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¹H NMR based serum metabolic profiles associated with pathological progression of pancreatic islet β cell tumor in Rip1-Tag2 mice.

Yang Y, Liu Y, Zheng L, Zhang Q, Gu Q, Wang L, Wang L - Int. J. Biol. Sci. (2015)

Bottom Line: Multivariate analysis results showed the serum metabonome at hyperplasia stage shared the similar characteristics with the ones at normal stage as a result of slight proliferation of pancreatic islet β cells.In addition to the changes mentioned above, several metabolites were identified as early biomarkers for tumorigenesis, including increased methionine, citrate and choline, and reduced acetate, taurine and glucose, which suggested the activated energy and amino acid metabolism.The combined metabolic and multivariate statistics approach provides a robust method for screening the biomarkers of disease progression and examining the association between gene and metabolism.

View Article: PubMed Central - PubMed

Affiliation: 1. School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China ; 2. Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.

ABSTRACT
Pancreatic islet β cell tumor is the most common islet cell tumor. A well-characterized tumor progression in Rip1-Tag2 mice undergoes five stages, involving normal, hyperplasia, angiogenic islets, tumorigenesis and invasive carcinoma. (1)H NMR based metabonomics was applied to identify potential biomarkers for monitoring pancreatic islet β cell tumor progression in Rip1-Tag2 mice. Multivariate analysis results showed the serum metabonome at hyperplasia stage shared the similar characteristics with the ones at normal stage as a result of slight proliferation of pancreatic islet β cells. At angiogenic islets stage, the up-regulated glycolysis, disturbed choline and phospholipid metabolism composed the metabolic signature. In addition to the changes mentioned above, several metabolites were identified as early biomarkers for tumorigenesis, including increased methionine, citrate and choline, and reduced acetate, taurine and glucose, which suggested the activated energy and amino acid metabolism. All the changes were aggravated at invasive carcinoma stage, coupled with notable changes in alanine, glutamate and glycine. Moreover, the distinct metabolic phenotype was found associated with the implanting of SV40 large T antigen in Rip1-Tag2 mice. The combined metabolic and multivariate statistics approach provides a robust method for screening the biomarkers of disease progression and examining the association between gene and metabolism.

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500MHz sera 1H CPMG NMR spectra from C57 (A, 3 weeks) and Rip1-Tag2 mice (B, 5 weeks; C,8 weeks; D,10 weeks; E,14 weeks). Note: 1. lipid (mainly LDL and VLDL); 2. isoleucine (Ile); 3. leucine (Leu); 4. valine (Val); 5. lactate (Lac); 6. alanine (Ala); 7. acetate (Ace); 8. methionine (Met); 9.glutamate (Glu); 10. pyruvate (Pyr); 11.glutamine (Gln); 12.citrate (Cit); 13.dimethylamine (DMA); 14. creatine (Cr); 15.choline (Cho); 16. glycerophosphocholine + phosphocholine (GPC+PC); 17. taurine (Tau); 18. Trimethylamine-N-oxide (TMAO) and Betaine (Bet); 19. glycine (Gly); 20. threonine (Thr); 21. myo-inositol (MI); 22. α-glucose (α-Glc); 23. β-glucose (β-Glc); 24. unsaturated lipid; 25. tyrosine (Tyr); 26. 1-methylhistidine; 27. phenylalanine; 28. formate.
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Figure 2: 500MHz sera 1H CPMG NMR spectra from C57 (A, 3 weeks) and Rip1-Tag2 mice (B, 5 weeks; C,8 weeks; D,10 weeks; E,14 weeks). Note: 1. lipid (mainly LDL and VLDL); 2. isoleucine (Ile); 3. leucine (Leu); 4. valine (Val); 5. lactate (Lac); 6. alanine (Ala); 7. acetate (Ace); 8. methionine (Met); 9.glutamate (Glu); 10. pyruvate (Pyr); 11.glutamine (Gln); 12.citrate (Cit); 13.dimethylamine (DMA); 14. creatine (Cr); 15.choline (Cho); 16. glycerophosphocholine + phosphocholine (GPC+PC); 17. taurine (Tau); 18. Trimethylamine-N-oxide (TMAO) and Betaine (Bet); 19. glycine (Gly); 20. threonine (Thr); 21. myo-inositol (MI); 22. α-glucose (α-Glc); 23. β-glucose (β-Glc); 24. unsaturated lipid; 25. tyrosine (Tyr); 26. 1-methylhistidine; 27. phenylalanine; 28. formate.

Mentions: Five typical sera 1H CPMG spectra from C57 (Fig. 2A) and Rip1-Tag2 mice at hyperplasia (Fig. 2B, 5 weeks), angiogenic islets (Fig. 2C, 8 weeks), tumor (Fig. 2D, 10 weeks) and invasive carcinoma (Fig. 2E, 14 weeks) stages were shown in Fig. 2, respectively. There are nearly no variability in metabolite composition and chemical shift perturbation among these spectra. The peaks were assigned on the basis of the published data 26-27 and determined by two dimension spectroscopy. The CPMG pulse sequence highlighted the smaller molecules through editing out those broad resonances. No obvious differences between the five groups were found visually due to the individual variability. Therefore, all the samples must be analyzed together by use of multivariate data analysis in order to get meaningful metabolites for different groups.


