Proteomic analysis of laser capture microdissected focal lesions in a rat model of progenitor marker-positive hepatocellular carcinoma

被引:9
|
作者
Michael, Adeola O. Adebayo [1 ,2 ,8 ]
Ahsan, Nagib [3 ,4 ]
Zabala, Valerie [1 ,2 ]
Francois-Vaughan, Heather [1 ,2 ]
Post, Stephanie [5 ]
Brilliant, Kate E. [4 ]
Salomon, Arthur R. [4 ,6 ]
Sanders, Jennifer A. [1 ,2 ,7 ]
Gruppuso, Philip A. [1 ,2 ,6 ]
机构
[1] Rhode Isl Hosp, Dept Pediat, Providence, RI 02903 USA
[2] Brown Univ, Providence, RI 02912 USA
[3] Brown Univ, Div Biol & Med, Providence, RI 02912 USA
[4] Rhode Isl Hosp, Ctr Canc Res Dev, Prote Core Facil, Providence, RI USA
[5] Brown Univ, Dept Environm & Evolutionary Biol, Providence, RI 02912 USA
[6] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA
[7] Brown Univ, Dept Pathol & Lab Med, Providence, RI 02912 USA
[8] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USA
关键词
hepatocellular carcinoma; liver; microdissection; proteomics; pre-neoplasias; PARAFFIN-EMBEDDED TISSUE; GENE-EXPRESSION; MASS-SPECTROMETRY; SEQUENTIAL-ANALYSIS; PRENEOPLASTIC FOCI; HEPATOCYTE NODULES; MESSENGER-RNA; EARLY EVENT; LIVER; PROGRESSION;
D O I
10.18632/oncotarget.15219
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
We have shown previously that rapamycin, the canonical inhibitor of the mechanistic target of rapamycin (mTOR) complex 1, markedly inhibits the growth of focal lesions in the resistant hepatocyte (Solt-Farber) model of hepatocellular carcinoma (HCC) in the rat. In the present study, we characterized the proteome of persistent, pre-neoplastic focal lesions in this model. One group was administered rapamycin by subcutaneous pellet for 3 weeks following partial hepatectomy and euthanized 4 weeks after the cessation of rapamycin. A second group received placebo pellets. Results were compared to unmanipulated control animals and to animals that underwent an incomplete Solt-Farber protocol to activate hepatic progenitor cells. Regions of formalin-fixed, paraffin-embedded tissue were obtained by laser capture microdissection (LCM). Proteomic analysis yielded 11,070 unique peptides representing 2,227 proteins. Quantitation of the peptides showed increased abundance of known HCC markers (e.g., glutathione S-transferase-P, epoxide hydrolase, 6 others) and potential markers (e.g., aflatoxin aldehyde reductase, glucose 6-phosphate dehydrogenase, 10 others) in foci from placebo-treated and rapamycin-treated rats. Peptides derived from cytochrome P450 enzymes were generally reduced. Comparisons of the rapamycin samples to normal liver and to the progenitor cell model indicated that rapamycin attenuated a loss of differentiation relative to placebo. We conclude that early administration of rapamycin in the Solt-Farber model not only inhibits the growth of pre-neoplastic foci but also attenuates the loss of differentiated function. In addition, we have demonstrated that the combination of LCM and mass spectrometry-based proteomics is an effective approach to characterize focal liver lesions.
引用
收藏
页码:26041 / 26056
页数:16
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