ADNP prompts the cisplatin-resistance of bladder cancer via TGF-β-mediated epithelial-mesenchymal transition (EMT) pathway

Abstract

Activity-dependent neuroprotective protein (ADNP) is vital for embryonic development and brain formation. Besides, the upregulated expression of ADNP enhances tumorigenesis in some human tumors like bladder cancer (BC). However, the potential roles of ADNP in drug resistance and the related mechanisms in BC is unknown. We performed this study to elucidate the influence of ADNP in the chemoresistance of BC and tried to explore the underlying molecular mechanism. The expressions of ADNP in BC from progression and non-progression patient specimens were measured by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). In vitro experiments including colony formation, cell counting kit-8 (CCK-8), wound healing, and in vivo tumorigenesis assay were performed to explore the effects of ADNP on chemoresistance of BC. The impacts of ADNP on TGF-β/Smad signaling pathways were explored by western blot. Our results showed that the expression of ADNP mRNA and protein were significantly upregulated in BC tissues of the patients who suffered tumor-progression via RT-PCR and western blot. Cox regression survival analysis revealed that patients with high ADNP expression closely linked to shorter tumor-free survival. ADNP downregulation in BC showed more sensitive to cisplatin in vivo, while ADNP overexpression showed the opposite results. Additionally, we confirmed that ADNP promoted cell migration and EMT, thereby inducing cisplatin resistance, which may be related to TGF-β / Smad signaling pathway.

Specific RNA m6A modification sites in bone marrow mesenchymal stem cells from the jawbone marrow of type 2 diabetes patients with dental implant failure

“…Activity-dependent neuroprotector homeobox (ADNP), a transcription factor and cytoskeletal-binding protein, plays a crucial role in cellular growth and proliferation. 38 Wound healing experiments have shown that ADNP promotes cell migration. 39 NAP, a brief peptide with eight amino acids derived from ADNP, acts as a protective agent against cerebral ischaemia, central nervous system complications of DM, and retinal damage induced by different insults.…”

Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism

“…Overall, there is increasing consensus that ADNP contributes to tumorigenesis and cancer progression. Transcriptional assessment of ADNP levels in a large cohort of bladder cancer specimens highlighted a significant overexpression in the patients with tumor progression and the association of higher ADNP protein levels to poor prognosis in such patients [ 161 ]. In bladder cancer, ADNP promotes tumor cell growth and proliferation by enhancing the AKT-MDM2-p53 molecular axis which stabilizes cyclin D1 and ultimately leads to cell cycle acceleration from G1 phase to S phase [ 162 ].…”

“…In bladder cancer, ADNP promotes tumor cell growth and proliferation by enhancing the AKT-MDM2-p53 molecular axis which stabilizes cyclin D1 and ultimately leads to cell cycle acceleration from G1 phase to S phase [ 162 ]. In another study, ADNP was found to promote bladder cancer cell migration via TGF- β -mediated epithelial-mesenchymal transition (EMT) pathway [ 161 ]. In that respect, it is relevant to mention that ADNP was recently identified as a binding partner of the ZEB1/NuRD complex (zinc finger E-box-binding homeobox 1/Nucleosome Remodeling and Deacetylase) which is critically involved in epigenetic cancer programming of EMT hallmarks [ 163 ].…”

The Roles of miRNAs in Predicting Bladder Cancer Recurrence and Resistance to Treatment

“…In addition to recurrence, EMT is also involved in mediating chemoresistance; in fact, EMT, recurrence, and chemoresistance work in concert with one another. Studies have found that EMT markers are upregulated in chemoresistant cells, with restoration of sensitivity via TGF-beta downregulation [ 75 ] and that oncogenic proteins modulate EMT to induce resistance to chemotherapeutic agents [ 76 , 77 ]. Two key pathways that have been linked to the EMT phenotype are Wnt signaling [ 78 , 79 ] and TGF-beta [ 80 , 81 ].…”