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.
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.
Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.|The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.|Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Wen
W
Ye
Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Cui
C
Chen
Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Ying
Y
Gao
Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Zou-Shan
ZS
Zheng
Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Yi
Y
Xu
Department of Ultrasound, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Miao
M
Yun
Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Hui-Wen
HW
Weng
The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.|Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Dan
D
Xie
Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Sheng
S
Ye
Department of Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.|The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Jia-Xing
JX
Zhang
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology*
D020598:Proto-Oncogene Proteins c-myb; C493557:SLC34A2 protein, human; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb