DOI QR코드

DOI QR Code

Differential Expression of IQGAP1/2 in Hepatocellular Carcinoma and its Relationship with Clinical Outcomes

  • Xia, Fa-Da (Department of General Surgery, Xiangya Hospital, Central South University) ;
  • Wang, Zhuo-Lu (Department of General Surgery, Xiangya Hospital, Central South University) ;
  • Chen, Hong-Xi (Department of General Surgery, Xiangya Hospital, Central South University) ;
  • Huang, Yun (Department of General Surgery, Xiangya Hospital, Central South University) ;
  • Li, Jin-Dong (Department of General Surgery, Xiangya Hospital, Central South University) ;
  • Wang, Zhi-Ming (Department of General Surgery, Xiangya Hospital, Central South University) ;
  • Li, Xin-Ying (Department of General Surgery, Xiangya Hospital, Central South University)
  • Published : 2014.06.30

Abstract

Purpose: To investigate IQGAP1 and IQGAP2 expression in hepatocellular carcinoma (HCC) and itsassociation with HCC clinicopathological characteristics and survival outcomes. Methods: IQGAP1 and IQGAP2 mRNA and protein were measured in HCC tissues, para-tumor tissues and normal tissues by RT-PCR and Western blotting. We further examined 150 HCC samples with adjacent para-tumor tissues and 11 normal specimens by immunohistochemistry to evaluate the correlation of IQGAP1 and IQGAP2 with clinicopathological features and prognosis. Results: IQGAP1 mRNA and protein were up-regulated while IQGAP2 mRNA and protein were down-regulated in human HCC tissues compared with para-tumor and normal liver tissues (p<0.05). IQGAP1 expression was higher in primary HCC (122/150, 81.3%) than matched adjacent tissues (30/150, 20%, p<0.001), whereas IQGAP2 was lower (31/150, 20.7% as compared to 112/150, 74.7%, P<0.001). Positive IQGAP1 expression correlated with larger tumor size (p=0.002), advanced TNM stage (p=0.002) and tumor differentiation (III and IV, p=0.034). Negative IQGAP2 expression was significantly associated with larger tumor size (p=0.009), multicentric tumor occurrence (p=0.01), advanced TNM stage (0.009) and tumor differentiation (III and IV, p=0.020). Survival analysis revealed that patients with either IQGAP1+ or IQGAP2-tumors had significantly reduced disease-free survival (p<0.001 and 0.006 respectively) and overall survival (p<0.001 for both). Multivariate analysis showed that IQGAP1/2 switch was an independent prognosis factor for disease-free survival (HR=2.824) and overall survival (HR=2.189). Conclusion: Positive IQGAP1 and negative IQGAP2 expression were closely correlated with tumor progression and could be used as adjunctive biomarkers to improve prognostication for HCC patients.

Keywords

References

  1. Berk V, Kaplan MA, Tonyali O, et al (2013). Efficiency and side effects of sorafenib therapy for advanced hepatocellular carcinoma: a retrospective study by the Anatolian society of medical oncology. Asian Pac J Cancer Prev, 14, 7367-9. https://doi.org/10.7314/APJCP.2013.14.12.7367
  2. Bernards A (2003). GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. Biochim Biophys Acta, 1603, 47-82.
  3. Breuhahn K, Longerich T, Schirmacher P (2006). Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene, 25, 3787-800. https://doi.org/10.1038/sj.onc.1209556
  4. Briggs MW, Sacks DB (2003). IQGAP proteins are integral components of cytoskeletal regulation. Embo Rep, 4, 571-4. https://doi.org/10.1038/sj.embor.embor867
  5. Brill S, Li S, Lyman CW, et al (1996). The Ras GTPase-activatingprotein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases. Mol Cell Biol, 16, 4869-78. https://doi.org/10.1128/MCB.16.9.4869
  6. Brown MD, Sacks DB (2006). IQGAP1 in cellular signaling: bridging the GAP. Trends Cell Biol, 16, 242-9. https://doi.org/10.1016/j.tcb.2006.03.002
  7. Bruix J, Sherman M (2011). Management of hepatocellular carcinoma: an update. Hepatology, 53, 1020-2. https://doi.org/10.1002/hep.24199
  8. Casteel DE, Turner S, Schwappacher R, et al (2012). Rho isoformspecific interaction with IQGAP1 promotes breast cancer cell proliferation and migration. J Biol Chem, 287, 38367-78. https://doi.org/10.1074/jbc.M112.377499
  9. Chen F, Zhu HH, Zhou LF, et al (2010). IQGAP1 is overexpressed in hepatocellular carcinoma and promotes cell proliferation by Akt activation. Exp Mol Med, 42, 477-83. https://doi.org/10.3858/emm.2010.42.7.049
  10. Dong PX, Jia N, Xu ZJ, et al (2008). Silencing of IQGAP1 by shRNA inhibits the invasion of ovarian carcinoma HO-8910PM cells in vitro. J Exp Clin Cancer Res, 27, 77-84. https://doi.org/10.1186/1756-9966-27-77
  11. Elliott SF, Allen G, Timson DJ (2012). Biochemical analysis of the interactions of IQGAP1 C-terminal domain with CDC42. World J Biol Chem, 3, 53-60. https://doi.org/10.4331/wjbc.v3.i3.53
  12. Eom DW, Kang GH, Han SH, et al (2011). Gastric micropapillary carcinoma: A distinct subtype with a significantly worse prognosis in TNM stages I and II. Am J Surg Pathol, 35, 84-91 https://doi.org/10.1097/PAS.0b013e3181ff61e2
  13. Gnatenko DV, Xu X, Zhu W, Schmidt VA (2013). Transcript profiling identifies iqgap2(-/-) mouse as a model for advanced human hepatocellular carcinoma. PLoS One, 8, e71826. https://doi.org/10.1371/journal.pone.0071826
  14. Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor-Robinson SD (2008). Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol, 14, 4300-8. https://doi.org/10.3748/wjg.14.4300
  15. Grohmanova K, Schlaepfer D, Hess D, et al (2004). Phosphorylation of IQGAP1 modulates its binding to Cdc42, revealing a new type of rho-GTPase regulator. J Biol Chem, 279, 48495-504. https://doi.org/10.1074/jbc.M408113200
  16. Hart MJ, Callow MG, Souza B, Polakis P (1996). IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs. EMBO J, 15, 2997-3005.
  17. Jadeski L, Mataraza JM, Jeong HW, Li Z, Sacks DB (2008). IQGAP1 stimulates proliferation and enhances tumorigenesis of human breast epithelial cells. J Biol Chem, 283, 1008-17. https://doi.org/10.1074/jbc.M708466200
  18. Jin SH, Akiyama Y, Fukamachi H, et al (2008). IQGAP2 inactivation through aberrant promoter methylation and promotion of invasion in gastric cancer cells. Int J Cancer, 122, 1040-6.
  19. Joyal JL, Annan RS, Ho YD, et al (1997). Calmodulin modulates the interaction between IQGAP1 and Cdc42. Identification of IQGAP1 by nanoelectrospray tandem mass spectrometry. J Biol Chem, 272, 15419-25. https://doi.org/10.1074/jbc.272.24.15419