¹H NMR based serum metabolic profiles associated with pathological progression of pancreatic islet β cell tumor in Rip1-Tag2 mice.

Yang Y, Liu Y, Zheng L, Zhang Q, Gu Q, Wang L, Wang L - Int. J. Biol. Sci. (2015)

500MHz sera 1H CPMG NMR spectra from C57 (A, 3 weeks) and Rip1-Tag2 mice (B, 5 weeks; C,8 weeks; D,10 weeks; E,14 weeks). Note: 1. lipid (mainly LDL and VLDL); 2. isoleucine (Ile); 3. leucine (Leu); 4. valine (Val); 5. lactate (Lac); 6. alanine (Ala); 7. acetate (Ace); 8. methionine (Met); 9.glutamate (Glu); 10. pyruvate (Pyr); 11.glutamine (Gln); 12.citrate (Cit); 13.dimethylamine (DMA); 14. creatine (Cr); 15.choline (Cho); 16. glycerophosphocholine + phosphocholine (GPC+PC); 17. taurine (Tau); 18. Trimethylamine-N-oxide (TMAO) and Betaine (Bet); 19. glycine (Gly); 20. threonine (Thr); 21. myo-inositol (MI); 22. α-glucose (α-Glc); 23. β-glucose (β-Glc); 24. unsaturated lipid; 25. tyrosine (Tyr); 26. 1-methylhistidine; 27. phenylalanine; 28. formate.
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Related In: Results  -  Collection

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Figure 2: 500MHz sera 1H CPMG NMR spectra from C57 (A, 3 weeks) and Rip1-Tag2 mice (B, 5 weeks; C,8 weeks; D,10 weeks; E,14 weeks). Note: 1. lipid (mainly LDL and VLDL); 2. isoleucine (Ile); 3. leucine (Leu); 4. valine (Val); 5. lactate (Lac); 6. alanine (Ala); 7. acetate (Ace); 8. methionine (Met); 9.glutamate (Glu); 10. pyruvate (Pyr); 11.glutamine (Gln); 12.citrate (Cit); 13.dimethylamine (DMA); 14. creatine (Cr); 15.choline (Cho); 16. glycerophosphocholine + phosphocholine (GPC+PC); 17. taurine (Tau); 18. Trimethylamine-N-oxide (TMAO) and Betaine (Bet); 19. glycine (Gly); 20. threonine (Thr); 21. myo-inositol (MI); 22. α-glucose (α-Glc); 23. β-glucose (β-Glc); 24. unsaturated lipid; 25. tyrosine (Tyr); 26. 1-methylhistidine; 27. phenylalanine; 28. formate.
Mentions: Five typical sera 1H CPMG spectra from C57 (Fig. 2A) and Rip1-Tag2 mice at hyperplasia (Fig. 2B, 5 weeks), angiogenic islets (Fig. 2C, 8 weeks), tumor (Fig. 2D, 10 weeks) and invasive carcinoma (Fig. 2E, 14 weeks) stages were shown in Fig. 2, respectively. There are nearly no variability in metabolite composition and chemical shift perturbation among these spectra. The peaks were assigned on the basis of the published data 26-27 and determined by two dimension spectroscopy. The CPMG pulse sequence highlighted the smaller molecules through editing out those broad resonances. No obvious differences between the five groups were found visually due to the individual variability. Therefore, all the samples must be analyzed together by use of multivariate data analysis in order to get meaningful metabolites for different groups.

Bottom Line: Multivariate analysis results showed the serum metabonome at hyperplasia stage shared the similar characteristics with the ones at normal stage as a result of slight proliferation of pancreatic islet β cells.In addition to the changes mentioned above, several metabolites were identified as early biomarkers for tumorigenesis, including increased methionine, citrate and choline, and reduced acetate, taurine and glucose, which suggested the activated energy and amino acid metabolism.The combined metabolic and multivariate statistics approach provides a robust method for screening the biomarkers of disease progression and examining the association between gene and metabolism.

View Article: PubMed Central - PubMed

Affiliation: 1. School of Basic Course, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China ; 2. Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.

ABSTRACT
Pancreatic islet β cell tumor is the most common islet cell tumor. A well-characterized tumor progression in Rip1-Tag2 mice undergoes five stages, involving normal, hyperplasia, angiogenic islets, tumorigenesis and invasive carcinoma. (1)H NMR based metabonomics was applied to identify potential biomarkers for monitoring pancreatic islet β cell tumor progression in Rip1-Tag2 mice. Multivariate analysis results showed the serum metabonome at hyperplasia stage shared the similar characteristics with the ones at normal stage as a result of slight proliferation of pancreatic islet β cells. At angiogenic islets stage, the up-regulated glycolysis, disturbed choline and phospholipid metabolism composed the metabolic signature. In addition to the changes mentioned above, several metabolites were identified as early biomarkers for tumorigenesis, including increased methionine, citrate and choline, and reduced acetate, taurine and glucose, which suggested the activated energy and amino acid metabolism. All the changes were aggravated at invasive carcinoma stage, coupled with notable changes in alanine, glutamate and glycine. Moreover, the distinct metabolic phenotype was found associated with the implanting of SV40 large T antigen in Rip1-Tag2 mice. The combined metabolic and multivariate statistics approach provides a robust method for screening the biomarkers of disease progression and examining the association between gene and metabolism.

Show MeSH
Related in: MedlinePlus