title: PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma.
abstract: Protein Kinase cAMP-Dependent Regulatory Type I Alpha (PRKAR1A) is a tissue-specific extinguisher that transduces a signal through phosphorylation of different target proteins. Loss of PRKAR1A was frequently observed in endocrine neoplasia and stromal cell tumors. However, a few cases were seen in epithelial tumors. Previously, we first found that PRKAR1A was downregulated in lung adenocarcinoma patients. Thus, the present study aimed to clarify its clinical implication and biological function as a tumor suppressor in lung adenocarcinoma. The low levels of PRKAR1A transcript were correlated with tumor progression and poor overall survival. The re-expression of PRKAR1A in H1299 cells suppressed the tumor cell proliferation and migration; stable knockdown (KD) of PRKAR1A in A549 cells enhanced this function both in vitro and in vivo. Moreover, KD of PRKAR1A in A549 cells promoted the statistical colonization of circulating tumor cells to the lungs in nude mice. These effects by PRKAR1A were attributed to inhibiting E-cadherin expression. Elevated E-cadherin significantly suppressed the PRKAR1A-KD induced cell proliferation and migration. Most notably, deletion of PRKAR1A inhibited E-cadherin by activating ERK/Snail signaling. In conclusion, PRKAR1A was a potent suppressor, and through the inhibition of PRKAR1A-ERK-Snail-E-cadherin axis could serve as a potential therapeutic target.
authors.affiliation: Department of Thoracic Surgery, Xiangya Hospital, Central South University, Xiangya Road 87th, Changsha, 410008, Hunan, P. R. China.
authors.forename: Shaoqiang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery, Xiangya Hospital, Central South University, Xiangya Road 87th, Changsha, 410008, Hunan, P. R. China.
authors.forename: Yuanda
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of endocrinology, Xiangya Hospital, Central South University, Xiangya Road 87th, Changsha, 410008, Hunan, P. R. China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Thoracic Surgery, Xiangya Hospital, Central South University, Xiangya Road 87th, Changsha, 410008, Hunan, P. R. China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Thoracic Surgery, Xiangya Hospital, Central South University, Xiangya Road 87th, Changsha, 410008, Hunan, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Thoracic Surgery, Xiangya Hospital, Central South University, Xiangya Road 87th, Changsha, 410008, Hunan, P. R. China.
authors.forename: Wolong
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Institute of Medical Sciences, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Xiangya Road 87th, Changsha, 410008, Hunan, P. R. China.
authors.forename: Chaojun
authors.initials: C
authors.lastname: Duan
authors.affiliation: Department of Thoracic Surgery, Xiangya Hospital, Central South University, Xiangya Road 87th, Changsha, 410008, Hunan, P. R. China.
authors.forename: Chunfang
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000378:metabolism*; D000368:Aged; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases