過氧化物酶體增殖物激活受體α在結直腸癌發病機制中的作用_《中國普外基礎與臨床雜志》

作者：

魏仁杰 ¹ , 楊烈 ¹ , 章烈 ¹ , 盧鈾 ² , 胡建昆 ¹ , 莫顯明 ³ ,  周總光 ¹

1.四川大學華西醫院胃腸外科中心（四川成都 610041）;;
2.四川大學華西醫院腫瘤科（四川成都 610041）;;
3.四川大學華西醫院生物治療國家重點實驗室醫學干細胞生物學中心（四川成都 610041）;

關鍵詞：

過氧化物酶體增殖物活化受體α 結直腸癌發病機制

視頻：

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摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

目的　探討過氧化物酶體增殖物激活受體α （PPARα）在結直腸癌發病機制中的作用。
方法　對PPARα與結直腸癌的發病機制相關研究的文獻進行綜述。
結果　PPARα在結直腸癌發病機制中對結直腸癌細胞增殖、凋亡、分化的作用仍存在爭議。
結論　PPARα有可能參與了結直腸癌細胞增殖、分化、凋亡等的調控過程，但其具體作用機制以及其上、下游的信號通路仍不清楚。此外，PPARα可能參與了結直腸癌部分化療藥物的耐藥機制，但其作用也不甚明了。因此，需要更多的研究工作來進一步探究PPARα與結直腸癌的關系。

引用本文： 魏仁杰,楊烈,章烈,盧鈾,胡建昆,莫顯明,周總光. 過氧化物酶體增殖物激活受體α在結直腸癌發病機制中的作用. 中國普外基礎與臨床雜志, 2013, 20(11): 1320-1324. doi: 復制

1.	Lee CH， Olson P， Hevener A， et al. PPARdelta regulates glucosemetabolism and insulin sensitivity[J]. Proc Natl Acad Sci U S A， 2006， 103(9)：3444-3449.
2.	Miles PD， Barak Y， He W， et al. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency[J]. J Clin Invest， 2000， 105(3)：287-292.
3.	Schoonjans K， Staels B， Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation[J]. Biochim Biophys Acta， 1996， 1302(2)：93-109.
4.	Theocharis S， Margeli A， Vielh P， et al. Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators[J]. Cancer Treat Rev， 2004， 30(6)：545-554.
5.	Peters JM， Aoyama T， Cattley RC， et al. Role of peroxisome proliferator-activated receptor alpha in altered cell cycle regulation in mouse liver[J]. Carcinogenesis， 1998， 19(11)：1989-1994.
6.	Kitamura S， Miyazaki Y， Shinomura Y， et al. Peroxisome proliferator-activated receptor gamma induces growth arrest and differentiation markers of human colon cancer cells[J]. Jpn J Cancer Res， 1999， 90(1)：75-80.
7.	Yang L， Zhang H， Zhou ZG， et al. Biological function and prognostic significance of peroxisome proliferator-activated receptor δ in rectal cancer[J]. Clin Cancer Res， 2011， 17(11)：3760-3770.
8.	Takayama O， Yamamoto H， Damdinsuren B， et al. Expression of PPARdelta in multistage carcinogenesis of the colorectum：implications of malignant cancer morphology[J]. Br J Cancer， 2006， 95(7)：889-895.
9.	楊烈，周總光. 結直腸癌發病機理的新位點——PPARδ[J]. 中國普外基礎與臨床雜志， 2006， 13(4)：484-486.
10.	Sher T， Yi HF， McBride OW， et al. cDNA cloning， chromosomalmapping， and functional characterization of the human peroxisomeproliferator activated receptor[J]. Biochemistry， 1993， 32(21)：5598-5604.
11.	Corton JC， Anderson SP， Stauber A. Central role of peroxisome proliferator-activated receptors in the actions of peroxisome prolif-erators[J]. Annu Rev Pharmacol Toxicol， 2000， 40：491-518.
12.	Shahidi F， Miraliakbari H. Omega-3 (n-3) fatty acids in health and disease：Part 1—cardiovascular disease and cancer[J]. J Med Food， 2004， 7(4)：387-401.
13.	Braissant O， Foufelle F， Scotto C， et al. Differential expression of peroxisome proliferator-activated receptors (PPARs)：tissuedistribution of PPAR-alpha， -beta， and -gamma in the adult rat[J].Endocrinology， 1996， 137(1)：354-366.
14.	Mukherjee R， Jow L， Croston GE， et al. Identification， charac-terization， and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma 2 versus PPAR-gamma 1 and activation with retinoid X receptor agonists and anta-gonists[J]. J Biol Chem， 1997， 272(12)：8071-8076.
15.	Auboeuf D， Rieusset J， Fajas L， et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans：no alteration in adipose tissue of obese and NIDDM patients[J]. Diabetes， 1997， 46(8)：1319-1327.
16.	Huin C， Corriveau L， Bianchi A， et al. Differential expression of peroxisome proliferator-activated receptors (PPARs) in the developing human fetal digestive tract[J]. J Histochem Cytochem， 2000， 48(5)：603-611.
17.	Park JI， Kwak JY. The role of peroxisome proliferator-activated receptors in colorectal cancer[J]. PPAR Res， 2012， 2012， ArticleID 876418. http：//dx. doi. org/10. 1155/2012/876418.
18.	Barger PM， Browning AC， Garner AN， et al. p38 mitogen-acti-vated protein kinase activates peroxisome proliferator-activated receptor alpha：a potential role in the cardiac metabolic stress response[J]. J Biol Chem， 2001， 276(48)：44495-44501.
19.	Burns KA， Vanden Heuvel JP. Modulation of PPAR activity via phosphorylation[J]. Biochim Biophys Acta， 2007， 1771(8)：952-960.
20.	Eaden JA， Abrams KR， Mayberry JF. The risk of colorectalcancer in ulcerative colitis：a meta-analysis[J]. Gut， 2001， 48(4)：526-535.
21.	(6)：985-989.
22.	Tanaka T， Kohno H， Yoshitani S， et al. Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemicallyinduced colitis and formation of aberrant crypt foci in rats[J]. Cancer Res， 2001， 61(6)：2424-2428.
23.	Kohno H， Suzuki R， Sugie S， et al. Suppression of colitis-relatedmouse colon carcinogenesis by a COX-2 inhibitor and PPAR ligands[J]. BMC Cancer， 2005， 5：46. doi：10.1186/1471-2407-5-46.
24.	Matthiessen MW， Pedersen G， Albrektsen T， et al. Peroxisome proliferator-activated receptor expression and activation in normal human colonic epithelial cells and tubular adenomas[J]. Scand J Gastroenterol， 2005， 40(2)：198-205.
25.	Mutoh M， Niho N， Wakabayashi K. Concomitant suppression of hyperlipidemia and intestinal polyp formation by increasing lipoprotein lipase activity in APC-deficient mice[J]. Biol Chem， 2006， 387(4)：381-385.
26.	Martinasso G， Oraldi M， Trombetta A， et al. Involvement of PPARs in cell proliferation and apoptosis in human colon cancer specimens and in normal and cancer cell lines[J]. PPAR Res， 2007， 2007：93416.
27.	Roberts RA， Chevalier S， Hasmall SC， et al. PPAR alpha and the regulation of cell division and apoptosis[J]. Toxicology， 2002， 181-182：167-170.
28.	Klaunig JE， Babich MA， Baetcke KP， et al. PPARalpha agonist-induced rodent tumors：modes of action and human relevance[J]. Crit Rev Toxicol， 2003， 33(6)：655-780.
29.	Ignacio Barrasa J， Olmo N， Pérez-Ramos P， et al. Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells[J]. Apoptosis， 2011， 16(10)：1054-1067.
30.	Barrasa JI， Santiago-Gómez A， Olmo N， et al. Resistance to butyrate impairs bile acid-induced apoptosis in human colon ade-nocarcinoma cells via up-regulation of Bcl-2 and inactivation of Bax[J]. Biochim Biophys Acta， 2012， 1823(12)：2201-2209.
31.	Makishima M， Okamoto AY， Repa JJ， et al. Identification of a nuclear receptor for bile acids[J]. Science， 1999， 284(5418)：1362-1365.
32.	Oshio H， Abe T， Onogawa T， et al. Peroxisome proliferator-activated receptor alpha activates cyclooxygenase-2 gene transcription through bile acid transport in human colorectal cancer cell lines[J]. J Gastroenterol， 2008， 43(7)：538-549.
33.	Bertagnolli MM. Chemoprevention of colorectal cancer withcyclooxygenase-2 inhibitors：two steps forward， one step back[J]. Lancet Oncol， 2007， 8(5)：439-443.
34.	Ikawa H， Kameda H， Kamitani H， et al. Effect of PPAR activators on cytokine-stimulated cyclooxygenase-2 expression in humancolorectal carcinoma cells[J]. Exp Cell Res， 2001， 267(1)：73-80.
35.	Lachal S， Ford J， Shulkes A， et al. PPARalpha agonists stimulate progastrin production in human colorectal carcinoma cells[J]. Regul Pept， 2004， 120(1-3)：243-251.
36.	Konturek PC， Bielanski W， Konturek SJ， et al. Progastrin and cyclooxygenase-2 in colorectal cancer[J]. Dig Dis Sci， 2002， 47(9)：1984-1991.
37.	Huin C， Schohn H， Hatier R， et al. Expression of peroxisome proliferator-activated receptors alpha and gamma in differentiatinghuman colon carcinoma Caco-2 cells[J]. Biol Cell， 2002， 94(1)：15-27.
38.	Varanasi U， Chu R， Huang Q， et al. Identification of a peroxisomeproliferator-responsive element upstream of the human peroxisomalfatty acyl coenzyme A oxidase gene[J]. J Biol Chem， 1996， 271(4)：2147-2155.
39.	Lauer C， Völkl A， Riedl S， et al. Impairment of peroxisomal biogenesis in human colon carcinoma[J]. Carcinogenesis， 1999，.
40.	Aung CS， Faddy HM， Lister EJ， et al. Isoform specific changes in PPAR alpha and beta in colon and breast cancer with differentiation[J]. Biochem Biophys Res Commun， 2006， 340(2)：656-660.
41.	Tong JL， Zhang CP， Nie F， et al. MicroRNA 506 regulates expr-ession of PPAR alpha in hydroxycamptothecin-resistant human colon cancer cells[J]. FEBS Lett， 2011， 585(22)：3560-3568.
42.	Watanabe M， Sowa Y， Yogosawa M， et al. Novel MEK inhibitortrametinib and other retinoblastoma gene (RB)-reactivating agentsenhance efficacy of 5-fluorouracil on human colon cancer cells[J]. Cancer Sci， 2013， 104(6)：687-693.
43.	Grabacka M， Pierzchalska M， Reiss K. Peroxisome proliferator activated receptor α ligands as anticancer drugs targeting mitocho-ndrial metabolism[J]. Curr Pharm Biotechnol， 2013， 14(3)：342-356.
44.	Camarero N， Mascaró C， Mayordomo C， et al. Ketogenic HMGCS2 is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer[J]. Mol Cancer Res， 2006， 4(9)：645-653.
45.	Sánchez-Aragó M， Chamorro M， Cuezva JM. Selection of cancercells with repressed mitochondria triggers colon cancer progression[J]. Carcinogenesis， 2010， 31(4)：567-576.
46.	Scatena R， Bottoni P， Giardina B. Mitochondria， PPARs， andcancer：Is receptor-independent action of PPAR agonists a key?[J]. PPAR Res， 2008， 2008：256251. doi：10.1155/2008/256251.

1. Lee CH， Olson P， Hevener A， et al. PPARdelta regulates glucosemetabolism and insulin sensitivity[J]. Proc Natl Acad Sci U S A， 2006， 103(9)：3444-3449.
2. Miles PD， Barak Y， He W， et al. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency[J]. J Clin Invest， 2000， 105(3)：287-292.
3. Schoonjans K， Staels B， Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation[J]. Biochim Biophys Acta， 1996， 1302(2)：93-109.
4. Theocharis S， Margeli A， Vielh P， et al. Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators[J]. Cancer Treat Rev， 2004， 30(6)：545-554.
5. Peters JM， Aoyama T， Cattley RC， et al. Role of peroxisome proliferator-activated receptor alpha in altered cell cycle regulation in mouse liver[J]. Carcinogenesis， 1998， 19(11)：1989-1994.
6. Kitamura S， Miyazaki Y， Shinomura Y， et al. Peroxisome proliferator-activated receptor gamma induces growth arrest and differentiation markers of human colon cancer cells[J]. Jpn J Cancer Res， 1999， 90(1)：75-80.
7. Yang L， Zhang H， Zhou ZG， et al. Biological function and prognostic significance of peroxisome proliferator-activated receptor δ in rectal cancer[J]. Clin Cancer Res， 2011， 17(11)：3760-3770.
8. Takayama O， Yamamoto H， Damdinsuren B， et al. Expression of PPARdelta in multistage carcinogenesis of the colorectum：implications of malignant cancer morphology[J]. Br J Cancer， 2006， 95(7)：889-895.
9. 楊烈，周總光. 結直腸癌發病機理的新位點——PPARδ[J]. 中國普外基礎與臨床雜志， 2006， 13(4)：484-486.
10. Sher T， Yi HF， McBride OW， et al. cDNA cloning， chromosomalmapping， and functional characterization of the human peroxisomeproliferator activated receptor[J]. Biochemistry， 1993， 32(21)：5598-5604.
11. Corton JC， Anderson SP， Stauber A. Central role of peroxisome proliferator-activated receptors in the actions of peroxisome prolif-erators[J]. Annu Rev Pharmacol Toxicol， 2000， 40：491-518.
12. Shahidi F， Miraliakbari H. Omega-3 (n-3) fatty acids in health and disease：Part 1—cardiovascular disease and cancer[J]. J Med Food， 2004， 7(4)：387-401.
13. Braissant O， Foufelle F， Scotto C， et al. Differential expression of peroxisome proliferator-activated receptors (PPARs)：tissuedistribution of PPAR-alpha， -beta， and -gamma in the adult rat[J].Endocrinology， 1996， 137(1)：354-366.
14. Mukherjee R， Jow L， Croston GE， et al. Identification， charac-terization， and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma 2 versus PPAR-gamma 1 and activation with retinoid X receptor agonists and anta-gonists[J]. J Biol Chem， 1997， 272(12)：8071-8076.
15. Auboeuf D， Rieusset J， Fajas L， et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans：no alteration in adipose tissue of obese and NIDDM patients[J]. Diabetes， 1997， 46(8)：1319-1327.
16. Huin C， Corriveau L， Bianchi A， et al. Differential expression of peroxisome proliferator-activated receptors (PPARs) in the developing human fetal digestive tract[J]. J Histochem Cytochem， 2000， 48(5)：603-611.
17. Park JI， Kwak JY. The role of peroxisome proliferator-activated receptors in colorectal cancer[J]. PPAR Res， 2012， 2012， ArticleID 876418. http：//dx. doi. org/10. 1155/2012/876418.
18. Barger PM， Browning AC， Garner AN， et al. p38 mitogen-acti-vated protein kinase activates peroxisome proliferator-activated receptor alpha：a potential role in the cardiac metabolic stress response[J]. J Biol Chem， 2001， 276(48)：44495-44501.
19. Burns KA， Vanden Heuvel JP. Modulation of PPAR activity via phosphorylation[J]. Biochim Biophys Acta， 2007， 1771(8)：952-960.
20. Eaden JA， Abrams KR， Mayberry JF. The risk of colorectalcancer in ulcerative colitis：a meta-analysis[J]. Gut， 2001， 48(4)：526-535.
21. (6)：985-989.
22. Tanaka T， Kohno H， Yoshitani S， et al. Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemicallyinduced colitis and formation of aberrant crypt foci in rats[J]. Cancer Res， 2001， 61(6)：2424-2428.
23. Kohno H， Suzuki R， Sugie S， et al. Suppression of colitis-relatedmouse colon carcinogenesis by a COX-2 inhibitor and PPAR ligands[J]. BMC Cancer， 2005， 5：46. doi：10.1186/1471-2407-5-46.
24. Matthiessen MW， Pedersen G， Albrektsen T， et al. Peroxisome proliferator-activated receptor expression and activation in normal human colonic epithelial cells and tubular adenomas[J]. Scand J Gastroenterol， 2005， 40(2)：198-205.
25. Mutoh M， Niho N， Wakabayashi K. Concomitant suppression of hyperlipidemia and intestinal polyp formation by increasing lipoprotein lipase activity in APC-deficient mice[J]. Biol Chem， 2006， 387(4)：381-385.
26. Martinasso G， Oraldi M， Trombetta A， et al. Involvement of PPARs in cell proliferation and apoptosis in human colon cancer specimens and in normal and cancer cell lines[J]. PPAR Res， 2007， 2007：93416.
27. Roberts RA， Chevalier S， Hasmall SC， et al. PPAR alpha and the regulation of cell division and apoptosis[J]. Toxicology， 2002， 181-182：167-170.
28. Klaunig JE， Babich MA， Baetcke KP， et al. PPARalpha agonist-induced rodent tumors：modes of action and human relevance[J]. Crit Rev Toxicol， 2003， 33(6)：655-780.
29. Ignacio Barrasa J， Olmo N， Pérez-Ramos P， et al. Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells[J]. Apoptosis， 2011， 16(10)：1054-1067.
30. Barrasa JI， Santiago-Gómez A， Olmo N， et al. Resistance to butyrate impairs bile acid-induced apoptosis in human colon ade-nocarcinoma cells via up-regulation of Bcl-2 and inactivation of Bax[J]. Biochim Biophys Acta， 2012， 1823(12)：2201-2209.
31. Makishima M， Okamoto AY， Repa JJ， et al. Identification of a nuclear receptor for bile acids[J]. Science， 1999， 284(5418)：1362-1365.
32. Oshio H， Abe T， Onogawa T， et al. Peroxisome proliferator-activated receptor alpha activates cyclooxygenase-2 gene transcription through bile acid transport in human colorectal cancer cell lines[J]. J Gastroenterol， 2008， 43(7)：538-549.
33. Bertagnolli MM. Chemoprevention of colorectal cancer withcyclooxygenase-2 inhibitors：two steps forward， one step back[J]. Lancet Oncol， 2007， 8(5)：439-443.
34. Ikawa H， Kameda H， Kamitani H， et al. Effect of PPAR activators on cytokine-stimulated cyclooxygenase-2 expression in humancolorectal carcinoma cells[J]. Exp Cell Res， 2001， 267(1)：73-80.
35. Lachal S， Ford J， Shulkes A， et al. PPARalpha agonists stimulate progastrin production in human colorectal carcinoma cells[J]. Regul Pept， 2004， 120(1-3)：243-251.
36. Konturek PC， Bielanski W， Konturek SJ， et al. Progastrin and cyclooxygenase-2 in colorectal cancer[J]. Dig Dis Sci， 2002， 47(9)：1984-1991.
37. Huin C， Schohn H， Hatier R， et al. Expression of peroxisome proliferator-activated receptors alpha and gamma in differentiatinghuman colon carcinoma Caco-2 cells[J]. Biol Cell， 2002， 94(1)：15-27.
38. Varanasi U， Chu R， Huang Q， et al. Identification of a peroxisomeproliferator-responsive element upstream of the human peroxisomalfatty acyl coenzyme A oxidase gene[J]. J Biol Chem， 1996， 271(4)：2147-2155.
39. Lauer C， Völkl A， Riedl S， et al. Impairment of peroxisomal biogenesis in human colon carcinoma[J]. Carcinogenesis， 1999，.
40. Aung CS， Faddy HM， Lister EJ， et al. Isoform specific changes in PPAR alpha and beta in colon and breast cancer with differentiation[J]. Biochem Biophys Res Commun， 2006， 340(2)：656-660.
41. Tong JL， Zhang CP， Nie F， et al. MicroRNA 506 regulates expr-ession of PPAR alpha in hydroxycamptothecin-resistant human colon cancer cells[J]. FEBS Lett， 2011， 585(22)：3560-3568.
42. Watanabe M， Sowa Y， Yogosawa M， et al. Novel MEK inhibitortrametinib and other retinoblastoma gene (RB)-reactivating agentsenhance efficacy of 5-fluorouracil on human colon cancer cells[J]. Cancer Sci， 2013， 104(6)：687-693.
43. Grabacka M， Pierzchalska M， Reiss K. Peroxisome proliferator activated receptor α ligands as anticancer drugs targeting mitocho-ndrial metabolism[J]. Curr Pharm Biotechnol， 2013， 14(3)：342-356.
44. Camarero N， Mascaró C， Mayordomo C， et al. Ketogenic HMGCS2 is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer[J]. Mol Cancer Res， 2006， 4(9)：645-653.
45. Sánchez-Aragó M， Chamorro M， Cuezva JM. Selection of cancercells with repressed mitochondria triggers colon cancer progression[J]. Carcinogenesis， 2010， 31(4)：567-576.
46. Scatena R， Bottoni P， Giardina B. Mitochondria， PPARs， andcancer：Is receptor-independent action of PPAR agonists a key?[J]. PPAR Res， 2008， 2008：256251. doi：10.1155/2008/256251.

《中國普外基礎與臨床雜志》

過氧化物酶體增殖物激活受體α在結直腸癌發病機制中的作用

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《中國普外基礎與臨床雜志》

過氧化物酶體增殖物激活受體α在結直腸癌發病機制中的作用

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

Format

Content

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