2 expression is a common feature of many malignancies where it promotes tumorigenesis through multiple mechanisms. Elevated PTGS2 levels are linked to enhanced angiogenesis, increased cell proliferation, invasion, and metastasis in cancers including breast, colon, lung, ovarian, and cholangiocarcinoma. For instance, in breast cancer PTGS2 is upregulated via oncogenic HER‑2 signals"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", whereas in lung and other cancers, PTGS2-driven PGE₂ production facilitates tumor cell dissemination and matrix remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "14"}]}, {"type": "t", "text": " Additional studies have demonstrated that endoplasmic reticulum stress and viral oncogenes (e.g., from hepatitis B) can induce PTGS2 expression to promote invasion"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", and genetic polymorphisms or microRNA‐mediated regulation of PTGS2 further impact cancer risk and progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "20"}]}, {"type": "t", "text": " In ovarian"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", lung adenocarcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": ", cholangiocarcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": ", and colorectal cancers"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "27"}]}, {"type": "t", "text": "its overexpression is associated with aggressive phenotypes.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPTGS2 expression and activity are regulated at multiple levels. Hypoxic conditions, endoplasmic reticulum stress, and viral infections trigger transcriptional activation of PTGS2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": " Furthermore, posttranscriptional regulation by RNA-binding proteins such as HuR—whose translocation and phosphorylation (mediated by kinases including PKCδ) enhance PTGS2 mRNA stability—coupled with microRNA interactions (for example, by miR‑16) constitute additional layers of control."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "36"}]}, {"type": "t", "text": " These regulatory mechanisms underscore the context‐dependent expression of PTGS2, as highlighted by comparative analyses of its distribution in normal versus diseased tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGiven its prominent role in orchestrating inflammatory, proliferative, and immunomodulatory pathways, PTGS2 constitutes an attractive therapeutic target. Its inhibition using selective drugs has been shown to reduce tumor invasiveness and improve outcomes in ischemic and inflammatory diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "38", "end_ref": "40"}]}, {"type": "t", "text": " Recently, novel agents such as cannabidiol have been reported to trigger proapoptotic pathways in cancer cells via initial upregulation of PTGS2 and its downstream targets."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "41"}]}, {"type": "t", "text": " In parallel, emerging evidence regarding epigenetic modifications such as gene promoter methylation suggests additional strategies for modulating PTGS2 expression in cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "42"}]}, {"type": "t", "text": " Collectively, these findings affirm the multifaceted functions of PTGS2 and aide in guiding the development of targeted therapies.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Fei Liu, Justin D Mih, Barry S Shea, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.201004082"}], "href": "https://doi.org/10.1083/jcb.201004082"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20733059"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20733059"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Masayuki Fukata, Anli Chen, Arielle Klepper, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: Role in proliferation and apoptosis in the intestine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2006.06.017"}], "href": "https://doi.org/10.1053/j.gastro.2006.06.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16952555"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16952555"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Lilian Calderón-Garcidueñas, Antonieta Mora-Tiscareño, Esperanza Ontiveros, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Air pollution, cognitive deficits and brain abnormalities: a pilot study with children and dogs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Cogn (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bandc.2008.04.008"}], "href": "https://doi.org/10.1016/j.bandc.2008.04.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18550243"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18550243"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Bianca Rocca, Paola Secchiero, Giovanni Ciabattoni, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.112202999"}], "href": "https://doi.org/10.1073/pnas.112202999"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12032335"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12032335"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Christine A Martey, Stephen J Pollock, Chantal K Turner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cigarette smoke induces cyclooxygenase-2 and microsomal prostaglandin E2 synthase in human lung fibroblasts: implications for lung inflammation and cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Lung Cell Mol Physiol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajplung.00239.2003"}], "href": "https://doi.org/10.1152/ajplung.00239.2003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15234907"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15234907"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Natasa Obermajer, Ravikumar Muthuswamy, Jamie Lesnock, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2011-07-365825"}], "href": "https://doi.org/10.1182/blood-2011-07-365825"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21972293"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21972293"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Anastasia Papafili, Michael R Hill, David J Brull, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/01.atv.0000030340.80207.c5"}], "href": "https://doi.org/10.1161/01.atv.0000030340.80207.c5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12377741"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12377741"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Makoto Murakami, Karin Nakashima, Daisuke Kamei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M305108200"}], "href": "https://doi.org/10.1074/jbc.M305108200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12835322"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12835322"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Kotha Subbaramaiah, Larry Norton, William Gerald, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111415200"}], "href": "https://doi.org/10.1074/jbc.M111415200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11901151"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11901151"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Gaorav P Gupta, Don X Nguyen, Anne C Chiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mediators of vascular remodelling co-opted for sequential steps in lung metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature05760"}], "href": "https://doi.org/10.1038/nature05760"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17429393"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17429393"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jeng-Wei Tjiu, Jau-Shiuh Chen, Chia-Tung Shun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor-associated macrophage-induced invasion and angiogenesis of human basal cell carcinoma cells by cyclooxygenase-2 induction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jid.2008.310"}], "href": "https://doi.org/10.1038/jid.2008.310"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18843292"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18843292"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Shinsuke Kiritoshi, Takeshi Nishikawa, Kazuhiro Sonoda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential role in diabetic nephropathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/diabetes.52.10.2570"}], "href": "https://doi.org/10.2337/diabetes.52.10.2570"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14514642"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14514642"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Francesco Cipollone, Elena Toniato, Stefano Martinotti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JAMA (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1001/jama.291.18.2221"}], "href": "https://doi.org/10.1001/jama.291.18.2221"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15138244"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15138244"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Jui-Hsiang Hung, Ih-Jen Su, Huan-Yao Lei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-kappaB and pp38 mitogen-activated protein kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M403568200"}], "href": "https://doi.org/10.1074/jbc.M403568200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15319438"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15319438"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Takashi Kuwano, Shintaro Nakao, Hidetaka Yamamoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.03-0473com"}], "href": "https://doi.org/10.1096/fj.03-0473com"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14769824"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14769824"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Enrique Lara-Pezzi, Maria Victoria Gómez-Gaviro, Beatriz G Gálvez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI15887"}], "href": "https://doi.org/10.1172/JCI15887"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12488433"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12488433"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Xuemei Zhang, Xiaoping Miao, Wen Tan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gastro.2005.05.003"}], "href": "https://doi.org/10.1016/j.gastro.2005.05.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16083713"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16083713"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Antonio Strillacci, Cristiana Griffoni, Pasquale Sansone, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-101 downregulation is involved in cyclooxygenase-2 overexpression in human colon cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2008.12.010"}], "href": "https://doi.org/10.1016/j.yexcr.2008.12.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19133256"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19133256"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Carsten Denkert, Klaus-Jürgen Winzer, Berit-Maria Müller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cncr.11437"}], "href": "https://doi.org/10.1002/cncr.11437"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12784332"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12784332"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Daniele Campa, Shanbeh Zienolddiny, Valentina Maggini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgh008"}], "href": "https://doi.org/10.1093/carcin/bgh008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14604894"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14604894"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Carsten Denkert, Martin Köbel, Sören Pest, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of cyclooxygenase 2 is an independent prognostic factor in human ovarian carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0002-9440(10)64912-7"}], "href": "https://doi.org/10.1016/S0002-9440(10"}, {"type": "t", "text": "64912-7) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11891188"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11891188"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Jen-Liang Su, Jin-Yuan Shih, Men-Luh Yen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.can-03-1301"}], "href": "https://doi.org/10.1158/0008-5472.can-03-1301"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14744769"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14744769"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Rafael Rosell, Giorgio Scagliotti, Kathleen D Danenberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1206419"}], "href": "https://doi.org/10.1038/sj.onc.1206419"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12789263"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12789263"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Jinyi Shao, Chaeyong Jung, Chunming Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prostaglandin E2 Stimulates the beta-catenin/T cell factor-dependent transcription in colon cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M413056200"}], "href": "https://doi.org/10.1074/jbc.M413056200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15899904"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15899904"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Shuji Ogino, Gregory J Kirkner, Katsuhiko Nosho, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-08-1841"}], "href": "https://doi.org/10.1158/1078-0432.CCR-08-1841"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19088039"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19088039"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Kanae Echizen, Osamu Hirose, Yusuke Maeda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inflammation in gastric cancer: Interplay of the COX-2/prostaglandin E2 and Toll-like receptor/MyD88 pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.12901"}], "href": "https://doi.org/10.1111/cas.12901"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27079437"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27079437"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "G P Boland, I S Butt, R Prasad, et al. "}, {"type": "b", "children": [{"type": "t", "text": "COX-2 expression is associated with an aggressive phenotype in ductal carcinoma in situ."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.bjc.6601534"}], "href": "https://doi.org/10.1038/sj.bjc.6601534"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14735188"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14735188"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Xin Hua Liu, Alexander Kirschenbaum, Min Lu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prostaglandin E2 induces hypoxia-inducible factor-1alpha stabilization and nuclear localization in a human prostate cancer cell line."