Sun Yan, Fan Jiquan, Wang Bo, Meng Zibo, Ren Dianyun, Zhao Jingyuan, Liu Zhiqiang, Li Dan, Jin Xin, Wu Heshui
Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430022, China.
Sino-German Laboratory of Personalized Medicine for Pancreatic, Cancer Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430022, China.
Am J Cancer Res. 2020 Jan 1;10(1):148-163. eCollection 2020.
Pancreatic cancer is a malignant tumor with the worst prognosis worldwide. This cancer type requires new insight to help with diagnosis and, eventually, treatment. Adenosine deaminases acting on RNA 1 (ADAR1) is reportedly overexpressed in many types of tumors, such as lung, liver, breast, and esophageal cancers. However, the biological significance and specific mechanism of ADAR1 in pancreatic cancer have not been explored. In this study, we reveal that the expression level of ADAR1 is significantly up-regulated in pancreatic cancer tissues. We also find that highly expressed ADAR1 is closely associated with poor prognosis in pancreatic cancer specimens. Overexpressed ADAR1 equally increased the growth activity of pancreatic cancer cells and . We further demonstrate that ADAR1 stabilizes c-Myc through AKT signaling, which contributes to cancer cell resistance to BET inhibitors in pancreatic cancer cells. Moreover, we reveal that EZH2 regulates ADAR1 expression, and EZH2 and BET inhibitors show synergistic inhibition in pancreatic cancer. Collectively, these findings suggest that ADAR1 could serve as a new diagnostic and prognostic marker for the treatment of pancreatic cancer.
胰腺癌是全球预后最差的恶性肿瘤。这种癌症类型需要新的见解来辅助诊断，并最终用于治疗。据报道，作用于RNA的腺苷脱氨酶1（ADAR1）在许多类型的肿瘤中过度表达，如肺癌、肝癌、乳腺癌和食管癌。然而，ADAR1在胰腺癌中的生物学意义和具体机制尚未得到探索。在本研究中，我们发现胰腺癌组织中ADAR1的表达水平显著上调。我们还发现，高表达的ADAR1与胰腺癌标本的不良预后密切相关。ADAR1过表达同样增加了胰腺癌细胞的生长活性。我们进一步证明，ADAR1通过AKT信号通路稳定c-Myc，这有助于胰腺癌细胞对BET抑制剂产生抗性。此外，我们发现EZH2调节ADAR1的表达，并且EZH2和BET抑制剂在胰腺癌中显示出协同抑制作用。总的来说，这些发现表明ADAR1可作为胰腺癌治疗的新诊断和预后标志物。
