Upregulated TRIO expression correlates with a malignant phenotype in human hepatocellular carcinoma

详细信息    查看全文

• 作者：Bin Wang ; JiaQing Fang ; Lei Qu ; Zhongwei Cao ; JianGuo Zhou ; Biao Deng
• 关键词：TRIO ; HCC ; Prognosis ; Cell proliferation ; Cell adhesion ; Cell invasion ; Apoptosis
• 刊名：Tumor Biology
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：36
• 期：9
• 页码：6901-6908
• 全文大小：797 KB
• 参考文献：1.Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMed CrossRef
  2.Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology. 2008;48:2047–63.PubMed CrossRef
  3.El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.PubMed CrossRef
  4.Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48:1312–27.PubMed PubMedCentral CrossRef
  5.Chang YJ, Li LT, Chen HA, Hung CS, Wei PL. Silencing survivin activates autophagy as an alternative survival pathway in HCC cells. Tumour Biol. 2014;35:9957–66.PubMed CrossRef
  6.Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002;420:629–35.PubMed CrossRef
  7.Bellanger JM, Astier C, Sardet C, Ohta Y, Stossel TP, Debant A. The Rac1- and RhoG-specific GEF domain of Trio targets filamin to remodel cytoskeletal actin. Nat Cell Biol. 2000;2:888–92.PubMed CrossRef
  8.Debant A, Serra-Pages C, Seipel K, O'Brien S, Tang M, Park SH, et al. The multidomain protein Trio binds the LAR transmembrane tyrosine phosphatase, contains a protein kinase domain, and has separate rac-specific and rho-specific guanine nucleotide exchange factor domains. Proc Natl Acad Sci U S A. 1996;93:5466–71.PubMed PubMedCentral CrossRef
  9.Peng YJ, He WQ, Tang J, Tao T, Chen C, Gao YQ, et al. Trio is a key guanine nucleotide exchange factor coordinating regulation of the migration and morphogenesis of granule cells in the developing cerebellum. J Biol Chem. 2010;285:24834–44.PubMed PubMedCentral CrossRef
  10.Bateman J, Shu H, Van Vactor D. The guanine nucleotide exchange factor trio mediates axonal development in the Drosophila embryo. Neuron. 2000;26:93–106.PubMed CrossRef
  11.McPherson CE, Eipper BA, Mains RE. Multiple novel isoforms of Trio are expressed in the developing rat brain. Gene. 2005;347:125–35.PubMed CrossRef
  12.Blangy A, Vignal E, Schmidt S, Debant A, Gauthier-Rouviere C, Fort P. TrioGEF1 controls Rac- and Cdc42-dependent cell structures through the direct activation of rhoG. J Cell Sci. 2000;113(Pt 4):729–39.PubMed
  13.Zheng M, Simon R, Mirlacher M, Maurer R, Gasser T, Forster T, et al. TRIO amplification and abundant mRNA expression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer. Am J Pathol. 2004;165:63–9.PubMed PubMedCentral CrossRef
  14.Adamowicz M, Radlwimmer B, Rieker RJ, Mertens D, Schwarzbach M, Schraml P, et al. Frequent amplifications and abundant expression of TRIO, NKD2, and IRX2 in soft tissue sarcomas. Genes Chromosomes Cancer. 2006;45:829–38.PubMed CrossRef
  15.Lane J, Martin TA, Mansel RE, Jiang WG. The expression and prognostic value of the guanine nucleotide exchange factors (GEFs) Trio, Vav1 and TIAM-1 in human breast cancer. Int Semin Surg Oncol. 2008;5:23.PubMed PubMedCentral CrossRef
  16.Salhia B, Tran NL, Chan A, Wolf A, Nakada M, Rutka F, et al. The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma. Am J Pathol. 2008;173:1828–38.PubMed PubMedCentral CrossRef
  17.Cao Z, Fu B, Deng B, Zeng Y, Wan X, Qu L. Overexpression of chemokine (C-X-C) ligand 1 (CXCL1) associated with tumor progression and poor prognosis in hepatocellular carcinoma. Cancer Cell Int. 2014;14:86.PubMed PubMedCentral CrossRef
  18.Qu L, Deng B, Zeng Y, Cao Z. Decreased expression of the Nkx2.8 gene correlates with tumor progression and a poor prognosis in HCC cancer. Cancer Cell Int. 2014;14:28.PubMed PubMedCentral CrossRef
  19.Yano T, Yamazaki Y, Adachi M, Okawa K, Fort P, Uji M, et al. Tara up-regulates E-cadherin transcription by binding to the Trio RhoGEF and inhibiting Rac signaling. J Cell Biol. 2011;193:319–32.PubMed PubMedCentral CrossRef
  20.McClung HM, Golembieski WA, Schultz CR, Jankowski M, Schultz LR, Rempel SA. Deletion of the SPARC acidic domain or EGF-like module reduces SPARC-induced migration and signaling through p38 MAPK/HSP27 in glioma. Carcinogenesis. 2012;33:275–84.PubMed PubMedCentral CrossRef
  21.George MD, Wine RN, Lackford B, Kissling GE, Akiyama SK, Olden K, et al. P38 mitogen-activated protein kinase interacts with vinculin at focal adhesions during fatty acid-stimulated cell adhesion. Biochem Cell Biol. 2013;91:404–18.PubMed PubMedCentral CrossRef
  22.Reddy KB, Nabha SM, Atanaskova N. Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev. 2003;22:395–403.PubMed CrossRef
  23.Keshet Y, Seger R. The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions. Methods Mol Biol. 2010;661:3–38.PubMed CrossRef
  24.Aznar S, Lacal JC. Rho signals to cell growth and apoptosis. Cancer Lett. 2001;165:1–10.PubMed CrossRef
  25.Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.PubMed CrossRef
  26.Ma Y, She XG, Ming YZ, Wan QQ. MiR-24 promotes the proliferation and invasion of HCC cells by targeting SOX7. Tumour Biol. 2014;35:10731–6.PubMed CrossRef
  27.Canel M, Serrels A, Frame MC, Brunton VG. E-cadherin-integrin crosstalk in cancer invasion and metastasis. J Cell Sci. 2013;126:393–401.PubMed CrossRef
  28.Galliher AJ, Schiemann WP. Src phosphorylates Tyr284 in TGF-beta type II receptor and regulates TGF-beta stimulation of p38 MAPK during breast cancer cell proliferation and invasion. Cancer Res. 2007;67:3752–8.PubMed CrossRef
  
