• 1.蘭州大學(xué)第二醫(yī)院普外科（甘肅蘭州 730030）;;
  • 2.蘭州大學(xué)第二醫(yī)院甘肅省消化系腫瘤重點(diǎn)實(shí)驗(yàn)室（甘肅蘭州 730030）;

目的 　探討Notch信號(hào)通路的結(jié)構(gòu)特點(diǎn)、功能以及在消化系腫瘤中的研究進(jìn)展。
方法 　采用文獻(xiàn)復(fù)習(xí)的方法，對(duì)研究Notch信號(hào)通路在消化系腫瘤分子機(jī)理的相關(guān)文獻(xiàn)加以綜述。
結(jié)果 　Notch信號(hào)通路不僅在細(xì)胞正常發(fā)育、分化增殖和凋亡中起著重要的作用，而且與多種腫瘤的發(fā)生和發(fā)展具有相關(guān)性。
結(jié)論 　對(duì)Notch信號(hào)通路進(jìn)行合理的調(diào)控有可能為腫瘤的治療開辟新的途徑。

引用本文： 蓋大偉,郭凌云,劉濤,李玉民. Notch信號(hào)通路在消化系腫瘤中的研究進(jìn)展△. 中國普外基礎(chǔ)與臨床雜志, 2013, 20(10): 1188-1192. doi: 復(fù)制

1. Artavanis-Tsakonas S， Matsuno K， Fortini ME. Notch signaling[J]. Science， 1995， 268(5208)： 225-232.
2. Mumm JS， Kopan R. Notch signaling：from the outside in[J]. Dev Biol， 2000， 228(2)：151-165.
3. South AP， Cho RJ， Aster JC. The double-edged sword of Notch signaling in cancer[J]. Semin Cell Dev Biol， 2012， 23(4)：458-464.
4. Ranganathan P， Weaver KL， Capobianco AJ. Notch signalling in solid tumours： a little bit of everything but not all the time[J]. Nat Rev Cancer， 2011， 11(5)：338-351.
5. Apelqvist A， Li H， Sommer L， et al. Notch signalling controls pancreatic cell differentiation[J]. Nature， 1999， 400(6747)：877-881.
6. Bray SJ. Notch signalling：a simple pathway becomes complex[J]. Nat Rev Mol Cell Biol， 2006， 7(9)：678-689.
7. Jarriault S， Brou C， Logeat F， et al. Signalling downstream of activated mammalian Notch[J]. Nature， 1995， 377(6547)：355-358.
8. Burstein HJ， Schwartz RS. Molecular origins of cancer[J]. N Engl J Med， 2008， 358(5)：527.
9. Hu YY， Zheng MH， Zhang R， et al. Notch signaling pathway and cancer metastasis[J]. Adv Exp Med Biol， 2012， 727：186-198.
10. Phillips HS， Kharbanda S， Chen R， et al. Molecular subclasses of high-grade glioma predict prognosis， delineate a pattern of disease progression， and resemble stages in neurogenesis[J]. Cancer Cell， 2006， 9(3)：157-173.
11. Schroeter EH， Kisslinger JA， Kopan R. Notch-1 signallingrequires ligand-induced proteolytic release of intracellular domain[J]. Nature， 1998， 393(6683)：382-386.
12. Fan X， Mikolaenko I， Elhassan I， et al. Notch1 and notch2 have opposite effects on embryonal brain tumor growth[J]. Cancer Res， 2004， 64(21)：7787-7793.
13. Dang TP， Gazdar AF， Virmani AK， et al. Chromosome 19 translocation， overexpression of Notch3， and human lung cancer[J]. J Natl Cancer Inst， 2000， 92(16)：1355-1357.
14. Park JT， Li M， Nakayama K， et al. Notch3 gene amplification in ovarian cancer[J]. Cancer Res， 2006， 66(12)：6312-6318.
15. Reedijk M， Odorcic S， Chang L， et al. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival[J]. Cancer Res， 2005， 65(18)：8530-8537.
16. Proweller A， Tu L， Lepore JJ， et al. Impaired notch signaling promotes de novo squamous cell carcinoma formation[J]. CancerRes， 2006， 66(15)：7438-7444.
17. Sekine A， Akiyama Y， Yanagihara K， et al. Hath1 up-regulates gastric mucin gene expression in gastric cells[J]. Biochem BiophysRes Commun， 2006， 344(4)：1166-1171.
18. Tamagawa Y， Ishimura N， Uno G， et al. Notch signaling pathwayand Cdx2 expression in the development of Barrett’s esophagus[J].Lab Invest， 2012， 92(6)：896-909.
19. Zhou BB， Zhang H， Damelin M， et al. Tumour-initiating cells：challenges and opportunities for anticancer drug discovery[J]. Nat Rev Drug Discov， 2009， 8(10)：806-823.
20. Snijders AM， Schmidt BL， Fridlyand J， et al. Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma[J]. Oncogene， 2005， 24(26)：4232-4242.
21. Leethanakul C， Patel V， Gillespie J， et al. Distinct pattern ofexpression of differentiation and growth-related genes in squamouscell carcinomas of the head and neck revealed by the use of laser capture microdissection and cDNA arrays[J]. Oncogene， 2000， 19(28)：3220-3224.
22. Sekine A， Akiyama Y， Yanagihara K， et al. Hath1 up-regulates gastric mucin gene expression in gastric cells[J]. Biochem BiophysRes Commun， 2006， 344(4)：1166-1171.
23. Yeh TS， Wu CW， Hsu KW， et al. The activated Notch1 signal pathway is associated with gastric cancer progression throughcyclooxygenase-2[J]. Cancer Res， 2009， 69(12)：5039-5048.
24. Mills JC， Shivdasani RA. Gastric epithelial stem cells[J]. Gastroenterology， 2011， 140(2)：412-424.
25. Fan R， Chen P， Zhao D， et al. Cooperation of deregulated Notch signaling and Ras pathway in human hepatocarcinogenesis[J]. J Mol Histol， 2011， 42(5)：473-481.
26. Qi R， An H， Yu Y， et al. Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis[J]. Cancer Res， 2003， 63(23)：8323-8329.
27. Yao Z， Mishra L. Cancer stem cells and hepatocellular carcinoma[J]. Cancer Biol Ther， 2009， 8(18)：1691-1698.
28. Wang M， Xue L， Cao Q， et al. Expression of Notch1， Jagged1 and beta-catenin and their clinicopathological significance in hepatocellular carcinoma[J]. Neoplasma， 2009， 56(6)：533-541.
29. Sonoshita M， Aoki M， Fuwa H， et al. Suppression of colon cancermetastasis by Aes through inhibition of Notch signaling[J]. Cancer Cell， 2011， 19(1)：125-137.
30. Yabuuchi S， Pai SG， Campbell NR， et al. Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer[J]. Cancer Lett， 2013， 335(1)：41-51.
31. Avila JL， Kissil JL. Notch signaling in pancreatic cancer：oncogene or tumor suppressor?[J]. Trends Mol Med， 2013， 19(5)：320-327.
32. Miyamoto Y， Maitra A， Ghosh B， et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatictumorigenesis[J]. Cancer Cell， 2003， 3(6)：565-576.
33. Mullendore ME， Koorstra JB， Li YM， et al. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer[J]. Clin Cancer Res， 2009， 15(7)：2291-2301.
34. Mazur PK， Einwachter H， Lee M， et al. Notch2 is required for progression of pancreatic intraepithelial neoplasia and developmentof pancreatic ductal adenocarcinoma[J]. Proc Natl Acad Sci U S A， 2010， 107(30)：13438-13443.
35. Hruban RH， Wilentz RE， Goggins M， et al. Pathology of incipientpancreatic cancer[J]. Ann Oncol， 1999， 10 Suppl 4：9-11.
36. Walther A， Johnstone E， Swanton C， et al. Genetic prognostic and predictive markers in colorectal cancer[J]. Nat Rev Cancer， 2009， 9(7)：489-499.
37. Yin L， Velazquez OC， Liu ZJ. Notch signaling： emerging mole-cular targets for cancer therapy[J]. Biochem Pharmacol， 2010， 80(5)：690-701.
38. Konsavage WJ， Kyler SL， Rennoll SA， et al. Wnt/beta-catenin signaling regulates Yes-associated protein (YAP) gene expression in colorectal carcinoma cells[J]. J Biol Chem， 2012， 287(15)：11730-11739.
39. Zhang H， Ye Y， Bai Z， et al. The COX-2 selective inhibitor-independent COX-2 effect on colon carcinoma cells is associated with the Delta1/Notch1 pathway[J]. Dig Dis Sci， 2008， 53(8)：2195-2203.
40. Yeung TM， Gandhi SC， Bodmer WF. Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells[J]. Proc Natl Acad Sci U S A， 2011， 108(11)：4382-4387.
41. Wilson BJ， Schatton T， Frank MH， et al. Colorectal cancer stem cells： biology and therapeutic implications[J]. Curr Colorectal Cancer Rep， 2011， 7(2)：128-135.
42. Yasui H， Hideshima T， Richardson PG， et al. Novel therapeutic strategies targeting growth factor signalling cascades in multiple myeloma[J]. Br J Haematol， 2006， 132(4)：385-397.
43. Iso T， Maeno T， Oike Y， et al. Dll4-selective Notch signalinginduces ephrinB2 gene expression in endothelial cells[J]. BiochemBiophys Res Commun， 2006， 341(3)：708-714.
44. Wu Y， Cain-Hom C， Choy L， et al. Therapeutic antibody targetingof individual Notch receptors[J]. Nature， 2010， 464(7291)：1052-1057.
45. Katoh M， Katoh M. Bioinformatics for cancer management in the post-genome era[J]. Technol Cancer Res Treat， 2006， 5(2)：169-175.
46. Hyde LA， Mchugh NA， Chen J， et al. Studies to investigate thein vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3， 5-difluorophenyl)-2-hydroxyethanoyl]-N1- [(7S)-5-methyl-6-oxo-6， 7-di hydro-5H-dibenzo[b， d]azepin-7-yl]-L-alaninamide (LY411， 575) in the CRND8 mouse[J]. J PharmacolExp Ther， 2006， 319(3)：1133-1143.
  1. 1. Artavanis-Tsakonas S， Matsuno K， Fortini ME. Notch signaling[J]. Science， 1995， 268(5208)： 225-232.
  2. 2. Mumm JS， Kopan R. Notch signaling：from the outside in[J]. Dev Biol， 2000， 228(2)：151-165.
  3. 3. South AP， Cho RJ， Aster JC. The double-edged sword of Notch signaling in cancer[J]. Semin Cell Dev Biol， 2012， 23(4)：458-464.
  4. 4. Ranganathan P， Weaver KL， Capobianco AJ. Notch signalling in solid tumours： a little bit of everything but not all the time[J]. Nat Rev Cancer， 2011， 11(5)：338-351.
  5. 5. Apelqvist A， Li H， Sommer L， et al. Notch signalling controls pancreatic cell differentiation[J]. Nature， 1999， 400(6747)：877-881.
  6. 6. Bray SJ. Notch signalling：a simple pathway becomes complex[J]. Nat Rev Mol Cell Biol， 2006， 7(9)：678-689.
  7. 7. Jarriault S， Brou C， Logeat F， et al. Signalling downstream of activated mammalian Notch[J]. Nature， 1995， 377(6547)：355-358.
  8. 8. Burstein HJ， Schwartz RS. Molecular origins of cancer[J]. N Engl J Med， 2008， 358(5)：527.
  9. 9. Hu YY， Zheng MH， Zhang R， et al. Notch signaling pathway and cancer metastasis[J]. Adv Exp Med Biol， 2012， 727：186-198.
