c-Myc-PD-L1 Axis Sustained Gemcitabine-Resistance in Pancreatic Cancer.
c-Myc-PD-L1 Axis Sustained Gemcitabine-Resistance in Pancreatic Cancer.
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胰腺癌中的 c-Myc-PD-L1 轴持续吉西他滨耐药
DOI：
10.3389/fphar.2022.851512
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发表时间：
2022
影响因子：
5.6
通讯作者：
Lu, Linlin
中科院分区：
文献类型：
--
作者：
Yao, Jingjing;Huang, Min;Shen, Qinghong;Ding, Ming;Yu, Shaofang;Guo, Yajuan;Lin, Yuefang;Zheng, Yaqiu;Chen, Wenbo;Yan, Wenxin;Liu, Zhongqiu;Wang, Dawei;Hu, Ming;Lu, Linlin
胰腺癌在癌症相关死亡中排名第四，5年总生存率低于10%。吉西他滨（dFdC）被认为是胰腺癌患者的一线药物。然而，由于耐药性，临床有效性不足20%。最重要的是，压倒性的证据表明，c-Myc和PD-L1在胰腺癌患者中通常高度表达。然而，dFdC耐药胰腺癌是否与c-Myc和PD-L1相关尚未阐明。在我们目前的研究中，我们发现c-Myc和PD-L1在胰腺癌组织中的表达明显高于癌旁组织。类似地，与亲本细胞相比，c-Myc和PD-L1表达在dFdc抗性Panc-1细胞中也显著升高。此外，在Panc-1细胞中，dFdC和c-Myc抑制剂的组合增强了dFdC敏感性。有趣的是，当c-Myc过表达时，其敏感性降低。此外，当用c-Myc抑制剂处理时，PD-L1蛋白表达显著下调。从18个化合物中筛选出青蒿琥酯（artesunate，ARTS）与dFdC联合应用，可逆转dFdC耐药的Panc-1细胞对dFdC的耐药性，并抑制DMBA诱导的胰腺癌。总之，我们的数据显示，dFdC耐药的机制可能是c-Myc过表达导致PD-L1表达增加，ARTS可以通过抑制c-Myc和PD-L1来克服dFdC耐药的胰腺癌。我们的研究结果不仅表明c-Myc和PD-L1是dFdC耐药胰腺癌的新型预后生物标志物，而且还提供了ARTS作为克服dFdC耐药的有希望的候选物。
Pancreatic cancer ranks fourth among cancer-related deaths, with a 5-years overall survival rate being below 10%. Gemcitabine (dFdC) has been considered the first-line drug for patients with pancreatic cancer. However, the clinical effectiveness is less than 20% due to drug resistance. Most importantly, overwhelming evidence suggested c-Myc and PD-L1 were generally highly expressed in pancreatic cancer patients. However, whether dFdC-resistant pancreatic cancer is associated with c-Myc and PD-L1 has not been elucidated. In our present study, we found that the expression of c-Myc and PD-L1 was markedly increased in pancreatic tumor tissues compared with adjacent tissues. Similarly, c-Myc and PD-L1 expression were also remarkably elevated in dFdC-resistant Panc-1 cells compared with parental cells. In addition, dFdC sensitivity was enhanced by the combination of dFdC and c-Myc inhibitors in Panc-1 cells. Interestingly, its sensitivity was reduced when c-Myc was overexpressed. Moreover, PD-L1 protein expression was dramatically down-regulated when treated with c-Myc inhibitors. Furthermore, artesunate (ARTS) screened from 18 compounds could reverse dFdC resistance in combination with dFdC in dFdC-resistant Panc-1 cells in vitro and suppressed DMBA-induced pancreatic cancer in vivo. In summary, our data revealed that the mechanism of dFdC resistance may be that c-Myc overexpression contributed to increased PD-L1 expression, and ARTS could overcome dFdC-resistant pancreatic cancer by inhibiting c-Myc and PD-L1. Our findings not only suggest c-Myc and PD-L1 as novel prognostic biomarkers in dFdC-resistant pancreatic cancer, but also provide ARTS as a promising candidate for overcoming dFdC resistance.
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影响因子：
3.3
作者：
Tang Y;Song G;Liu H;Yang S;Yu X;Shi L
通讯作者：
Shi L
DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW
影响因子：
9.7
作者：
Wang, Shuang-Jia;Gao, Yue;Sun, Bei
通讯作者：
Sun, Bei
影响因子：
11.5
作者：
Biliran, Hector, Jr.;Banerjee, Sanjeev;Liao, Joshua D.
通讯作者：
Liao, Joshua D.
影响因子：
3.8
作者：
Osvaldt, Alessandro B.;Wendt, Luiz R.;Rohde, Luiz
通讯作者：
Rohde, Luiz