Evaluation of the Association between Androgen Receptor and AURKA and Its Prognostic Value in Gastric Cancer
Background: It is well-known that Aurora kinase A (AURKA) shows oncogenic properties in various tumor types including gastric cancer (GC). Moreover, previous studies have demonstrated that AURKA has a specific androgen receptor (AR) binding site in its promoter; thus, it could be regulated by AR. Since it has been shown that AR overexpresses in gastric cancer (GC) as a male-predominant tumor, the goal of this study was to evaluate the association between AR and AURKA and its prognostic value in GC patients.
Materials and Methods: We assessed the expression profile of AURKA in 60 fresh GC and adjacent non-tumor tissues and 50 normal gastric specimen by qRT-PCR, and investigated the association of AURKA expression with clinicopathological features. Furthermore, we evaluated possible correlation between AURKA and AR to elucidate a novel prognostic marker using Kaplan-Meier method and Cox regression model.
Conclusion: Among GC patients, 65% (39/60) overexpressed AURKA relative to normal gastric tissues. AURKA overexpression was significantly correlated with the AR overexpression in GC patients. Although AURKA expression alone was not remarkably associated with poor outcome, we provided some evidence that combined evaluation of AURKA and AR expression could independently predict survival of GC patients adjusted for other variables (HR=1.7, CI=1.314-3.833 p=0.042).
Conclusion: These results indicate that AR and AURKA may crosstalk to promote GC progression. Our findings have clinical importance because they suggest simultaneous assessment of AURKA and AR expression as a novel potential prognostic marker.
2. Lens SM, Voest EE, Medema RH. Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer. 2010; 10(12):825-41.
3. Kumano M, Miyake H, Terakawa T, et al. Suppressed tumour growth and enhanced chemosensitivity by RNA interference targeting Aurora-A in the PC3 human prostate cancer model. BJU Int. 2010; 106(1):121-7.
4. Zhou H, Kuang J, Zhong L, et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet. 1998; 20(2):189-93.
5. Buschhorn HM, Klein RR, Chambers SM, et al. Aurora-A over-expression in high-grade PIN lesions and prostate cancer. Prostate. 2005; 64(4):341-6.
6. Katsha A, Soutto M, Sehdev V, et al. Aurora kinase A promotes inflammation and tumorigenesis in mice and human gastric neoplasia. Gastroenterology. 2013; 145(6):1312-22.e1-8.
7. Mesic A, Rogar M, Hudler P, et al. Association of the AURKA and AURKC gene polymorphisms with an increased risk of gastric cancer. IUBMB Life. 2016; 68(8):634-44.
8. Zhou X, Wang P, Zhao H. The association between AURKA gene rs2273535 polymorphism and gastric cancer risk in a Chinese population. Front Physiol. 2018; 9:1124.
9. Ma WL, Hsu CL, Wu MH, et al. Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma. Gastroenterology. 2008; 135(3):947-55, 955.e1-5.
10. Li Y, Izumi K, Miyamoto H. The role of the androgen receptor in the development and progression of bladder cancer. Jpn J Clin Oncol. 2012; 42(7):569-77.
11. Konduri S, Schwarz MA, Cafasso D, et al. Androgen receptor blockade in experimental combination therapy of pancreatic cancer. J Surg Res. 2007; 142(2):378-86.
12. Tang W, Liu R, Yan Y, et al. Expression of estrogen receptors and androgen receptor and their clinical significance in gastric cancer. Oncotarget. 2017; 8(25):40765-40777.
13. Tian Y, Wan H, Lin Y, et al. Androgen receptor may be responsible for gender disparity in gastric cancer. Med Hypotheses. 2013; 80(5):672-4.
14. Waltering KK, Helenius MA, Sahu B, et al. Increased expression of androgen receptor sensitizes prostate cancer cells to low levels of androgens. Cancer Res. 2009; 69(20):8141-9.
15.Ylipää A, Kivinummi K, Kohvakka A, et al. Transcriptome Sequencing Reveals PCAT5 as a Novel ERG-Regulated Long Noncoding RNA in Prostate Cancer. Cancer Res. 2015; 75(19):4026-31.
16. Kivinummi K, Urbanucci A, Leinonen K, et al. The expression of AURKA is androgen regulated in castration-resistant prostate cancer. Sci Rep. 2017; 7(1):17978.
17. Hassani S, Ghaffari P, Chahardouli B, et al. Disulfiram/copper causes ROS levels alteration, cell cycle inhibition, and apoptosis in acute myeloid leukaemia cell lines with modulation in the expression of related genes. Biomed Pharmacother. 2018; 99:561-569.
18. Sehdev V, Katsha A, Arras J, et al. HDM2 regulation by AURKA promotes cell survival in gastric cancer. Clin Cancer Res. 2014; 20(1):76-86.
19. Katsha A, Arras J, Soutto M, et al. AURKA regulates JAK2-STAT3 activity in human gastric and esophageal cancers. Mol Oncol. 2014; 8(8):1419-28.
20. Liu X, Li Z, Song Y, et al. AURKA induces EMT by regulating histone modification through Wnt/beta-catenin and PI3K/Akt signaling pathway in gastric cancer. Oncotarget. 2016; 7(22):33152-64.
21. Feng H, Cheng AS, Tsang DP, et al. Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives beta-catenin/T cell factor-dependent hepatocarcinogenesis. J Clin Invest. 2011; 121(8):3159-75.
22. Zhang BG, Du T, Zang MD, et al. Androgen receptor promotes gastric cancer cell migration and invasion via AKT-phosphorylation dependent upregulation of matrix metalloproteinase 9. Oncotarget; 2014; 5(21): 10584-95.
23. Kominea A, Konstantinopoulos PA, Kapranos N, et al. Androgen receptor (AR) expression is an independent unfavorable prognostic factor in gastric cancer. J Cancer Res Clin Oncol. 2004; 130(5):253-8.
24. Pomerantz MM, Li F, Takeda DY, et al. The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nat Genet. 2015; 47(11):1346-51.
25. Urbanucci A, Sahu B, Seppälä J, et al. Overexpression of androgen receptor enhances the binding of the receptor to the chromatin in prostate cancer. Oncogene. 2012; 31(17):2153-63.