Department of Urology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, 570311, People's Republic of China.
Department of Science and Education, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), No. 19, Xiuhua Road, Xiuying District, Haikou, 570311, People's Republic of China.
J Transl Med. 2021 Mar 17;19(1):112. doi: 10.1186/s12967-021-02709-5.
Bladder cancer (BCa) is a common malignancy characterized by high heterogeneity, yet the current treatment modalities are limited. The aim of the present investigation was to unravel the functional role of Karyopherin alpha 2 (KPNA2), a tumor facilitator identified in multiple malignancies, in the progression of BCa.
BCa tissues and adjacent normal tissues were surgically resected and analyzed from patients with BCa to determine the expression profile of KPNA2 and Chromobox 8 (CBX8) by RT-qPCR, Western blot analysis and immunohistochemistry. The relationship among KPNA2, CBX8 and PR domain zinc finger protein 1 (PRDM1) was explored by co-immunoprecipitation and chromatin-immunoprecipitation. The functions of KPNA2, CBX8 and PRDM1 on BCa cell proliferation, migration and invasion were evaluated. Next, a nude mouse model of BCa was established for validating the roles of KPNA2, CBX8 and PRDM1 in vivo.
KPNA2 and CBX8 were highly expressed in BCa and are in association with dismal oncologic outcomes of patients with BCa. KPNA2 promoted nuclear import of CBX8. CBX8 downregulated PRDM1 by recruiting BCOR in the promoter region of PRDM1. Overexpression of KPNA2 promoted the malignant behaviors of BCa cells, which was counteracted by silencing of CBX8. Overexpressing PRDM1 attenuated the progression of BCa by inhibiting c-FOS expression. The tumor-promoting effects of KPNA2 via the PRDM1/c-FOS pathway were also validated in vivo.
Collectively, our findings attached great importance to the interplay between KPNA2 and CBX8 in BCa in mediating the development and progression of BCa, thus offering a promising candidate target for better BCa patient management.
膀胱癌（BCa）是一种常见的恶性肿瘤，具有高度异质性，但目前的治疗方法有限。本研究旨在揭示核输入蛋白α 2（KPNA2）在 BCa 进展中的功能作用，KPNA2 是在多种恶性肿瘤中发现的肿瘤促进剂。
从患有 BCa 的患者中手术切除和分析 BCa 组织和相邻正常组织，通过 RT-qPCR、Western blot 分析和免疫组织化学确定 KPNA2 和 Chromobox 8（CBX8）的表达谱。通过共免疫沉淀和染色质免疫沉淀探索 KPNA2、CBX8 和 PR 结构域锌指蛋白 1（PRDM1）之间的关系。评估 KPNA2、CBX8 和 PRDM1 对 BCa 细胞增殖、迁移和侵袭的功能。接下来，建立 BCa 裸鼠模型以验证 KPNA2、CBX8 和 PRDM1 在体内的作用。
KPNA2 和 CBX8 在 BCa 中高表达，并与 BCa 患者不良的肿瘤学结局相关。KPNA2 促进了 CBX8 的核内输入。CBX8 通过在 PRDM1 的启动子区域募集 BCOR 来下调 PRDM1。过表达 KPNA2 促进了 BCa 细胞的恶性行为，而沉默 CBX8 则拮抗了这一作用。过表达 PRDM1 通过抑制 c-FOS 表达来抑制 BCa 的进展。KPNA2 通过 PRDM1/c-FOS 途径的促肿瘤作用也在体内得到了验证。
总之，我们的研究结果强调了 KPNA2 和 CBX8 在 BCa 中相互作用在介导 BCa 的发生和发展中的重要性，从而为更好地管理 BCa 患者提供了有希望的候选治疗靶点。