  10. 10. Phillips HS， Kharbanda S， Chen R， et al. Molecular subclasses of high-grade glioma predict prognosis， delineate a pattern of disease progression， and resemble stages in neurogenesis[J]. Cancer Cell， 2006， 9(3)：157-173.
  11. 11. Schroeter EH， Kisslinger JA， Kopan R. Notch-1 signallingrequires ligand-induced proteolytic release of intracellular domain[J]. Nature， 1998， 393(6683)：382-386.
  12. 12. Fan X， Mikolaenko I， Elhassan I， et al. Notch1 and notch2 have opposite effects on embryonal brain tumor growth[J]. Cancer Res， 2004， 64(21)：7787-7793.
  13. 13. Dang TP， Gazdar AF， Virmani AK， et al. Chromosome 19 translocation， overexpression of Notch3， and human lung cancer[J]. J Natl Cancer Inst， 2000， 92(16)：1355-1357.
  14. 14. Park JT， Li M， Nakayama K， et al. Notch3 gene amplification in ovarian cancer[J]. Cancer Res， 2006， 66(12)：6312-6318.
  15. 15. Reedijk M， Odorcic S， Chang L， et al. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival[J]. Cancer Res， 2005， 65(18)：8530-8537.
  16. 16. Proweller A， Tu L， Lepore JJ， et al. Impaired notch signaling promotes de novo squamous cell carcinoma formation[J]. CancerRes， 2006， 66(15)：7438-7444.
  17. 17. Sekine A， Akiyama Y， Yanagihara K， et al. Hath1 up-regulates gastric mucin gene expression in gastric cells[J]. Biochem BiophysRes Commun， 2006， 344(4)：1166-1171.
  18. 18. Tamagawa Y， Ishimura N， Uno G， et al. Notch signaling pathwayand Cdx2 expression in the development of Barrett’s esophagus[J].Lab Invest， 2012， 92(6)：896-909.
  19. 19. Zhou BB， Zhang H， Damelin M， et al. Tumour-initiating cells：challenges and opportunities for anticancer drug discovery[J]. Nat Rev Drug Discov， 2009， 8(10)：806-823.
  20. 20. Snijders AM， Schmidt BL， Fridlyand J， et al. Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma[J]. Oncogene， 2005， 24(26)：4232-4242.
  21. 21. Leethanakul C， Patel V， Gillespie J， et al. Distinct pattern ofexpression of differentiation and growth-related genes in squamouscell carcinomas of the head and neck revealed by the use of laser capture microdissection and cDNA arrays[J]. Oncogene， 2000， 19(28)：3220-3224.
  22. 22. Sekine A， Akiyama Y， Yanagihara K， et al. Hath1 up-regulates gastric mucin gene expression in gastric cells[J]. Biochem BiophysRes Commun， 2006， 344(4)：1166-1171.
  23. 23. Yeh TS， Wu CW， Hsu KW， et al. The activated Notch1 signal pathway is associated with gastric cancer progression throughcyclooxygenase-2[J]. Cancer Res， 2009， 69(12)：5039-5048.
  24. 24. Mills JC， Shivdasani RA. Gastric epithelial stem cells[J]. Gastroenterology， 2011， 140(2)：412-424.
  25. 25. Fan R， Chen P， Zhao D， et al. Cooperation of deregulated Notch signaling and Ras pathway in human hepatocarcinogenesis[J]. J Mol Histol， 2011， 42(5)：473-481.
  26. 26. Qi R， An H， Yu Y， et al. Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis[J]. Cancer Res， 2003， 63(23)：8323-8329.
  27. 27. Yao Z， Mishra L. Cancer stem cells and hepatocellular carcinoma[J]. Cancer Biol Ther， 2009， 8(18)：1691-1698.
  28. 28. Wang M， Xue L， Cao Q， et al. Expression of Notch1， Jagged1 and beta-catenin and their clinicopathological significance in hepatocellular carcinoma[J]. Neoplasma， 2009， 56(6)：533-541.
