• 四川大學(xué)華西醫(yī)院病理科（成都610041）;

【摘要】目的 介紹抑癌基因胰腺癌缺失基因（DPC4）的改變與胰腺癌的發(fā)展及預(yù)后的關(guān)系。
方法 復(fù)習(xí)近幾年的相關(guān)文獻(xiàn)，進(jìn)行綜述。
結(jié)果 抑癌基因DPC4位于18號染色體上，其編碼產(chǎn)物為Smad 4蛋白。Smad 4蛋白是轉(zhuǎn)移生長因子-β信號傳導(dǎo)通路的中心分子，所有生物學(xué)效應(yīng)都是Smad 4蛋白與不同的Smads蛋白相互作用的結(jié)果。約有50%的胰腺癌發(fā)生DPC4基因的缺失或失活，DPC4基因的表達(dá)缺失與胰腺癌的發(fā)展及預(yù)后有密切關(guān)系。
結(jié)論 抑癌基因DPC4的改變與胰腺癌的發(fā)展及預(yù)后有密切關(guān)系，但仍需進(jìn)行深入研究。

引用本文： 熊開琴,張秀輝. 抑癌基因DPC4與胰腺癌的研究進(jìn)展. 中國普外基礎(chǔ)與臨床雜志, 2005, 12(4): 422-424. doi: 復(fù)制

1. Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1 [J]. Science, 1996; 271(5247)∶350.
2. Moskaluk CA, Hruban RH, Schutte M, et al. Genomic sequencing of DPC4 in the analysis of familial pancreatic carcinoma [J]. Diagn Mol Pathol, 1997; 6(2)∶85.
3. de Caestecker MP, Hemmati P, LarischBloch S, et al. Characterization of functional domains within Smad 4/DPC4 [J]. J Biol Chem， 1997; 272(21)∶13690.
4. Padgett RW, Cho SH, Evangelista C. Smads are the central component in transforming growth factorbeta signaling [J]. Pharmacol Ther, 1998; 78(1)∶47.
5. Feng XH, Zhang Y, Wu RY, et al. The tumor suppressor Smad 4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad 3 in TGFbetainduced transcriptional activation [J]. Genes Dev, 1998; 12(14)∶2153.
6. Miyaki M, Kuroki T. Role of Smad 4 (DPC4) inactivation in human cancer [J]. Biochem Biophys Res Commun, 2003; 306(4)∶799.
7. Liu F, Pouponnot C, Massague J. Dual role of the Smad 4/DPC4 tumor suppressor in TGFbetainducible transcriptional complexes [J]. Genes Dev, 1997; 11(23)∶3157.
8. de Caestecker MP, Yahata T, Wang D, et al. The Smad 4 activation domain (SAD) is a prolinerich, p300dependent transcriptional activation domain [J]. J Biol Chem, 2000; 275(3)∶2115.
9. Heldin CH, Miyazono K, ten Dijke P. TGFbeta signalling from cell membrane to nucleus through SMAD proteins [J]. Nature, 1997; 390(6659)∶465.
10. Jonson T, Gorunova L, Dawiskiba S, et al. Molecular analyses of the 15q and 18q SMAD genes in pancreatic cancer [J]. Genes Chromosomes Cancer, 1999; 24(1)∶62.
11. Imamura T, Takase M, Nishihara A, et al. Smad 6 inhibits signalling by the TGFbeta superfamily [J]. Nature, 1997; 389(6651)∶622.
12. Nakao A, Afrakhte M, Moren A, et al. Identification of Smad 7, a TGFbetainducible antagonist of TGFbeta signalling [J]. Nature, 1997; 389(6651)∶631.
13. Kuang CZ, Chen Y. Tumorderived Cterminal mutations of Smad 4 with decreased DNA binding activity and enhanced intramolecular interaction [J]. Oncogene, 2004; 23(5)∶1021.
14. Fink SP, Mikkola D, Willson JK, et al. TGFbetainduced nuclear localization of Smad 2 and Smad 3 in Smad 4 null cancer cell lines [J]. Oncogene, 2003; 22(9)∶1317.
15. Hahn SA, Hoque AT, Moskaluk CA, etKG*2 al. Homozygous deletion map at 18q21.1 in pancreatic cancer [J]. Cancer Res, 1996; 56(3)∶490.
