Abstract
BackgroundActivity-dependent neuroprotective protein (ADNP), which is involved in embryonic development and neurogenesis, has been proven to be upregulated in some human tumors. However, its role in bladder cancer (BC) has never been studied.ObjectiveWe aimed to investigate the mechanisms by which ADNP promotes the progression of BC.MethodsADNP expressions in BC cell lines and paired BC and adjacent normal tissues were measured by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry. Colony formation, Cell Counting Kit-8 (CCK-8), trypan blue exclusion assay, flow cytometry, and nude mice tumorigenesis assay were performed to explore the effects of ADNP on growth of BC in vivo and in vitro. The impacts of ADNP on AKT signaling pathways were measured by Western blot.ResultsThe expression of ADNP mRNA and protein was significantly upregulated in BC tissues compared with adjacent normal tissues. Immunohistochemical analysis of 221 BC and 51 adjacent normal tissue paraffin sections indicated that ADNP expression was significantly associated with histological classification and pathological T and N stages. Survival analysis revealed that patients with high ADNP expression have worse prognosis with respect to overall survival and progression-free disease. ADNP knockdown markedly delayed propagation of BC in vitro and the development of BC in vivo. ADNP overexpression showed the opposite effect. In addition, ADNP can markedly promote G1-S cell cycle transition in BC cells. On the molecular level, we confirmed that ADNP mediated acceleration of G1-S transition was associated with activation of the AKT pathways in BC.ConclusionADNP is overexpressed in BC and promotes BC growth partly through AKT pathways. ADNP is crucial in predicting the outcome of BC patients and may be a potential therapeutic target in BC.
Highlights
Bladder cancer (BC), urothelial carcinoma, is one of the most prevalent urinary system malignancies [1]
In Cox regression analysis, we evaluated the potential of Activity-dependent neuroprotective protein (ADNP) as a predictive factor of prognosis; it showed high ADNP expression significantly increased the risk of mortality in both univariate (P < 0.001; Table 2) and multivariate analyses (P = 0.001)
We found that the mRNA and protein expression of ADNP were upregulated compared with normal bladder urothelial tissues, and overexpression of ADNP protein was significantly associated with higher pathological grade, advanced clinical stage, and poor prognosis in BC patients
Summary
Bladder cancer (BC), urothelial carcinoma, is one of the most prevalent urinary system malignancies [1]. 70% of all incident cases are non-muscle-invasive bladder cancer (NMBC), while 30% are muscle-invasive bladder cancer (MIBC) [3]. MIBC, to some extent, is more aggressive and prone to metastasis, and the 5-year survival rate is only 50% [5]. This dismal prognosis highlights the urgent need for accurate prognostic markers for BC that can be used for both treatment planning and follow-up. Its role in bladder cancer (BC) has never been studied
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