title: Thromboxane A2 receptor α promotes tumor growth through an autoregulatory feedback pathway.
abstract: Tobacco smoking can cause a number of cancers. The role of thromboxane synthase (TxAS) in smoking-related cancers is largely unknown. In this study, 37 pairs of tumor and non-tumor lung tissues of non-small-cell lung cancer, 5 lung cancer cell lines, and a mouse tumor model were used to study TxAS and its related molecules. A mouse model of smoking carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK)-induced lung tumor showed an increase in TxAS. Thromboxane A2 receptor (TP) was aberrant in lung cancer tissues of smokers. TxAS and TP were increased in lung tissues of NNK-treated mice. The in vitro studies showed that TPα rather than TPβ promoted tumor growth, and NNK increased TPα. NNK-induced TxAS, which depended on activation of cyclooxygenase-2 (COX-2), ERK and NF-κB, could be inhibited by miR-34b/c. TPα played a positive role in NNK-induced COX-2/ERK/NF-κB activation, leading to the upregulation of TxAS expression and thromboxane A2 (TxA2) synthesis. The newly synthesized TxA2 could further activate TPα, forming an autoregulatory feedback loop for TPα activation. Collectively, NNK promotes lung tumor growth via inducing TxAS and TPα, which constitutes an auto-positive feedback loop to exaggerate the growth. This study suggests that TPα and TxAS are the ideal targets against smoking-related lung cancer.
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin N.T., Hong Kong SAR, China.
authors.forename: Run-Yue
authors.initials: RY
authors.lastname: Huang
authors.forename: Ming-Yue
authors.initials: MY
authors.lastname: Li
authors.forename: Calvin S H
authors.initials: CS
authors.lastname: Ng
authors.forename: Innes Y P
authors.initials: IY
authors.lastname: Wan
authors.forename: Angel W Y
authors.initials: AW
authors.lastname: Kong
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.forename: Xiang
authors.initials: X
authors.lastname: Long
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Underwood
authors.forename: Tony S K
authors.initials: TS
authors.lastname: Mok
authors.forename: George G
authors.initials: GG
authors.lastname: Chen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics / Q000378:metabolism*; D013928:Thromboxane A2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000235:genetics / Q000378:metabolism
chemical_list: D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2; D051546:Cyclooxygenase 2; D013930:Thromboxane-A Synthase
keywords: autoregulation; cancer; lung; smoking; thromboxane A2 receptor; thromboxane synthase