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Identification of Differentiation-related Proteins in Gastric Adenocarcinoma Tissues by Proteomics

Author: ZhouXin
Tutor: GuanQuanLin
School: Lanzhou University
Course: Oncology
Keywords: gastric adenocarcinoma proteomics differentiation glycolysis
CLC: R735.2
Type: Master's thesis
Year: 2011
Downloads: 27
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Abstract


Objective:In order to identify differentiation-related proteins which may be closely correlated to differentiation of gastric cancer pathogenesis, we compared proteomic differences between well-differentiated gastric adenocarcinoma tissues and poorly-differentiated gastric adenocarcinoma tissues. These differentially expressed proteins could be potential differentiation-related cancer markers and will contribute to rationally improve diagnosis and treatment to gastric cancer.Materials and Methods:Fresh Primary gastric adenocarcinomas were collected on gastrectomy. The degree of cellular differentiation was classified into two groups according to the postoperative pathological diagnosis:poorly-differentiated group and well-differentiated group. Protein samples were extracted from tissues and total protein amount in each sample was assayed, then protein separating was performed using two-dimensional gel electrophoresis (2-DE). The gels were visualized using the coomassie brilliant blue and imaged by the scanner. The images were analyzed using PDQuest 8.0 software to identify differentially expressed protein spots between the two groups. The apparently different expressed protein spots were cut out manually from the gel, and identified successfully by MALDI-TOF MS or MS/MS and based on using the search algorithm MASCOT against the NCBInr protein sequence database. The interested proteins were detected by Western blotting to validate the protein quantification and identification results by proteomic approach.Results:(1) Seven proteins expressed in poorly-differentiated gastric adenocarcinoma (PDGA) tissues compared with and well-differentiated gastric adenocarcinoma (WDGA) tissues were identified. Proteins which were up-regulated in PDGA included calreticulin precursor,, tapasinERP57 heterodimer, pyruvate kinase isozymes M1/M2 isoform M2 (PKM2), class Pi glutathione S-transferase (GST-Pi), and chain A, crystal structure of human enolase 1 (ENO1). Proteins which were up-regulated in WDGA included:myosin-11 isoform SM2A and actin alpha cardiac. After annotation, they were classified into three categories:cytoskeleton system associated protein (myosin-11 isoform SM2A, actin alpha cardiac), molecular chaperone (calreticulin precursor, tapasinERP57 heterodimer), metabolism associated protein (GST-Pi, PKM2, ENO1). (2) The densitometric quantification results of PKM2 and ENO1 were detected by Western blotting. The changes of PKM2 and ENO1 in Western blot demonstrated similar trends as reported by 2-DE. In addition, since PKM2 and ENO1 are two important enzymes of glycolysis, we investigated the expression of another significant enzyme in glucose metabolism, aldolase A. In different differentiated gastric adenocarcinomas, the expression of aldolase A had a similar trend as PKM2 and ENO1. Moreover, we also examined PKLR which was isoenzyme of PKM2, and NSE/ENO2 which was isoenzyme of ENO1 to observe whether PKLR and ENO2/NSE had the same trend with their isoenzyme in PDGA and WDGA. The results showed that the expression of NSE/ENO2 was consistent with the ENO1 but PKLR had the opposite trend with PKM2. Furthermore, ENO1 protein, as being of concern, was tested in three pairs of poorly, moderately and well differentiated gastric adenocarcinomas and corresponding non-cancerous gastric tissues to evaluate the correlation of ENO1 expression with the differentiation of gastric cancer. The result indicated that the ENO1 expression was closely correlated to the tumor differentiation because the expression of ENO1 was linearly decreased from poorly differentiated tumor, moderately differentiated tumor, to well differentiated tumor. In addition, significant difference existed between gastric tumors and their adjacent normal mucosae.Conclusion:In summary, our proteomic analysis revealed that the differentiation of gastric cancer is a complex process involving multiple factors such as cytoskeleton system associated protein (myosin-11 isoform SM2A, actin alpha cardiac), molecular chaperone (calreticulin precursor, tapasinERP57 heterodimer), metabolism associated protein (GST-Pi, PKM2, ENO1). Overexpression of glycolytic enzymes such as PKM2, ENO1 in PDGA compared with WDGA provided a detailed profiling of the relationship between glycolysis and degree of tumor differentiation at the molecular level. These differentially expressed proteins could be potential differentiation-related cancer markers and will contribute to rationally improve diagnosis and treatment to gastric cancer. More study of these proteins may be expected to improve the prognosis of gastric cancer patients and reduce mortality in patients with poorly differentiated adenocarcinoma.

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CLC: > Medicine, health > Oncology > Gastrointestinal Cancer > Gastric neoplasms
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