DOI QR코드

DOI QR Code

Identification of Homer1 as a Potential Prognostic Marker for Intrahepatic Cholangiocarcinoma

  • Wu, San-Yun (Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Yu, Ming-Xia (Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Li, Xiao-Gai (Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Xu, Shu-Fang (Department of Intensive Care Unit, Central Hospital of Wuhan) ;
  • Shen, Ji (Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Sun, Zhen (Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors Hubei Cancer Clinical Study Center) ;
  • Zhou, Xin (Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Chen, Xing-Zhen (Department of Physiology, University of Alberta) ;
  • Tu, Jian-Cheng (Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University)
  • Published : 2014.04.01

Abstract

Background: The aim of the present study was to analyze whether Homer1 is a potential prognostic marker for intrahepatic cholangiocarcinoma (ICC). Materials and Methods: The expression of Homer1 in ICC tissue was detected with immunohistochemistry and levels of protein in ICC and paratumor tissues were evaluated by Western blotting. Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance. Results: Homer1 expression was high in 67.4% (58/86) of ICC samples, and there was significant difference between ICC and adjacent noncancerous tissues (p<0.001); high expression was associated with poor histologic differentiation (p=0.019), TNM stage (p=0.014), lymph node metastasis (p=0.040), and lymphatic invasion (p=0.025). On Kaplan-Meier analysis, a comparison of survival curves of low versus high expressors of Homer1 revealed a highly significant difference in OS (p=0.001) and DFS (p=0.006), indicating that high expression of Homer1 was linked with a worse prognosis. Multivariate analyses showed that Homer1 expression was an independent risk factor predicting overall survival[Hazard ratio(HR), 7.52; 95% confidence interval (CI), 2.63-21.47; p=0.002] and disease-free survival (HR, 11.56; 95%CI, 5.17-25.96; p<0.001) in ICC. Conclusions: Homer1 promotes lymphatic invasion and associates with lymph node metastasis and poor prognosis of ICC. The current study shows that Homer1 may be an independent prognostic factor for ICC patients after curative resection, and it provides an important basis for screening/treating high-risk patients.

