title: Activation of RAS/ERK alone is insufficient to inhibit RXRα function and deplete retinoic acid in hepatocytes.
abstract: Activation of RAS/ERK signaling pathway, depletion of retinoid, and phosphorylation of retinoid X receptor alpha (RXRα) are frequent events found in liver tumors and thought to play important roles in hepatic tumorigenesis. However, the relationships among them still remained to be elucidated. By exploring the transgenic mouse model of hepatic tumorigenesis induced by liver-specific expression of H-ras12V oncogene, the activation of RAS/ERK, the mRNA expression levels of retinoid metabolism-related genes, the contents of retinoid metabolites, and phosphorylation of RXRα were determined. RAS/ERK signaling pathway was gradually and significantly activated in hepatic tumor adjacent normal liver tissues (P) and hepatic tumor tissues (T) of H-ras12V transgenic mice compared with normal liver tissues (Wt) of wild type mice. On the contrary, the mRNA expression levels of retinoid metabolism-related genes were significantly reduced in P and T compared with Wt. Interestingly, the retinoid metabolites 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (atRA), the well known ligands for nuclear transcription factor RXR and retinoic acid receptor (RAR), were significantly decreased only in T compared with Wt and P, although the oxidized polar metabolite of atRA, 4-keto-all-trans-retinoic-acid (4-keto-RA) was significantly decreased in both P and T compared with Wt. To our surprise, the functions of RXRα were significantly blocked only in T compared with Wt and P. Namely, the total protein levels of RXRα were significantly reduced and the phosphorylation levels of RXRα were significantly increased only in T compared with Wt and P. Treatment of H-ras12V transgenic mice at 5-week-old or 5-month-old with atRA had no effect on the prevention of tumorigenesis or cure of developed nodules in liver. These events imply that the depletion of 9cRA and atRA and the inhibition of RXRα function in hepatic tumors involve more complex mechanisms besides the activation of RAS/ERK pathway.
authors.affiliation: Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116044, PR China. Electronic address: wangaiguotl@hotmail.com.
authors.forename: Ai-Guo
authors.initials: AG
authors.lastname: Wang
authors.affiliation: Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116044, PR China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Song
authors.affiliation: Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116044, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116044, PR China.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Li
authors.affiliation: Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116044, PR China.
authors.forename: Jian-Yi
authors.initials: JY
authors.lastname: Dong
authors.affiliation: Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116044, PR China.
authors.forename: Hai-Peng
authors.initials: HP
authors.lastname: Cui
authors.affiliation: Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116044, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yao
authors.affiliation: Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116044, PR China.
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Li
authors.affiliation: Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116044, PR China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Gao
authors.affiliation: Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116044, PR China.
authors.forename: Ze-Wen
authors.initials: ZW
authors.lastname: Qiu
authors.affiliation: Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116044, PR China.
authors.forename: Fu-Jin
authors.initials: FJ
authors.lastname: Wang
authors.affiliation: Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116044, PR China. Electronic address: wangjingyus@163.com.
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047490:Retinoid X Receptor alpha / Q000235:genetics* / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D059016:Tumor Microenvironment
chemical_list: D047490:Retinoid X Receptor alpha; D000077556:Alitretinoin; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System
keywords: H-ras12V; Hepatic tumor; RXRα; Retinoic acid