Decreased expression of BTG3 was linked to carcinogenesis, aggressiveness, and prognosis of ovarian carcinoma

B-cell translocation gene 3 (BTG3) is a member of the BTG family which inhibits cell proliferation, metastasis, and angiogenesis, and also regulates cell-cycle progression and differentiation in a variety of cell types. However, there is no study to analyze BTG3 expression in epithelial ovarian carcinoma (EOC). Here, we investigated the expression of BTG3 in EOC carcinogenesis and subsequent progression. BTG3 mRNA expression was detected by real-time RT–PCR in ovarian benign and malignant tumors. The expression of BTG3 protein was examined by immunohistochemistry on tissue microarrays containing ovarian normal tissue, benign and borderline epithelial ovarian tumors, and EOCs. Relationships of BTG3 with both EOC clinicopathology and prognosis were analyzed statistically. The expression of BTG3 protein was also evaluated in ovarian normal tissue, benign tumors, and EOCs by western blot. The BTG3 mRNA expression level was higher in ovarian normal tissue and benign tumors than that in borderline, primary, and metastatic carcinoma (p < 0.05), and was negatively correlated with dedifferentiation and FIGO staging of EOC (p < 0.05). Using western blot, BTG3 protein was found lower in EOCs compared to the normal and benign tumors (p < 0.05), and poorly differentiated EOCs showed lower BTG3 expression than well-differentiated and moderately differentiated EOCs (p < 0.05). Immunohistochemically, BTG3 protein expression was statistically lower in EOCs than normal tissue and benign tumors (p < 0.05). EOC patients with low BTG3 protein expression showed a higher incidence of metastasis (p = 0.020), poor differentiation (p = 0.030), and shorter disease-free time and overall survival time (p < 0.05). By using Cox’s proportional hazard model, BTG3 protein expression and FIGO staging were independent prognostic factors for both disease-free time and overall survival time of EOCs (p < 0.05). It was suggested that down-regulated BTG3 expression might play roles in the pathogenesis and aggressiveness of EOC. BTG3 protein expression may be considered as a good marker to indicate the favorable prognosis of EOCs.

[1]  S. Shieh,et al.  The candidate tumor suppressor BTG3 is a transcriptional target of p53 that inhibits E2F1 , 2007, The EMBO journal.

[2]  G. Rodriguez,et al.  Ovarian cancer: etiology, risk factors, and epidemiology. , 2012, Clinical obstetrics and gynecology.

[3]  A. Jemal,et al.  Cancer Statistics, 2007 , 2007, CA: a cancer journal for clinicians.

[4]  H. Yokosawa,et al.  Antiproliferative proteins of the BTG/Tob family are degraded by the ubiquitin-proteasome system. , 2002, European journal of biochemistry.

[5]  K. Tsuneyama,et al.  Improved 1-h rapid immunostaining method using intermittent microwave irradiation: practicability based on 5 years application in Toyama Medical and Pharmaceutical University Hospital , 2004, Modern Pathology.

[6]  T. Shibahara,et al.  Analysis of the ANA gene as a candidate for the chromosome 21q oral cancer susceptibility locus , 2001, British Journal of Cancer.

[7]  S. Shieh,et al.  Loss of the candidate tumor suppressor BTG3 triggers acute cellular senescence via the ERK–JMJD3–p16INK4a signaling axis , 2012, Oncogene.

[8]  R. Bast,et al.  A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. , 1983, The New England journal of medicine.

[9]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[10]  G. S. Winkler,et al.  The Anti-Proliferative Activity of BTG/TOB Proteins Is Mediated via the Caf1a (CNOT7) and Caf1b (CNOT8) Deadenylase Subunits of the Ccr4-Not Complex , 2012, PloS one.

[11]  K. Miyazono,et al.  ANA Deficiency Enhances Bone Morphogenetic Protein-induced Ectopic Bone Formation via Transcriptional Events* , 2009, Journal of Biological Chemistry.

[12]  J. Yokota,et al.  Deficiency of antiproliferative family protein Ana correlates with development of lung adenocarcinoma , 2009, Cancer science.

[13]  R. Berkowitz,et al.  Correlates of the preoperative level of CA125 at presentation of ovarian cancer. , 2010, Gynecologic oncology.

[14]  A. Sood,et al.  Preoperative CA 125 Levels: An Independent Prognostic Factor for Epithelial Ovarian Cancer , 2002, Obstetrics and gynecology.

[15]  R. Dahiya,et al.  Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B‐Cell translocation gene 3 in prostate cancer , 2009, Cancer.

[16]  Rajvir Dahiya,et al.  MicroRNA‐205–directed transcriptional activation of tumor suppressor genes in prostate cancer , 2010, Cancer.

[17]  R. Dahiya,et al.  BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. , 2009, Carcinogenesis.

[18]  Z. Rahmani.  APRO4 negatively regulates Src tyrosine kinase activity in PC12 cells , 2006, Journal of Cell Science.

[19]  L. Duret,et al.  Cloning of the mouse BTG3 gene and definition of a new gene family (the BTG family) involved in the negative control of the cell cycle , 1997, Leukemia.

[20]  Toru Suzuki,et al.  Nuclear localization of Tob is important for regulation of its antiproliferative activity , 2004, Oncogene.

[21]  Takahisa Nakamura,et al.  Association of ANA, a Member of the Antiproliferative Tob Family Proteins, with a Cafl Component of the CCR4 Transcriptional Regulatory Complex , 2001, Japanese journal of cancer research : Gann.

[22]  C A SALVATORE,et al.  [Carcinoma of the ovary]. , 1960, Anais brasileiros de ginecologia.

[23]  D. Patterson,et al.  Methylation-mediated downregulation of the B-cell translocation gene 3 (BTG3) in breast cancer cells. , 2008, Gene expression.

[24]  Bernd Holleczek,et al.  Survival of ovarian cancer patients in Germany in the early 21st century: a period analysis by age, histology, laterality, and stage , 2013, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[25]  C. Kosary.  FIGO stage, histology, histologic grade, age and race as prognostic factors in determining survival for cancers of the female gynecological system: an analysis of 1973-87 SEER cases of cancers of the endometrium, cervix, ovary, vulva, and vagina. , 1994, Seminars in surgical oncology.

[26]  Ping Liu,et al.  CD105/Ki67 Coexpression Correlates With Tumor Progression and Poor Prognosis in Epithelial Ovarian Cancer , 2011, International Journal of Gynecologic Cancer.

[27]  Vinay Varadan,et al.  DNA methylation patterns in luminal breast cancers differ from non‐luminal subtypes and can identify relapse risk independent of other clinical variables , 2011, Molecular oncology.

[28]  Szilard Nemes,et al.  Up-regulation of cell cycle arrest protein BTG2 correlates with increased overall survival in breast cancer, as detected by immunohistochemistry using tissue microarray , 2010, BMC Cancer.

[29]  G. S. Winkler,et al.  The mammalian anti‐proliferative BTG/Tob protein family , 2010, Journal of cellular physiology.