16. Schutte M, Hruban RH, Hedrick L, et al. DPC4 gene in various tumor types [J]. Cancer Res, 1996; 56(11)∶2527.
17. Rozenblum E, Schutte M, Goggins M, et al. Tumorsuppressive pathways in pancreatic carcinoma [J]. Cancer Res, 1997; 57(9)∶1731.
18. Hoque AT, Hahn SA, Schutte M, et al. DPC4 gene mutation in colitis associated neoplasia [J]. Gut, 1997; 40(1)∶120.
19. Hahn SA, Bartsch D, Schroers A, et al. Mutations of the DPC4/Smad 4 gene in biliary tract carcinoma [J]. Cancer Res, 1998; 58(6)∶1124.
20. Bartsch D, Hahn SA, Danichevski KD, et al. Mutations of the DPC4/Smad 4 gene in neuroendocrine pancreatic tumors [J]. Oncogene, 1999; 18(14)∶2367.
21. Takagi Y, Kohmura H, Futamura M, et al. Somatic alterations of the DPC4 gene in human colorectal cancers in vivo [J]. Gastroenterology, 1996; 111(5)∶1369.
22. Miyaki M, Kuroki T. Role of Smad 4 (DPC4) inactivation in human cancer [J]. Biochem Biophys Res Commun, 2003; 306(4)∶799.
23. Zhang H, Zhang YC, Hu XM, et al. Loss of DPC4 expression and its correlation with clinicopathological parameters in pancreatic carcinoma [J]. World J Gastroenterol, 2003; 9(12)∶2764.
24. Perren A, Saremaslani P, Schmid S, et al. DPC4/Smad 4: no mutations, rare allelic imbalances, and retained protein expression in pancreatic endocrine tumors [J]. Diagn Mol Pathol, 2003; 12(4)∶181.
25. Maitra A, Adsay NV, Argani P, et al. Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray [J]. Mod Pathol, 2003; 16(9)∶902.
26. Biankin AV, Biankin SA, Kench JG, et al. Aberrant p16(INK4A) and DPC4/Smad 4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma [J]. Gut, 2002; 50(6)∶861.
27. Tascilar M, Skinner HG, Rosty C, et al. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma [J]. Clin Cancer Res, 2001; 7(12)∶4115.
28. Holloway S, Davis M, Jaber R, et al. A clinically relevant model of human pancreatic adenocarcinoma identifies patterns of metastasis associated with alterations of the TGFbeta/Smad 4 signaling pathway [J]. Int J Gastrointest Cancer, 2003; 33(1)∶61.
29. Sohn TA, Su GH, Ryu B, et al. Highthroughput drug screening of the DPC4 tumorsuppressor pathway in human pancreatic cancer cells [J]. Ann Surg, 2001; 233(5)∶696.
  1. 1. Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1 [J]. Science, 1996; 271(5247)∶350.
  2. 2. Moskaluk CA, Hruban RH, Schutte M, et al. Genomic sequencing of DPC4 in the analysis of familial pancreatic carcinoma [J]. Diagn Mol Pathol, 1997; 6(2)∶85.
  3. 3. de Caestecker MP, Hemmati P, LarischBloch S, et al. Characterization of functional domains within Smad 4/DPC4 [J]. J Biol Chem， 1997; 272(21)∶13690.
  4. 4. Padgett RW, Cho SH, Evangelista C. Smads are the central component in transforming growth factorbeta signaling [J]. Pharmacol Ther, 1998; 78(1)∶47.
  5. 5. Feng XH, Zhang Y, Wu RY, et al. The tumor suppressor Smad 4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad 3 in TGFbetainduced transcriptional activation [J]. Genes Dev, 1998; 12(14)∶2153.
  6. 6. Miyaki M, Kuroki T. Role of Smad 4 (DPC4) inactivation in human cancer [J]. Biochem Biophys Res Commun, 2003; 306(4)∶799.
  7. 7. Liu F, Pouponnot C, Massague J. Dual role of the Smad 4/DPC4 tumor suppressor in TGFbetainducible transcriptional complexes [J]. Genes Dev, 1997; 11(23)∶3157.
  8. 8. de Caestecker MP, Yahata T, Wang D, et al. The Smad 4 activation domain (SAD) is a prolinerich, p300dependent transcriptional activation domain [J]. J Biol Chem, 2000; 275(3)∶2115.