  20. Luo R, Zhang M, Liu L, et al (2013). Decrease of fibulin-3 in hepatocellular carcinoma indicates poor prognosis. PLoS One, 8, e70511. https://doi.org/10.1371/journal.pone.0070511
  21. Maluccio M, Covey A (2012). Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J Clin, 62, 394-9. https://doi.org/10.3322/caac.21161
  22. McCallum SJ, Wu WJ, Cerione RA (1996). Identification of a putative effector for Cdc42Hs with high sequence similarity to the RasGAP-related protein IQGAP1 and a Cdc42Hs binding partner with similarity to IQGAP2. J Biol Chem, 271, 21732-7. https://doi.org/10.1074/jbc.271.36.21732
  23. Nabeshima K, Shimao Y, Inoue T, Koono M (2002). Immunohistochemical analysis of IQGAP1 expression in human colorectal carcinomas: its overexpression in carcinomas and association with invasion fronts. Cancer Lett, 176, 101-9. https://doi.org/10.1016/S0304-3835(01)00742-X
  24. Nishikawa H, Kimura T, Kita R, Osaki Y (2013). Treatment for hepatocellular carcinoma in elderly patients: a literature review. J Cancer, 4, 635-43. https://doi.org/10.7150/jca.7279
  25. Schmidt VA (2012). Watch the GAP: emerging roles for IQ motif-containing GTPase-activating proteins IQGAPs in hepatocellular carcinoma. Int J Hepatol, 2012, 958673.
  26. Schmidt VA, Chiariello CS, Capilla E, Miller F, Bahou WF (2008). Development of hepatocellular carcinoma in Iqgap2-deficient mice is IQGAP1 dependent. Mol Cell Biol, 28, 1489-502. https://doi.org/10.1128/MCB.01090-07
  27. Thomas M (2009). Molecular targeted therapy for hepatocellular carcinoma. J Gastroenterol, 44, 136-41. https://doi.org/10.1007/s00535-008-2252-z
  28. Van Hengel J, D'Hooge P, Hooghe B, et al (2008). Continuous cell injury promotes hepatic tumorigenesis in cdc42-deficient mouse liver. Gastroenterology, 134, 781-92. https://doi.org/10.1053/j.gastro.2008.01.002
  29. Walch A, Seidl S, Hermannstadter C, et al (2008). Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer. Mod Pathol, 21, 544-52. https://doi.org/10.1038/modpathol.2008.3
  30. Wang JB, Sonn R, Tekletsadik YK, Samorodnitsky D, Osman MA (2009). IQGAP1 regulates cell proliferation through a novel CDC42-mTOR pathway. J Cell Sci, 122, 2024-33. https://doi.org/10.1242/jcs.044644
  31. Wang NY, Wang C, Li W, et al (2014). Prognostic value of serum AFP, AFP-L3, and GP73 in monitoring short-term treatment response and recurrence of hepatocellular carcinoma after radiofrequency ablation. Asian Pac J Cancer Prev, 15, 1539-44. https://doi.org/10.7314/APJCP.2014.15.4.1539
  32. White CD, Brown MD, Sacks DB (2009). IQGAPs in cancer: a family of scaffold proteins underlying tumorigenesis. Febs Lett, 583, 1817-24. https://doi.org/10.1016/j.febslet.2009.05.007
  33. White CD, Erdemir HH, Sacks DB (2012). IQGAP1 and its binding proteins control diverse biological functions. Cell Signal, 24, 826-34. https://doi.org/10.1016/j.cellsig.2011.12.005
  34. White CD, Khurana H, Gnatenko DV, et al (2010). IQGAP1 and IQGAP2 are reciprocally altered in hepatocellular carcinoma. BMC Gastroenterol, 10, 125. https://doi.org/10.1186/1471-230X-10-125
  35. Xie Y, Yan J, Cutz JC, et al (2012). IQGAP2, A candidate tumour suppressor of prostate tumorigenesis. Biochim Biophys Acta, 1822, 875-84. https://doi.org/10.1016/j.bbadis.2012.02.019
  36. Yu XL (2014). Serum peroxiredoxin 3 is a useful biomarker for early diagnosis and assessemnt of prognosis of hepatocellular carcinoma in Chinese patients. Asian Pac J Cancer Prev, 15, 2979-86. https://doi.org/10.7314/APJCP.2014.15.7.2979

Cited by

  1. KLHL21, a novel gene that contributes to the progression of hepatocellular carcinoma vol.16, pp.1, 2016, https://doi.org/10.1186/s12885-016-2851-7
  2. Golgi protein 73 and its diagnostic value in liver diseases pp.09607722, 2019, https://doi.org/10.1111/cpr.12538
  3. Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma vol.5, pp.12, 2018, https://doi.org/10.1098/rsos.181006