Overexpression of SLC34A2 is an Independent Prognostic Indicator in Bladder Cancer and Its Depletion Suppresses Tumor Growth Via Decreasing C-Myc Expression and Transcriptional Activity

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2017 Feb 3

PMID 28151475

Citations 13

Authors

Wen Ye

Cui Chen

Ying Gao

Zou-Shan Zheng

Yi Xu

Miao Yun

Hui-Wen Weng

Dan Xie

Sheng Ye

Jia-Xing Zhang

Affiliations

Soon will be listed here.

Abstract

Solute carrier family 34 member 2 (SLC34A2), a pH-sensitive sodium-dependent phosphate transporter, is associated with several human cancers. In this study, we investigate the clinical significance of SLC34A2 and its function in human bladder cancer (BC). The expression dynamics of SLC34A2 were examined in two independent cohorts of BC samples by quantitative PCR, western blotting and immunohistochemical staining. In the training cohort (156 cases), we applied the X-tile program software to assess the optimal cutoff points for biomarkers in order to accurately classify patients according to clinical outcome. In the validation cohort (130 cases), the cutoff score derived from X-title analysis was investigated to determine the association of SLC34A2 expression with survival outcome. A series of in vitro and in vivo assays were then performed to elucidate the function of SLC34A2 in BC and its underlying mechanisms. Results showed that SLC34A2 was significantly upregulated in BC cell lines and clinical samples. In both two cohorts of BC samples, high expression of SLC34A2 was associated with large tumor size, advanced T status and poor patients' survival. The depletion of SLC34A2 in BC suppressed cellular viability, colony formation and anchorage-independent growth in vitro, and inhibited xenograft tumor growth in vivo, whereas overexpression of SLC34A2 had the converse effect. Simultaneously, downregulation of SLC34A2 decreased the transcriptional activity and protein expression level of c-Myc in BC cells, whereas restoration of c-Myc expression could compromise the anti-proliferation effect of SLC34A2 depletion. Furthermore, miR-214 was proved as a negative regulator of SLC34A2. Our present study illustrated that SLC34A2 has an important role in promoting proliferation and tumorigenicity of BC, and may represent a novel therapeutic target for this disease.

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References

Stine Z, Walton Z, Altman B, Hsieh A, Dang C . MYC, Metabolism, and Cancer. Cancer Discov. 2015; 5(10):1024-39. PMC: 4592441. DOI: 10.1158/2159-8290.CD-15-0507. View

Wang L, Fu D, Qiu Y, Xing X, Xu F, Han C . Genome-wide screening and identification of long noncoding RNAs and their interaction with protein coding RNAs in bladder urothelial cell carcinoma. Cancer Lett. 2014; 349(1):77-86. DOI: 10.1016/j.canlet.2014.03.033. View

Ricketts C, Morris M, Gentle D, Brown M, Wake N, Woodward E . Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma. Epigenetics. 2012; 7(3):278-90. PMC: 3335951. DOI: 10.4161/epi.7.3.19103. View

Yin B, Kiyamova R, Chua R, Caballero O, Gout I, Gryshkova V . Monoclonal antibody MX35 detects the membrane transporter NaPi2b (SLC34A2) in human carcinomas. Cancer Immun. 2008; 8:3. PMC: 2935786. View

Kiyamova R, Gryshkova V, Ovcharenko G, Lituyev D, Malyuchik S, Usenko V . Development of monoclonal antibodies specific for the human sodium-dependent phosphate co-transporter NaPi2b. Hybridoma (Larchmt). 2008; 27(4):277-84. DOI: 10.1089/hyb.2008.0015. View

Hashimoto M, Wang D, Kamo T, Zhu Y, Tsujiuchi T, Konishi Y . Isolation and localization of type IIb Na/Pi cotransporter in the developing rat lung. Am J Pathol. 2000; 157(1):21-7. PMC: 1850224. DOI: 10.1016/S0002-9440(10)64512-9. View

Dos Santos M, Yeda F, Tsuruta L, Horta B, Pimenta Jr A, Degaki T . Rebmab200, a humanized monoclonal antibody targeting the sodium phosphate transporter NaPi2b displays strong immune mediated cytotoxicity against cancer: a novel reagent for targeted antibody therapy of cancer. PLoS One. 2013; 8(7):e70332. PMC: 3729455. DOI: 10.1371/journal.pone.0070332. View

Dang C . MYC on the path to cancer. Cell. 2012; 149(1):22-35. PMC: 3345192. DOI: 10.1016/j.cell.2012.03.003. View

Yoshino H, Chiyomaru T, Enokida H, Kawakami K, Tatarano S, Nishiyama K . The tumour-suppressive function of miR-1 and miR-133a targeting TAGLN2 in bladder cancer. Br J Cancer. 2011; 104(5):808-18. PMC: 3048214. DOI: 10.1038/bjc.2011.23. View

10.

Bender Kim C, Jackson E, Woolfenden A, Lawrence S, Babar I, Vogel S . Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell. 2005; 121(6):823-35. DOI: 10.1016/j.cell.2005.03.032. View

11.

Hong S, Minai-Tehrani A, Chang S, Jiang H, Lee S, Lee A . Knockdown of the sodium-dependent phosphate co-transporter 2b (NPT2b) suppresses lung tumorigenesis. PLoS One. 2013; 8(10):e77121. PMC: 3806752. DOI: 10.1371/journal.pone.0077121. View

12.

Camp R, Dolled-Filhart M, Rimm D . X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004; 10(21):7252-9. DOI: 10.1158/1078-0432.CCR-04-0713. View

13.

Chen W, Zheng R, Zeng H, Zhang S, He J . Annual report on status of cancer in China, 2011. Chin J Cancer Res. 2015; 27(1):2-12. PMC: 4329176. DOI: 10.3978/j.issn.1000-9604.2015.01.06. View

14.

Zheng F, Liao Y, Cai M, Liu Y, Liu T, Chen S . The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut. 2011; 61(2):278-89. DOI: 10.1136/gut.2011.239145. View

15.

Shyian M, Gryshkova V, Kostianets O, Gorshkov V, Gogolev Y, Goncharuk I . Quantitative analysis of SLC34A2 expression in different types of ovarian tumors. Exp Oncol. 2011; 33(2):94-8. View

16.

Jemal A, Center M, DeSantis C, Ward E . Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010; 19(8):1893-907. DOI: 10.1158/1055-9965.EPI-10-0437. View

17.

Kopantzev E, Monastyrskaya G, Vinogradova T, Zinovyeva M, Kostina M, Filyukova O . Differences in gene expression levels between early and later stages of human lung development are opposite to those between normal lung tissue and non-small lung cell carcinoma. Lung Cancer. 2008; 62(1):23-34. DOI: 10.1016/j.lungcan.2008.02.011. View

18.

Enokida H, Yoshino H, Matsushita R, Nakagawa M . The role of microRNAs in bladder cancer. Investig Clin Urol. 2016; 57 Suppl 1:S60-76. PMC: 4910767. DOI: 10.4111/icu.2016.57.S1.S60. View

19.

Zhang X, Ke X, Pu Q, Yuan Y, Yang W, Luo X . MicroRNA-410 acts as oncogene in NSCLC through downregulating SLC34A2 via activating Wnt/β-catenin pathway. Oncotarget. 2016; 7(12):14569-85. PMC: 4924736. DOI: 10.18632/oncotarget.7538. View

20.

Yang L, Parkin D, Li L, Chen Y, Bray F . Estimation and projection of the national profile of cancer mortality in China: 1991-2005. Br J Cancer. 2004; 90(11):2157-66. PMC: 2409509. DOI: 10.1038/sj.bjc.6601813. View