Title ITPKA expression is a novel prognostic factor in hepatocellularcarcinoma

Background: Inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) has recently been found to be implicated in the tumor progression of various cancers. However, the expression and the prognostic value of ITPKA in hepatocellular carcinoma (HCC) remains unexplored. The aim of this study is to investigate the clinical significance of ITPKA expression in HCC. Methods: We determined the expression level of ITPKA in 135 cases of HCC tissues and the matched adjacent nontumorous tissues by quantitative real-time RT-PCR. The correlation between ITPKA expression and prognosis of HCC patients was further evaluated by univariate and multivariate analysis. Multivariate analysis of the prognostic factors was performed with Cox proportional hazards model. Results: Up-regulation of ITPKA occurred in 48.9 % of primary HCCs compared with their nontumor counterparts (P < 0.001). In addition, high expression of ITPKA was significantly associated with vascular invasion (P = 0.001) and TNM stage (P = 0.005). Kaplan–Meier analysis showed that the 5-year overall survival (OS) and relapse-free survival (RFS) rate in the group with high expression of ITPKA is poorer than that in low expression group (32.2 and 26.8 % versus 59.2 and 57.7 %). Univariate and multivariate analyses revealed that ITPKA was an independent prognostic factor for OS and RFS. Moreover, Stratified analysis revealed that its prognostic significance still existed within the subgroup of patients with early clinical stage (TNM stage I) or normal serum AFP level (≤25 μg/L). Conclusion: Our data indicated that ITPKA expression was significantly up-regulated in HCC and could serve as a potential novel prognostic biomarker for HCC patients after surgery.

[1]  Qi Liu,et al.  Gene and isoform expression signatures associated with tumor stage in kidney renal clear cell carcinoma , 2013, BMC Systems Biology.

[2]  Yun-fei Yuan,et al.  Identification of MACC1 as a novel prognostic marker in hepatocellular carcinoma , 2011, Journal of Translational Medicine.

[3]  U. Schumacher,et al.  Functional role of inositol‐1,4,5‐trisphosphate‐3‐kinase‐A for motility of malignant transformed cells , 2011, International journal of cancer.

[4]  N. Prevarskaya,et al.  Calcium in tumour metastasis: new roles for known actors , 2011, Nature Reviews Cancer.

[5]  Joon-Oh Park,et al.  Prognostic Factors in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib: A Retrospective Comparison with Previously Known Prognostic Models , 2011, Oncology.

[6]  Udo Schumacher,et al.  Inositol 1,4,5-Trisphosphate 3-Kinase-A Is a New Cell Motility-promoting Protein That Increases the Metastatic Potential of Tumor Cells by Two Functional Activities* , 2009, The Journal of Biological Chemistry.

[7]  M. Schell,et al.  Neuronal IP3 3-kinase is an F-actin-bundling protein: role in dendritic targeting and regulation of spine morphology. , 2009, Molecular biology of the cell.

[8]  Woong Sun,et al.  Inositol 1,4,5-Trisphosphate 3-Kinase A Functions As a Scaffold for Synaptic Rac Signaling , 2009, The Journal of Neuroscience.

[9]  C. Elling,et al.  Ins(1,4,5)P3 3-kinase-A overexpression induces cytoskeletal reorganization via a kinase-independent mechanism. , 2008, The Biochemical journal.

[10]  Joris R Delanghe,et al.  Diagnosing and monitoring hepatocellular carcinoma with alpha-fetoprotein: new aspects and applications. , 2008, Clinica chimica acta; international journal of clinical chemistry.

[11]  S. Schurmans,et al.  Inositol 1,3,4,5-tetrakisphosphate controls proapoptotic Bim gene expression and survival in B cells , 2007, Proceedings of the National Academy of Sciences.

[12]  M. Konstadoulakis,et al.  Strategies for the management of hepatocellular carcinoma , 2007, Nature Clinical Practice Oncology.

[13]  T. Onda,et al.  Down-regulation of 1D-myo-inositol 1,4,5-trisphosphate 3-kinase A protein expression in oral squamous cell carcinoma. , 2006, International journal of oncology.

[14]  M. Schell,et al.  The regulation and function of inositol 1,4,5-trisphosphate 3-kinases , 2006, Advances in enzyme regulation.

[15]  Alexander J Stokes,et al.  Fcepsilon RI control of Ras via inositol (1,4,5) trisphosphate 3-kinase and inositol tetrakisphosphate. , 2006, Cellular signalling.

[16]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[17]  M. Sherman Hepatocellular carcinoma: epidemiology, risk factors, and screening. , 2005, Seminars in liver disease.

[18]  A. R.,et al.  Review of literature , 1951, American Potato Journal.

[19]  J. York,et al.  A Molecular Basis for Inositol Polyphosphate Synthesis in Drosophila melanogaster* , 2004, Journal of Biological Chemistry.

[20]  S. Thorgeirsson,et al.  Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling , 2004, Hepatology.

[21]  L. Qin,et al.  Recent progress in predictive biomarkers for metastatic recurrence of human hepatocellular carcinoma: a review of the literature , 2004, Journal of Cancer Research and Clinical Oncology.

[22]  S. Fan,et al.  Hepatectomy for hepatocellular carcinoma: Patient selection and postoperative outcome , 2004, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[23]  S. Shears How versatile are inositol phosphate kinases? , 2004, The Biochemical journal.

[24]  B. Daniele,et al.  Alpha-fetoprotein and ultrasonography screening for hepatocellular carcinoma. , 2004, Gastroenterology.

[25]  M. Monden,et al.  Diagnosis of intrahepatic metastasis and multicentric carcinogenesis by microsatellite loss of heterozygosity in patients with multiple and recurrent hepatocellular carcinomas. , 2003, Journal of hepatology.

[26]  Peter Thorn,et al.  Calcium signalling: IP3 rises again… and again , 2001, Current Biology.

[27]  R. Irvine Inositol phosphates: Does IP4 run a protection racket? , 2001, Current Biology.

[28]  A. M. Riley,et al.  InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase , 2000, Nature.

[29]  X. Pesesse,et al.  The diversity and possible functions of the inositol polyphosphate 5-phosphatases. , 1998, Biochimica et biophysica acta.

[30]  Peter J. Cullen,et al.  Identification of a specific lns(l,3,4,5)P4-binding protein as a member of the GAP1 family , 1995, Nature.

[31]  C. D’Santos,et al.  Tissue- and cell-specific expression of Ins(1,4,5)P3 3-kinase isoenzymes. , 1995, The Biochemical journal.

[32]  M. Berridge Inositol trisphosphate and calcium signalling , 1993, Nature.

[33]  Potassium channels regulated by inositol 1,3,4,5-tetrakisphosphate and internal calcium in DDT1 MF-2 smooth muscle cells. , 1991, The Journal of biological chemistry.

[34]  O. Petersen,et al.  Synergism of inositol trisphosphate and tetrakisphosphate in activating Ca2+-dependent K+ channels , 1987, Nature.