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.
Highlights
Bladder cancer (BC) is one of the most common cancer worldwide, with 4386 300 new cases and 150 200 deaths each year.[1]
Studies reported that AT-II cells are potential cancer stem cells that lead to the development of non-small cell lung cancer (NSCLC),[8,9] suggesting potential relation between SLC34A2 and cancer
To investigate the expression status of SLC34A2 in BC, western blotting and quantitative RT-PCR analyses were performed in four BC cell lines (EJ, T24, 5637 and BIU-87), three normal bladder tissues and five fresh BC tissues paired with their adjacent non-neoplastic bladder tissues (ANTs)
Summary
Bladder cancer (BC) is one of the most common cancer worldwide, with 4386 300 new cases and 150 200 deaths each year.[1]. A large amount of investigations on BC have been focused on the identification of promising molecular biomarkers that could precisely evaluate patients’ progression risk and help clinicians to optimize individual therapeutic strategy.[3] For instance, we previously demonstrated that high expression of Rab[25] is associated with lymph node metastasis and inferior clinical outcome of BC patients.[4] To date, the search for specific biomarkers in BC cells that have clinical/prognostic value is still substantially limited. MiR-410 is reported to positively contribute to the tumorigenesis and development of NSCLC by downregulating SLC34A2.13 Hong et al.[14] showed downregulating SCL34A2 successfully suppressed lung cancer growth and decreased cancer cell proliferation and angiogenesis, and facilitated apoptosis. It is of great significance to explore the role of SLC34A2 in BC
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