Chemotherapy has been the standard treatment for liver cancer. However, intrinsic or acquired drug resistance remains a major barrier to successful treatment. At present, the underlying molecular mechanisms of chemoresistance in liver cancer have not been elucidated. Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family that has been found to be highly expressed in a variety of tumors, including liver cancer. It is unclear whether DPP9 affects chemoresistance in liver cancer. In this study, we find that DPP9 weakens the responses of liver cancer cells to chemotherapy drugs by up-regulating NQO1 and inhibiting intracellular ROS levels. In terms of mechanism, DPP9 inhibits ubiquitin-mediated degradation of NRF2 protein by binding to KEAP1, up-regulates NRF2 protein levels, promotes mRNA transcription of NQO1, and inhibits intracellular ROS levels. In addition, the NQO1 inhibitor dicoumarol can enhance the efficacy of chemotherapy drugs in liver cancer cells. Collectively, our findings suggest that inhibiting DPP9/NQO1 signaling can serve as a potential therapeutic strategy for liver cancer.

中文翻译：

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DPP9调节NQO1和ROS促进肝癌细胞对化疗的抵抗


化疗一直是肝癌的标准治疗方法。然而，内在或获得性耐药性仍然是成功治疗的主要障碍。目前，肝癌化疗耐药的分子机制尚未阐明。二肽基肽酶 9 (DPP9) 是二肽基肽酶 IV 家族的成员，已发现该家族在多种肿瘤（包括肝癌）中高表达。目前尚不清楚 DPP9 是否影响肝癌的化疗耐药性。在本研究中，我们发现DPP9通过上调NQO1和抑制细胞内ROS水平来减弱肝癌细胞对化疗药物的反应。从机制上看，DPP9通过与KEAP1结合抑制泛素介导的NRF2蛋白降解，上调NRF2蛋白水平，促进NQO1 mRNA转录，抑制细胞内ROS水平。此外，NQO1抑制剂双香豆素可以增强化疗药物对肝癌细胞的疗效。总的来说，我们的研究结果表明，抑制 DPP9/NQO1 信号传导可以作为肝癌的潜在治疗策略。