DOI QR코드

DOI QR Code

Expression of Smoothened Protein in Colon Cancer and its Prognostic Value for Postoperative Liver Metastasis

  • Ding, Yin-Lu ;
  • Wang, Qi-San ;
  • Zhao, Wei-Min ;
  • Xiang, Lei
  • Published : 2012.08.31

Abstract

Backgrouds: The hedgehog (Hh) signaling pathway is composed of patched (PTCH) and smoothened (SMO), two transmembrane proteins, and downstream glioma-associated oncogene homolog (Gli) transcription factors. Hh signaling plays a pathological role in the occurrence and development of various cancers. Methods: To investigate the expression of SMO protein in colon cancer and its association with clinicopathological parameters and postoperative liver metastasis, immunohistochemistry was performed with paraffin-embedded specimens of 96 cases. Relationships between SMO protein expression and clinicopathological parameters, postoperative liver metastasis were analyzed. Results: IHC examination showed that SMO protein expression was significantly increased in colon cancer tissues compared to normal colon tissues (P = 0.042), positively related to lymph node metastases (P = 0.018) and higher T stages (P = 0.026). Postoperative live metastasis-free survival was significantly longer in the low SMO expression group than in those with high SMO expression ($48.7{\pm}8.02$ months vs $28.0{\pm}6.86$ months, P=0.036). Multivariate analysis showed SMO expression level to be an independent prognostic factor for postoperative live metastasis-free survival (95% confidence interval [CI] =1.46-2.82, P = 0.008). Conclusions: Our results suggest that in patients with colon cancer, the SMO expression level is an independent biomarker for postoperative liver metastasis, and SMO might play an important role in colon cancer progression.

