nach oben

Clinical and Translational Oncology

Erschienen in:

01.01.2014 | Research Article

Overexpression of retinoic acid-induced protein 3 predicts poor prognosis for hepatocellular carcinoma

verfasst von: J. Zheng, X. Guo, X. Gao, H. Liu, Y. Tu, Y. Zhang

Erschienen in: Clinical and Translational Oncology | Ausgabe 1/2014

Einloggen, um Zugang zu erhalten

Abstract

Aim

To investigate clinical significance of retinoic acid-induced protein 3 (RAI3) in hepatocellular carcinoma (HCC).

Methods

Expression of RAI3 at both mRNA and protein levels in tumor, para-tumor and normal liver tissues was detected in 106 HCC patients by real-time quantitative RT-PCR, Western blot and immunohistochemistry. Then, the correlation of RAI3 expression with clinicopathological characteristics and survivals of HCC patients was analyzed.

Results

Our data first found that RAI3 mRNA and protein expression were both significantly higher in HCC than in para-tumor (both P < 0.001) and normal liver tissues (both P < 0.001). The correlation analysis showed a positive correlation between RAI3 mRNA level and RAI3 protein level in HCC tissues (r = 0.8, P < 0.001). Immunohistochemistry data also revealed that overexpression of RAI3 was present in 73.6 % (78/106) of HCC tissues. In addition, high RAI3 protein expression was correlated with advanced TNM stage (P = 0.001), high serum AFP (P = 0.008), vascular invasion (P = 0.01) and tumor recurrence (P = 0.008). Moreover, HCC patients with overexpression of RAI3 had significantly shorter overall (P = 0.01) and disease-free survival (P = 0.01). Furthermore, multivariate analysis showed that overexpression of RAI3 was an independent prognostic factor for both overall (P = 0.02) and disease-free survival (P = 0.03) in HCC.

Conclusion

Our data for the first time provide a basis for the concept that overexpression of RAI3 may contribute to the malignant progression of HCC and predict poor prognosis for patients with this deadly disease after curative hepatectomy. RAI3 might be an important marker for tumor progression and prognosis, as well as a potential therapeutic target of HCC.

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRef

Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–36.PubMedCrossRef

El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.PubMedCrossRef

Jörissen H, Bektas N, Dahl E, Hartmann A, ten Haaf A, Di Fiore S, et al. Production and characterisation of monoclonal antibodies against RAI3 and its expression in human breast cancer. BMC Cancer. 2009;9:200.PubMedCentralPubMedCrossRef

Chen Y, Deng J, Fujimoto J, Kadara H, Men T, Lotan D, et al. Gprc5a deletion enhances the transformed phenotype in normal and malignant lung epithelial cells by eliciting persistent Stat3 signaling induced by autocrine leukemia inhibitory factor. Cancer Res. 2010;70:8917–26.PubMedCentralPubMedCrossRef

Robbins MJ, Michalovich D, Hill J, Calver AR, Medhurst AD, Gloger I, et al. Molecular cloning and characterization of two novel retinoic acid-inducible orphan G-protein-coupled receptors (GPRC5B and GPRC5C). Genomics. 2000;67:8–18.PubMedCrossRef

Tao Q, Cheng Y, Clifford J, Lotan R. Characterization of the murine orphan G-protein-coupled receptor gene Rai3 and its regulation by retinoic acid. Genomics. 2004;83:270–80.PubMedCrossRef

Fujimoto J, Kadara H, Garcia MM, Kabbout M, Behrens C, Liu DD, et al. G-protein coupled receptor family C, group 5, member A (GPRC5A) expression is decreased in the adjacent field and normal bronchial epithelia of patients with chronic obstructive pulmonary disease and non-small-cell lung cancer. J Thorac Oncol. 2012;7:1747–54.PubMedCentralPubMedCrossRef

Nagahata T, Sato T, Tomura A, Onda M, Nishikawa K, Emi M. Identification of RAI3 as a therapeutic target for breast cancer. Endocr Relat Cancer. 2005;12:65–73.PubMedCrossRef

10.

Cheng L, Yang S, Yang Y, Zhang W, Xiao H, Gao H, et al. Global gene expression and functional network analysis of gastric cancer identify extended pathway maps and GPRC5A as a potential biomarker. Cancer Lett. 2012;326:105–13.PubMedCrossRef

11.

Zougman A, Hutchins GG, Cairns DA, Verghese E, Perry SL, Jayne DG, et al. Retinoic acid-induced protein 3: identification and characterisation of a novel prognostic colon cancer biomarker. Eur J Cancer. 2013;49:531–9.PubMedCrossRef

12.

Wang W, Zhao LJ, Yang Y, Wang RY, Ren H, Zhao P, et al. Retinoic acid induced 16 enhances tumorigenesis and serves as a novel tumor marker for hepatocellular carcinoma. Carcinogenesis. 2012;33:2578–85.PubMedCrossRef

13.

Guo XD, Xiong L, Zou L, Zhao JM. Upregulation of bone morphogenetic protein 4 is associated with poor prognosis in patients with hepatocellular carcinoma. Pathol Oncol Res. 2012;18:635–40.PubMedCrossRef

14.

Hirano M, Zang L, Oka T, Ito Y, Shimada Y, Nishimura Y, et al. Novel reciprocal regulation of cAMP signaling and apoptosis by orphan G-protein-coupled receptor GPRC5A gene expression. Biochem Biophys Res Commun. 2006;351:185–91.PubMedCrossRef

15.

Acquafreda T, Soprano KJ, Soprano DR. GPRC5A: a potential tumor suppressor and oncogene. Cancer Biol Ther. 2009;8:963–5.PubMedCrossRef

16.

Connolly R, Nguyen NK, Sukumar S. Molecular Pathways: Current Role and Future Directions of the Retinoic Acid Pathway In Cancer Prevention and Treatment. Clin Cancer Res. 2013 (in press).

17.

Shim E, Yeum KJ, Tang G, Ahn SH, Hwang J, Lee-Kim YC. Retinoids, carotenoids, and tocopherols in breast adipose tissue and serum of benign breast disease and breast cancer patients. Nutr Cancer. 2012;64:956–63.PubMedCrossRef

18.

Garattini E, Paroni G, Terao M. Retinoids and breast cancer: new clues to increase their activity and selectivity. Breast Cancer Res. 2012;14:111.PubMedCrossRef

19.

Kadara H, Fujimoto J, Men T, Ye X, Lotan D, Lee JS, et al. A Gprc5a tumor suppressor loss of expression signature is conserved, prevalent, and associated with survival in human lung adenocarcinomas. Neoplasia. 2010;12:499–505.PubMedCentralPubMed

20.

Deng J, Fujimoto J, Ye XF, Men TY, Van Pelt CS, Chen YL, et al. Knockout of the tumor suppressor gene Gprc5a in mice leads to NF-kappaB activation in airway epithelium and promotes lung inflammation and tumorigenesis. Cancer Prev Res (Phila). 2010;3:424–37.PubMedCrossRef

21.

Wu Q, Ding W, Mirza A, Van Arsdale T, Wei I, Bishop WR, et al. Integrative genomics revealed RAI3 is a cell growth-promoting gene and a novel P53 transcriptional target. J Biol Chem. 2005;280:12935–43.PubMedCrossRef

Titel: Overexpression of retinoic acid-induced protein 3 predicts poor prognosis for hepatocellular carcinoma
verfasst von: J. Zheng
X. Guo
X. Gao
H. Liu
Y. Tu
Y. Zhang
Publikationsdatum: 01.01.2014
Verlag: Springer Milan
Erschienen in: Clinical and Translational Oncology / Ausgabe 1/2014
Print ISSN: 1699-048X
Elektronische ISSN: 1699-3055
DOI: https://doi.org/10.1007/s12094-013-1040-2

Springer Medizin

Overexpression of retinoic acid-induced protein 3 predicts poor prognosis for hepatocellular carcinoma

Abstract