• 作者单位：Bin Wang (1)
  JiaQing Fang (2)
  Lei Qu (1)
  Zhongwei Cao (3)
  JianGuo Zhou (4)
  Biao Deng (1)
  
  1. Department of General Surgery, Shanghai First People’s Hospital, Shanghai Jiao Tong University, 100 Haining Road, Shanghai, 200080, China
  2. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China
  3. Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, 100 Haining Road, Shanghai, 200080, China
  4. Department of General Surgery, Shanghai Sijing Hospital, 389 Sitong Road, Shanghai, 201601, China
  
• 刊物主题：Cancer Research;
• 出版者：Springer Netherlands
• ISSN：1423-0380

文摘

Triple functional domain protein (TRIO) is an evolutionarily conserved Dbl family guanine nucleotide exchange factors (GEFs) involved in cell proliferation and progression of some types of cancer. However, the expression and prognostic role of TRIO in hepatocellular carcinoma (HCC) have not yet been determined. Therefore, we attempted to determine the impact of TRIO on the clinical outcome of HCC patients to further identify its role in HCC. TRIO expression was examined using quantitative real-time PCR (qRT-PCR) and Western blotting in nonmalignant liver cells, HCC cells, and 93 paired of HCC tissues and adjacent noncancerous tissues. Statistical analyses were used to assess associations between TRIO expression and clinicopathological and prognostic factors. Small interfering RNA (siRNA)-mediated TRIO inhibition was performed in Hep3B and Huh7 cells to elucidate its roles in HCC. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was employed to measure cell proliferation, and apoptosis assay was analyzed by flow cytometry, respectively. Adhesion and transwell invasion assay were performed to determine the invasion ability of HCC cells in vitro. TRIO was significantly upregulated in the HCC cell lines and tissues compared with the nonmalignant liver cells and adjacent noncancerous liver tissues. In addition, high TRIO expression level associated with lymph node metastasis (P = 0.0183), clinical tumor node metastasis (TNM) stage (P = 0.0.0106), and decrease in overall survival (OS) (P = 0.017). Knockdown of TRIO on Hep3B and Huh7 cell lines suppressed cell proliferation and migration and induced apoptosis. Furthermore, silencing TRIO expression led to decrease of ras-related C3 botulinum toxin substrate 1 (Rac1), p-P38, B cell lymphoma 2 (BCL-2), and matrix metallopeptidase 9 (MMP-9). Our results demonstrated that TRIO protein expression is elevated and associated with a worse over survival rates in patients with HCC. Aberrant expression of TRIO might play an important role in HCC through promoting cell proliferation and invasion, and TRIO may be a novel therapeutic target for the treatment of HCC.