Advances of the Relationship Between Tumor Suppressor Gene DPC4 and Pancreatic Carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

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XIONG Kaiqin , ZHANG Xiuhui

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Pancreatic carcinoma Tumor suppressor gene DPC4 gene

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【Abstract】ObjectiveTo investigate the relationship between tumor suppressor gene DPC4 and the development and prognosis of pancreatic carcinoma.
MethodsRelevant literatures of recent years were reviewed.
ResultsDPC4 was located on chromosome 18. Its product was Smad 4 protein. Smad 4 protein was the central component of the transforming growth factor-beta signaling pathway, and all the biological effect was the results of interaction of Smad 4 and different Smads. The gene was deleted or inactive in about 50% of pancreatic carcinomas. The deletion of DPC4 had a great relation to the development and prognosis of pancreatic carcinoma.
ConclusionThe alteration of tumor suppressor gene DPC4 is connected with the development and prognosis of pancreatic carcinoma. However, this research should be further studied.

Citation： XIONG Kaiqin,ZHANG Xiuhui. Advances of the Relationship Between Tumor Suppressor Gene DPC4 and Pancreatic Carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2005, 12(4): 422-424. doi: Copy

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. 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.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Advances of the Relationship Between Tumor Suppressor Gene DPC4 and Pancreatic Carcinoma

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