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M201095200"}], "href": "https://doi.org/10.1074/jbc.M201095200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12401798"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12401798"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Hua Zhu, Jian-Ping Cong, Deborah Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of cyclooxygenase 2 blocks human cytomegalovirus replication."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.052713799"}], "href": "https://doi.org/10.1073/pnas.052713799"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11867761"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11867761"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Anke Doller, Andrea Huwiler, Roswitha Müller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protein kinase C alpha-dependent phosphorylation of the mRNA-stabilizing factor HuR: implications for posttranscriptional regulation of cyclooxygenase-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e06-09-0850"}], "href": "https://doi.org/10.1091/mbc.e06-09-0850"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17392515"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17392515"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Meei Ling Sheu, Feng Ming Ho, Rong Sen Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High glucose induces human endothelial cell apoptosis through a phosphoinositide 3-kinase-regulated cyclooxygenase-2 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/01.ATV.0000155462.24263.e4"}], "href": "https://doi.org/10.1161/01.ATV.0000155462.24263.e4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15653566"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15653566"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Dan A Dixon, Glen C Balch, Nancy Kedersha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20030616"}], "href": "https://doi.org/10.1084/jem.20030616"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12885872"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12885872"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Paola Pichiule, Juan C Chavez, Joseph C LaManna "}, {"type": "b", "children": [{"type": "t", "text": "Hypoxic regulation of angiopoietin-2 expression in endothelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M305146200"}], "href": "https://doi.org/10.1074/jbc.M305146200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14702352"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14702352"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Kanenori Endo, Byung-Il Yoon, Chawalit Pairojkul, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hepatology (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/jhep.2002.34435"}], "href": "https://doi.org/10.1053/jhep.2002.34435"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12143054"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12143054"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Anke Doller, El-Sayed Akool, Andrea Huwiler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Posttranslational modification of the AU-rich element binding protein HuR by protein kinase Cdelta elicits angiotensin II-induced stabilization and nuclear export of cyclooxygenase 2 mRNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01530-07"}], "href": "https://doi.org/10.1128/MCB.01530-07"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18285462"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18285462"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Lisa E Young, Ashleigh E Moore, Lena Sokol, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The mRNA stability factor HuR inhibits microRNA-16 targeting of COX-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1541-7786.MCR-11-0337"}], "href": "https://doi.org/10.1158/1541-7786.MCR-11-0337"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22049153"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22049153"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Nina Zidar, Katarina Odar, Damjan Glavac, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclooxygenase in normal human tissues--is COX-1 really a constitutive isoform, and COX-2 an inducible isoform?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1582-4934.2008.00430.x"}], "href": "https://doi.org/10.1111/j.1582-4934.2008.00430.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18657230"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18657230"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "A O Maree, R J Curtin, A Chubb, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclooxygenase-1 haplotype modulates platelet response to aspirin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Thromb Haemost (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1538-7836.2005.01555.x"}], "href": "https://doi.org/10.1111/j.1538-7836.2005.01555.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16150050"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16150050"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Sylvain Doré, Takashi Otsuka, Toshiaki Mito, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuronal overexpression of cyclooxygenase-2 increases cerebral infarction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Neurol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ana.10612"}], "href": "https://doi.org/10.1002/ana.10612"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12891667"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12891667"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Frank A Sinicrope, Sharlene Gill "}, {"type": "b", "children": [{"type": "t", "text": "Role of cyclooxygenase-2 in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Metastasis Rev (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1023/a:1025863029529"}], "href": "https://doi.org/10.1023/a:1025863029529"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15000150"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15000150"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Robert Ramer, Katharina Heinemann, Jutta Merkord, et al. "}, {"type": "b", "children": [{"type": "t", "text": "COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Ther (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1535-7163.MCT-12-0335"}], "href": "https://doi.org/10.1158/1535-7163.MCT-12-0335"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23220503"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23220503"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Francesco Perri, Rosa Cotugno, Ada Piepoli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant DNA methylation in non-neoplastic gastric mucosa of H. Pylori infected patients and effect of eradication."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Gastroenterol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1572-0241.2007.01284.x"}], "href": "https://doi.org/10.1111/j.1572-0241.2007.01284.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17509026"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17509026"}]}]}]}