  9. 9. Heldin CH, Miyazono K, ten Dijke P. TGFbeta signalling from cell membrane to nucleus through SMAD proteins [J]. Nature, 1997; 390(6659)∶465.
  10. 10. Jonson T, Gorunova L, Dawiskiba S, et al. Molecular analyses of the 15q and 18q SMAD genes in pancreatic cancer [J]. Genes Chromosomes Cancer, 1999; 24(1)∶62.
  11. 11. Imamura T, Takase M, Nishihara A, et al. Smad 6 inhibits signalling by the TGFbeta superfamily [J]. Nature, 1997; 389(6651)∶622.
  12. 12. Nakao A, Afrakhte M, Moren A, et al. Identification of Smad 7, a TGFbetainducible antagonist of TGFbeta signalling [J]. Nature, 1997; 389(6651)∶631.
  13. 13. Kuang CZ, Chen Y. Tumorderived Cterminal mutations of Smad 4 with decreased DNA binding activity and enhanced intramolecular interaction [J]. Oncogene, 2004; 23(5)∶1021.
  14. 14. Fink SP, Mikkola D, Willson JK, et al. TGFbetainduced nuclear localization of Smad 2 and Smad 3 in Smad 4 null cancer cell lines [J]. Oncogene, 2003; 22(9)∶1317.
  15. 15. Hahn SA, Hoque AT, Moskaluk CA, etKG*2 al. Homozygous deletion map at 18q21.1 in pancreatic cancer [J]. Cancer Res, 1996; 56(3)∶490.
  16. 16. Schutte M, Hruban RH, Hedrick L, et al. DPC4 gene in various tumor types [J]. Cancer Res, 1996; 56(11)∶2527.
  17. 17. Rozenblum E, Schutte M, Goggins M, et al. Tumorsuppressive pathways in pancreatic carcinoma [J]. Cancer Res, 1997; 57(9)∶1731.
  18. 18. Hoque AT, Hahn SA, Schutte M, et al. DPC4 gene mutation in colitis associated neoplasia [J]. Gut, 1997; 40(1)∶120.
  19. 19. Hahn SA, Bartsch D, Schroers A, et al. Mutations of the DPC4/Smad 4 gene in biliary tract carcinoma [J]. Cancer Res, 1998; 58(6)∶1124.
  20. 20. Bartsch D, Hahn SA, Danichevski KD, et al. Mutations of the DPC4/Smad 4 gene in neuroendocrine pancreatic tumors [J]. Oncogene, 1999; 18(14)∶2367.
  21. 21. Takagi Y, Kohmura H, Futamura M, et al. Somatic alterations of the DPC4 gene in human colorectal cancers in vivo [J]. Gastroenterology, 1996; 111(5)∶1369.
  22. 22. Miyaki M, Kuroki T. Role of Smad 4 (DPC4) inactivation in human cancer [J]. Biochem Biophys Res Commun, 2003; 306(4)∶799.
  23. 23. Zhang H, Zhang YC, Hu XM, et al. Loss of DPC4 expression and its correlation with clinicopathological parameters in pancreatic carcinoma [J]. World J Gastroenterol, 2003; 9(12)∶2764.
  24. 24. Perren A, Saremaslani P, Schmid S, et al. DPC4/Smad 4: no mutations, rare allelic imbalances, and retained protein expression in pancreatic endocrine tumors [J]. Diagn Mol Pathol, 2003; 12(4)∶181.
  25. 25. Maitra A, Adsay NV, Argani P, et al. Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray [J]. Mod Pathol, 2003; 16(9)∶902.
  26. 26. Biankin AV, Biankin SA, Kench JG, et al. Aberrant p16(INK4A) and DPC4/Smad 4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma [J]. Gut, 2002; 50(6)∶861.
  27. 27. Tascilar M, Skinner HG, Rosty C, et al. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma [J]. Clin Cancer Res, 2001; 7(12)∶4115.
  28. 28. Holloway S, Davis M, Jaber R, et al. A clinically relevant model of human pancreatic adenocarcinoma identifies patterns of metastasis associated with alterations of the TGFbeta/Smad 4 signaling pathway [J]. Int J Gastrointest Cancer, 2003; 33(1)∶61.
  29. 29. Sohn TA, Su GH, Ryu B, et al. Highthroughput drug screening of the DPC4 tumorsuppressor pathway in human pancreatic cancer cells [J]. Ann Surg, 2001; 233(5)∶696.