Keywords

Intrahepatic cholangiocarcinoma;Homer1;prognosis;survival

References

  1. Nagata S (1999). Fas ligand-induced apoptosis. Annu Rev Genet, 33, 29-55. https://doi.org/10.1146/annurev.genet.33.1.29
  2. Wang S, El-Deiry WS ( 2003). TRAIL and apoptosis induction by TNF-family death receptors. Oncogene, 22, 8628-33. https://doi.org/10.1038/sj.onc.1207232
  3. Xiao B, Tu JC, Petralia RS, et al (1998). Homer regulates the association of group I metabotropic glutamate receptors with multivalent complexes of Homer-related, synapt proteins. Neuron, 21, 707-16. https://doi.org/10.1016/S0896-6273(00)80588-7
  4. Yin H, Lu C, Tang Y, Wang H, et al (2013). Enhanced expression of EphrinB1 is associated with lymph node metastasis and poor prognosis in breast cancer. Cancer Biomark, 13, 261-7. https://doi.org/10.3233/CBM-130356
  5. Li Y, Cui J, Zhang CH, et al (2013). High-expression of DJ-1 and loss of PTEN associated with tumor metastasis and correlated with poor prognosis of gastric carcinoma. Int J Med Sci, 10, 1689-97. https://doi.org/10.7150/ijms.7292
  6. Li Z, Qiu HY, Jiao Y, et al (2013). Growth and differentiation effects of Homer3 on a leukemia cell line. Asian Pac J Cancer Prev, 14, 2525-8. https://doi.org/10.7314/APJCP.2013.14.4.2525
  7. Patel T (2002). Worldwide trends in mortality from biliary tract malignancies. BMC Cancer, 2, 10. https://doi.org/10.1186/1471-2407-2-10
  8. Salanova M, Volpe P, Blottner D (2013). Homer protein family regulation in skeletal muscle and neuromuscular adaptation. IUBMB Life, 65, 769-76. https://doi.org/10.1002/iub.1198
  9. Sandona D, Tibaldo E, Volpe P (2000). Evidence for the presence of two homer 1 transcripts in skeletal and cardiac muscles. Biochem Biophys Res Commun, 279, 348-53. https://doi.org/10.1006/bbrc.2000.3948
  10. Senol EP, Tasdelen I, Adim SB, et al (2013). A comparison of Ki 67 proliferative index in primary tumor and axillary metastatic lymph nodes with length of survival in patients with breast cancer. Bratisl Lek Listy, 114, 645-9.
  11. Shaib YH, El-Serag HB, Nooka AK, et al (2007). Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based case-control study. Am J Gastroenterol, 102, 1016-21. https://doi.org/10.1111/j.1572-0241.2007.01104.x
  12. Shin JN, Piya S, Yun CW, et al (2009). Homer1 regulates the susceptibility to TRAIL. Exp Cell Res, 315, 2249-55. https://doi.org/10.1016/j.yexcr.2009.04.004
  13. Soloviev MM, Ciruela F, Chan WY, et al (2000) Mouse brain and muscle tissues constit utively express high levels of Homer proteins. Eur J Biochem, 267, 634-9. https://doi.org/10.1046/j.1432-1327.2000.01078.x
  14. Suh I, Shibru D, Eisenhofer G, et al (2009). Candidate Genes Associated With Malignant Pheochromocytomas by Genome-Wide Expression Profiling. Ann Surg, 250, 983-90 https://doi.org/10.1097/SLA.0b013e3181b248bb
  15. Kawarada Y, Yamagiwa K, Das BC (2002). Analysis of the relationships between clinicopathologic factors and survival time in intrahepatic cholangiocarcinoma. Am J Surg, 183, 679-85. https://doi.org/10.1016/S0002-9610(02)00853-X
  16. Bodmer JL, Holler N, Reynard S, et al (2002). TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat Cell Biol, 2, 241-3.
  17. Brakeman PR, Lanahan AA, O'Brien R, et al (1997), Homer: a protein that selectively binds metabotropic glutamate receptors. Nature, 386, 284-8. https://doi.org/10.1038/386284a0
  18. Deng Y, Lin Y, Wu X (2002). TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIA BLO. Genes Dev, 16, 33-45. https://doi.org/10.1101/gad.949602
  19. Khan SA, Taylor-Robinson SD, Toledano MB, et al (2002). Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol, 37, 806-13. https://doi.org/10.1016/S0168-8278(02)00297-0
  20. Khan SA, Thomas HC, Davidson BR, et al (2005). Cholangiocarcinoma. Lancet, 366, 1303-14. https://doi.org/10.1016/S0140-6736(05)67530-7
  21. Kim Y, Seol DW (2003). TRAIL, a mighty apoptosis inducer. Mol Cells, 15, 283-93.
  22. Kischkel FC, Lawrence DA, Chuntharapai A, et al (2000). Apo2L/TRA IL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity, 12, 611-20. https://doi.org/10.1016/S1074-7613(00)80212-5
  23. Kuang AA, Diehl GE, Zhang J, et al (2000). FADD is required for DR4- and DR5-mediated apoptosis: lack of trail-induced apoptosis in FADD-deficient mouse embryonic fibroblasts. J Biol Chem, 275, 25065-8. https://doi.org/10.1074/jbc.C000284200
  24. LeBlanc HN, Ashkenazi A (2003). Apo2L/TRAIL and its death and decoy receptors, Cell Death Differ, 10, 66-75. https://doi.org/10.1038/sj.cdd.4401187
  25. LeBlanc HN, Lawrence D, Varfolomeev E, et al (2002). Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med, 8, 274-81. https://doi.org/10.1038/nm0302-274
  26. Alpini G, McGill JM, Larusso NF (2002). The pathobiology of biliary epithelia. Hepatology, 35, 1256-68. https://doi.org/10.1053/jhep.2002.33541
  27. Anderson CD, Pinson CW, Berlin J, et al (2004). Diagnosis and treatment of cholangiocarcinoma. Oncologist, 9, 43-57.

Cited by

  1. Intrahepatic cholangiocarcinoma prognostic determination using pre-operative serum C-reactive protein levels vol.16, pp.1, 2016, https://doi.org/10.1186/s12885-016-2827-7