Keywords

Colon neoplasm;smoothened gene;postoperative liver metastasis

References

  1. Altaba A, Stecca B, Snchez P (2004). Hedgehog-Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer. Cancer Letters, 204, 145-57. https://doi.org/10.1016/S0304-3835(03)00451-8
  2. Berman DM, Karhadkar SS, Maitra A, et al (2003). Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature, 425, 846-51. https://doi.org/10.1038/nature01972
  3. Bird NC, Mangnall D, Majeed AW (2006). Biology of colorectal liver metastases: A review. J Surg Oncol, 94, 68-80. https://doi.org/10.1002/jso.20558
  4. Bos PD, Zhang XHF, Nadal C, et al (2009). Genesthat mediate breast cancer metastasis to the brain. Nature, 459, 1005-9. https://doi.org/10.1038/nature08021
  5. Chaudary N, Pintilie M, Hedley D, et al (2012). Hedgehog pathway signaling in cervical carcinoma and outcome after chemoradiation. Cancer, 118, 3105-15. https://doi.org/10.1002/cncr.26635
  6. Cowan R, Hoban P, Kelsey A, et al (1997). The gene for the naevoid basal cell carcinoma syndrome acts as a tumoursuppressor gene in medulloblastoma. Br J Cancer, 76, 141-5. https://doi.org/10.1038/bjc.1997.354
  7. Ding Yl, Zhou Y, Xiang L, et al (2012). Expression of gliomaassociated oncogene homolog 1 is associated with invasion and postoperative liver metastasis in colon cancer. Int J Med Sci, 9, 334-8. https://doi.org/10.7150/ijms.4553
  8. Ecke I, Rosenberger A, Obenauer S, et al (2008). Cyclopamine treatment of full-blown Hh/Ptch-associated RMS partially inhibits Hh/Ptch signaling, but not tumor growth. Mol Carcinog, 47, 361-72. https://doi.org/10.1002/mc.20394
  9. Fidler IJ (1990). Critical factors in the biology of human cancer metastasis: twenty-eight GHA Clowes Memorial Award Lecture. Cancer Res, 50, 6130-8.
  10. Fukaya M, Isohata N, Ohta H, et al (2006). Hedgehog signal activation in gastric pit cell and in diffusetype gastric cancer. Gastroenterology, 131, 14-29. https://doi.org/10.1053/j.gastro.2006.05.008
  11. Ghali L, Wong ST, Green J, et al (1999). GLi-1 protein is expressed in basal cell carcinomas, outer root sheath keratinocytes and a subpopulation of mesenchymal cells. Normal Human Ski, 113, 595-99.
  12. Hirotsu M, Setoguchi T, Sasaki H, et al (2010). Smoothened as a new therapeutic target for human osteosarcoma. Molecular Cancer, 9, 5. https://doi.org/10.1186/1476-4598-9-5
  13. Jemal A, Siegel R, Xu J, et al (2010). Cancer statistics, 2010. CA Cancer J Clin, 60, 277-300. https://doi.org/10.3322/caac.20073
  14. Johnson RL, Rothman AL, Xie J, et al (1996). Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science, 272, 1668-71. https://doi.org/10.1126/science.272.5268.1668
  15. Karhadkar SS, Bova GS, Abdallah N, et al (2004). Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature, 431, 707-12. https://doi.org/10.1038/nature02962
  16. Kinzler KW, Vogelstein B (1990). The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. Mol Cell Bio, 10, 634-42. https://doi.org/10.1128/MCB.10.2.634
  17. Lees C, Howie S, Sartor RB, et al (2005). The hedgehog signaling pathway in the gastrointestinal tract: implications for development, homeostasis, and disease. Gastroenterology, 129, 1696-710. https://doi.org/10.1053/j.gastro.2005.05.010
  18. Mayo SC, Pawlik TM (2009). Current management of colorectal hepatic metastasis. Expert Rev Gastroenterol Hepatol, 3, 131-44. https://doi.org/10.1586/egh.09.8
  19. Minn AJ, Gupta GP, Siegel PM, et al (2005). Genes that mediate breastcancer metastasis to lung. Nature, 436, 518-24. https://doi.org/10.1038/nature03799
  20. Mori Y, Okumura T, Tsunoda S, et al (2006). Gli-1 expression is associated with lymph node metastasis and tumor progression in esophageal squamous cell carcinoma. Oncology, 70, 378-89. https://doi.org/10.1159/000098111
  21. Murone M, Luoh SM, Stone D, et al (2000). Gli regulation by the opposing activities of fused and suppressor of fused. Nat Cell Bio, 2, 310-2. https://doi.org/10.1038/35010610
  22. Ochiai H, Nakanishi Y, Fukasawa Y, et al (2008). A new formula for predicting liver metastasis in patients with colorectal cancer: immunohistochemical analysis of a large series of 439 surgically resected cases. Oncology, 75, 32-41. https://doi.org/10.1159/000151667
  23. Oishi N, Wang XW (2011). Novel therapeutic strategies for targeting liver cancer stem cells. Int J Biol Sci, 7, 517-35. https://doi.org/10.7150/ijbs.7.517
  24. Remmele W, Stegner HE (1987). Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe, 8, 138-40.
  25. Ruiz i Altaba A, Sánchez P, Dahmane N (2002). Gli and hedgehog in cancer: tumors, embryos and stem cells. Nat Rev Cancer, 2, 361-72. https://doi.org/10.1038/nrc796
  26. Sasaki H, Hui C, Nakafuku M, et al (1997). A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development, 124, 1313-22.
  27. Shao J, Zhang L, Gao J, et al (2006). Aberrant expression of PTCH (patched gene) and Smo (smoothened gene) in human pancreatic cancerous tissues and its association with hyperglycemia. Pancreas, 33, 38-44. https://doi.org/10.1097/01.mpa.0000222319.59360.21
  28. Shi Y, Moura U, Opitz I, et al (2012). Role of Hedgehog Signaling in Malignant Pleural Mesothelioma. Clin Cancer Res, doi:10.1158/1078-0432. CCR-12-0599 https://doi.org/10.1158/1078-0432.CCR-12-0599
  29. Soydinc HO, Duranyildiz D, Camlica H, et al (2011). Lack of diagnostic potential of Dickkopf-1 in colon and rectum cancers. Asian Pac J Cancer Prev, 12, 3187-9.
  30. Stecca B, Mas C, Clement V, et al (2007). Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci USA, 104, 5895-900. https://doi.org/10.1073/pnas.0700776104
  31. Sun L, Hu H, Peng L, et al (2011). P-cadherin promotes liver metastasis and is associated with poor prognosis in colon cancer. Am J Pathol, 179, 380-90. https://doi.org/10.1016/j.ajpath.2011.03.046
  32. Tan S, Zhang L, Zhong XM, et al (2011). Monoclonal antibodies against nucleophosmin mutants: potentials for the detection of acute myeloid leukemia. Int J Med Sci, 8, 309-14. https://doi.org/10.7150/ijms.8.309
  33. Thayer SP, di Magliano MP, Heiser PW, et al (2003). Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature, 425, 851-6. https://doi.org/10.1038/nature02009
  34. Tojo M, Mori T, Kiyosawa H, et al (1999). Expression of sonic hedgehog signal transducers, patched and smoothened, in human basal cell carcinoma. Pathol Int, 49, 687-94. https://doi.org/10.1046/j.1440-1827.1999.00938.x
  35. Watkins DN, Berman DM, Burkholder SG, et al (2003). Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature, 422, 313-7. https://doi.org/10.1038/nature01493
  36. Yang L, Bian Y, Huang S, et al (2011). Identification of signature genes for detecting hedgehog pathway activation in esophageal cancer. Pathol Oncol Res, 17, 387-91. https://doi.org/10.1007/s12253-010-9337-8
  37. Yassin AEB, Anwer MK, Mowafy HA, et al (2010). Optimization of 5-fluorouracil solid-lipid nanoparticles: a preliminary study to treat colon cancer. Int J Med Sci, 7, 398-408.
  38. Yoo YA, Kang MH, Kim JS, et al (2008). Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Carcinogenesis, 29, 480-90.
  39. Zhou Q, Peng RQ, Wu XJ, et al (2010). The density of macrophages in the invasive front is inversely correlated to liver metastasis in colon cancer. J Transl Med, 8, 13. https://doi.org/10.1186/1479-5876-8-13

Cited by

  1. Hedgehog Related Protein Expression in Breast Cancer: Gli-2 Is Associated with Poor Overall Survival vol.47, pp.2, 2013, https://doi.org/10.4132/KoreanJPathol.2013.47.2.116
  2. Down-regulated MYH11 Expression Correlates with Poor Prognosis in Stage II and III Colorectal Cancer vol.15, pp.17, 2014, https://doi.org/10.7314/APJCP.2014.15.17.7223
  3. SMO Expression in Colorectal Cancer: Associations with Clinical, Pathological, and Molecular Features vol.21, pp.13, 2014, https://doi.org/10.1245/s10434-014-3888-y
  4. SERPINA3 Silencing Inhibits the Migration, Invasion, and Liver Metastasis of Colon Cancer Cells vol.63, pp.9, 2018, https://doi.org/10.1007/s10620-018-5137-x
  5. Nuclear localization and Overexpression of Smoothened in Pancreatic and Colorectal Cancers pp.07302312, 2019, https://doi.org/10.1002/jcb.28477