  29. 29. Sonoshita M， Aoki M， Fuwa H， et al. Suppression of colon cancermetastasis by Aes through inhibition of Notch signaling[J]. Cancer Cell， 2011， 19(1)：125-137.
  30. 30. Yabuuchi S， Pai SG， Campbell NR， et al. Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer[J]. Cancer Lett， 2013， 335(1)：41-51.
  31. 31. Avila JL， Kissil JL. Notch signaling in pancreatic cancer：oncogene or tumor suppressor?[J]. Trends Mol Med， 2013， 19(5)：320-327.
  32. 32. Miyamoto Y， Maitra A， Ghosh B， et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatictumorigenesis[J]. Cancer Cell， 2003， 3(6)：565-576.
  33. 33. Mullendore ME， Koorstra JB， Li YM， et al. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer[J]. Clin Cancer Res， 2009， 15(7)：2291-2301.
  34. 34. Mazur PK， Einwachter H， Lee M， et al. Notch2 is required for progression of pancreatic intraepithelial neoplasia and developmentof pancreatic ductal adenocarcinoma[J]. Proc Natl Acad Sci U S A， 2010， 107(30)：13438-13443.
  35. 35. Hruban RH， Wilentz RE， Goggins M， et al. Pathology of incipientpancreatic cancer[J]. Ann Oncol， 1999， 10 Suppl 4：9-11.
  36. 36. Walther A， Johnstone E， Swanton C， et al. Genetic prognostic and predictive markers in colorectal cancer[J]. Nat Rev Cancer， 2009， 9(7)：489-499.
  37. 37. Yin L， Velazquez OC， Liu ZJ. Notch signaling： emerging mole-cular targets for cancer therapy[J]. Biochem Pharmacol， 2010， 80(5)：690-701.
  38. 38. Konsavage WJ， Kyler SL， Rennoll SA， et al. Wnt/beta-catenin signaling regulates Yes-associated protein (YAP) gene expression in colorectal carcinoma cells[J]. J Biol Chem， 2012， 287(15)：11730-11739.
  39. 39. Zhang H， Ye Y， Bai Z， et al. The COX-2 selective inhibitor-independent COX-2 effect on colon carcinoma cells is associated with the Delta1/Notch1 pathway[J]. Dig Dis Sci， 2008， 53(8)：2195-2203.
  40. 40. Yeung TM， Gandhi SC， Bodmer WF. Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells[J]. Proc Natl Acad Sci U S A， 2011， 108(11)：4382-4387.
  41. 41. Wilson BJ， Schatton T， Frank MH， et al. Colorectal cancer stem cells： biology and therapeutic implications[J]. Curr Colorectal Cancer Rep， 2011， 7(2)：128-135.
  42. 42. Yasui H， Hideshima T， Richardson PG， et al. Novel therapeutic strategies targeting growth factor signalling cascades in multiple myeloma[J]. Br J Haematol， 2006， 132(4)：385-397.
  43. 43. Iso T， Maeno T， Oike Y， et al. Dll4-selective Notch signalinginduces ephrinB2 gene expression in endothelial cells[J]. BiochemBiophys Res Commun， 2006， 341(3)：708-714.
  44. 44. Wu Y， Cain-Hom C， Choy L， et al. Therapeutic antibody targetingof individual Notch receptors[J]. Nature， 2010， 464(7291)：1052-1057.
  45. 45. Katoh M， Katoh M. Bioinformatics for cancer management in the post-genome era[J]. Technol Cancer Res Treat， 2006， 5(2)：169-175.
  46. 46. Hyde LA， Mchugh NA， Chen J， et al. Studies to investigate thein vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3， 5-difluorophenyl)-2-hydroxyethanoyl]-N1- [(7S)-5-methyl-6-oxo-6， 7-di hydro-5H-dibenzo[b， d]azepin-7-yl]-L-alaninamide (LY411， 575) in the CRND8 mouse[J]. J PharmacolExp Ther， 2006， 319(3)：1133-1143.