Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Radiology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, Sichuan Province, China.
Cell Death Dis. 2022 Feb 14;13(2):151. doi: 10.1038/s41419-022-04599-x.
Chemotherapy is one of the most frequently used therapies for the treatment of colon cancer (COAD). However, Oxaliplatin (L-OHP) resistance is a major obstacle to the effective treatment of COAD. Here, we investigated whether DNAJB8, a heat shock protein 40 (HSP40) family protein, could be used for the prognosis and therapy of L-OHP resistance in COAD. Treatment with small interfering RNA targeting DNAJB8 could restore the response to L-OHP in vitro and in vivo. On the mechanism, we demonstrated that DNAJB8 could interact with TP53 and inhibit the ubiquitination degradation of TP53, leading to MDR1 upregulation which promotes colon cancer L-OHP resistance. We found that small extracellular vesicle (sEV)-mediated transfer of DNAJB8 from L-OHP-resistant COAD cells to sensitive cells contributed to L-OHP resistance. A prognostic signature based on the DNAJB8 levels in both tissue and serum showed that COAD patients with high-risk scores exhibited significantly worse overall survival and disease-free survival than patients with low-risk scores. These results indicate that DNAJB8 levels in serum sEVs may serve as a biomarker for COAD. DNAJB8 from sEVs might be a promising therapeutic target for L-OHP resistance and a prognostic predictor of clinical response.
化疗是治疗结肠癌 (COAD) 最常用的方法之一。然而，奥沙利铂 (L-OHP) 耐药是 COAD 有效治疗的主要障碍。在这里，我们研究了 DNAJB8（热休克蛋白 40 (HSP40) 家族蛋白）是否可用于 COAD 中 L-OHP 耐药的预后和治疗。针对 DNAJB8 的小干扰 RNA 治疗可在体外和体内恢复对 L-OHP 的反应。在机制上，我们证明 DNAJB8 可以与 TP53 相互作用并抑制 TP53 的泛素化降解，导致 MDR1 上调，从而促进结肠癌 L-OHP 耐药。我们发现，来自 L-OHP 耐药 COAD 细胞的小细胞外囊泡 (sEV) 介导的 DNAJB8 转移到敏感细胞有助于 L-OHP 耐药。基于组织和血清中 DNAJB8 水平的预后特征表明，高风险评分的 COAD 患者的总生存期和无病生存期明显低于低风险评分的患者。这些结果表明，血清 sEV 中的 DNAJB8 水平可能是 COAD 的生物标志物。来自 sEV 的 DNAJB8 可能是 L-OHP 耐药的有前途的治疗靶点和临床反应的预后预测因子。
