PRDX2 调节干性，有助于膀胱癌对顺铂的耐药性和转移。

Department of Urology, Yantaishan Hospital, Binzhou Medical University, Yantai, Shandong, China.

Department of Clinical Laboratory, Yuhuangding Hospital, Qingdao University School of Medicine, Yantai, Shandong, China.

Environ Toxicol. 2024 May;39(5):2869-2880. doi: 10.1002/tox.24153. Epub 2024 Jan 31.

BACKGROUND

Cisplatin (CDDP)-based chemotherapy has emerged as the primary treatment for muscle-invasive bladder cancer and metastatic bladder cancer. Nevertheless, a significant proportion of patients experience rapidly developed chemoresistance, leading to treatment ineffectiveness. Existing evidence suggests that chemoresistance is governed by various factors, including tumor stem cells, epithelial mesenchymal transition, and reactive oxygen species (ROS). However, limited research has been conducted on the role of PRDX2, a crucial ROS scavenger, in the modulation of chemoresistance in bladder cancer.

METHODS

Cisplatin-resistant cell lines were established using the concentration gradient overlay method, and differentially expressed genes in resistant cells were screened through RNA sequencing. The expression of PRDX2 in cells and tissues was assessed using RT-qPCR, Western Blot, and immunohistochemistry. The expression of PRDX2 in bladder cancer and adjacent tissues was evaluated using a bladder cancer tissue microarray. Furthermore, the impact of PRDX2 knockdown on tumor formation and metastasis was investigated in vivo by applying subcutaneous tumor xenografts tail vein metastasis assays.

RESULTS

We demonstrated that PRDX2 is significantly upregulated in bladder tumors and cisplatin-resistant bladder tumor cell lines. Overexpression of PRDX2 can promote tumor proliferation, migration, and invasion both in vitro and in vivo. We have found that knockdown of PRDX2 expression can effectively reverse cell resistance to cisplatin. Mechanistically, our findings suggest that PRDX2 is involved in regulating tumor stemness and epithelial-mesenchymal transition (EMT). Knockdown of PRDX2 affects the PI3K-AKT and mTOR signaling pathways, thereby influencing tumor stemness and EMT, ultimately impacting the chemotherapy resistance of the tumor.

CONCLUSIONS

This study provides a new insight into the regulation of chemotherapy resistance in bladder cancer by PRDX2. Targeting PRDX2 can serve as a potent therapeutic target for chemotherapy resistance.

背景

顺铂（CDDP）为基础的化疗已成为肌层浸润性膀胱癌和转移性膀胱癌的主要治疗方法。然而，相当一部分患者迅速产生化疗耐药，导致治疗无效。现有证据表明，化疗耐药受多种因素控制，包括肿瘤干细胞、上皮间质转化和活性氧（ROS）。然而，关于 PRDX2（一种重要的 ROS 清除剂）在调节膀胱癌化疗耐药中的作用的研究有限。

方法

采用浓度梯度覆盖法建立顺铂耐药细胞系，通过 RNA 测序筛选耐药细胞中的差异表达基因。采用 RT-qPCR、Western blot 和免疫组织化学检测细胞和组织中 PRDX2 的表达。采用膀胱癌组织微阵列评估 PRDX2 在膀胱癌和相邻组织中的表达。此外，通过皮下肿瘤异种移植尾静脉转移实验在体内研究 PRDX2 敲低对肿瘤形成和转移的影响。

结果

我们证明 PRDX2 在膀胱癌和顺铂耐药膀胱癌细胞系中显著上调。PRDX2 的过表达可促进体外和体内肿瘤的增殖、迁移和侵袭。我们发现，敲低 PRDX2 表达可有效逆转细胞对顺铂的耐药性。机制上，我们的研究结果表明，PRDX2 参与调节肿瘤干细胞和上皮间质转化（EMT）。敲低 PRDX2 会影响 PI3K-AKT 和 mTOR 信号通路，从而影响肿瘤干细胞和 EMT，最终影响肿瘤的化疗耐药性。