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J Cancer 2021; 12(17):5114-5124. doi:10.7150/jca.58049 This issue Cite

Research Paper

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

Yu Xie^1,2, Shuai Zhu², Jinglei Zang³, Guanlin Wu⁴, Yuheng Wen², Yu Liang^2,5, Ying Long⁶, Weiming Guo⁷, Chuanbing Zang⁸, Xiang Hu¹, Gang Fan^2,9, Shuanglin Xiang^1✉, Jian Zhang^1✉

1. Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, Hunan Normal University, 410081 Changsha, China.
2. Department of Urology, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, 410013 Changsha, China.
3. Changsha Health Vocational College, 410600 Changsha, China.
4. Department of Pathology, School of Basic Medical Sciences, Fudan University, 200433 Shanghai, China.
5. Pingxiang Maternal and Child Care Hospital, 337000 Pingxiang, China.
6. Clinical Translational Research Center, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, 410013 Changsha, China.
7. The 2nd Affiliated Hospital of South China University, 421001 Hengyang, China.
8. Medizinische Klinik m. S. Hämatologie u. Onkologie, Campus Bejamin Franklin, Unviersitätsmedizin Berlin Charité, 12203 Berlin, Germany.
9. Department of Urology, Huazhong University of Science and Technology Union Shenzhen Hospital; the 6th Affiliated Hospital of Shenzhen University Health Science Center, 518060 Shenzhen, China.

✉ Corresponding authors: Prof. Dr. Jian Zhang, Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, Hunan Normal University, Yuelunan Road 168, Yuelu, Changsha. E-mail: hnc_uronet; Prof. Dr. Shuanglin Xiang, Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, Hunan Normal University, Yuelunan Road 168, Yuelu, Changsha. E-mail: 1715840770com. More

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.

Keywords: ADNP, bladder cancer, epithelial-mesenchymal transition, chemoresistance, TGF-β/Smad

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