YBX1作为抑制LRP1-β-catenin-Rrm1轴并克服胰腺癌中吉西他滨耐药性的治疗靶标
YBX1 as a therapeutic target to suppress the LRP1-β-catenin-RRM1 axis and overcome gemcitabine resistance in pancreatic cancer
影响因子:10.10000
分区:医学1区 Top / 肿瘤学2区
发表日期:2024 Oct 10
作者:
Borui Li, Faliang Xing, Jingyi Wang, Xiaohong Wang, Chenjie Zhou, Guixiong Fan, Qifeng Zhuo, Shunrong Ji, Xianjun Yu, Xiaowu Xu, Yi Qin, Zheng Li
摘要
胰腺导管腺癌（PDAC）高度恶性，预后较差，没有有效的普通基因突变治疗靶标。吉西他滨是一种用于PDAC的一线化学治疗性，由于耐药性，占5年的5年生存率。 Y-box结合蛋白1（YBX1）与多药耐药基因激活相关，在PDAC吉西他滨耐药中仍未降生。在体内和体外，我们在胰腺癌细胞中验证了YBX1的促销作用，尤其是吉西他滨耐药性。通过与LRP1启动子区域结合YBX1诱导的LRP1转录会显着改变胰腺癌细胞中β-catenin的浓度和分布。通过TCF3，β-catenin结合到RRM1的启动子区域（吉西他滨耐药的关键基因），可促进RRM1表达。与YBX1抑制剂SU056和吉西他滨有效降低了体内和体外实验的吉西他滨耐药性的组合疗法。高YBX1的表达通过YBX1-LRP1-β-catenin-RRM1轴促进了胰腺癌的发病机理和吉西他滨耐药性。将YBX1抑制剂与吉西他滨相结合，可以为克服吉西他滨耐药性的组合化疗提供一个新的方向，这在胰腺癌化学疗法期间经常发生。
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly malignant and has a poor prognosis, without effective therapeutic targets in common gene mutations. Gemcitabine, a first-line chemotherapeutic for PDAC, confers <10 % 5-year survival rate because of drug resistance. Y-box binding protein 1 (YBX1), associated with multidrug-resistance gene activation, remains unelucidated in PDAC gemcitabine resistance. In vivo and in vitro, we verified YBX1's promotional effects, especially gemcitabine resistance, in pancreatic cancer cells. YBX1-induced LRP1 transcription by binding to the LRP1 promoter region significantly altered the concentration and distribution of β-catenin in pancreatic cancer cells. Through TCF3, β-catenin bound to the promoter region of RRM1, a key gene for gemcitabine resistance, that promotes RRM1 expression. Combination therapy with the YBX1 inhibitor SU056 and gemcitabine effectively reduced gemcitabine resistance in in vivo and in vitro experiments. High YBX1 expression promoted pathogenesis and gemcitabine resistance in pancreatic cancer through the YBX1-LRP1-β-catenin-RRM1 axis. Combining YBX1 inhibitors with gemcitabine may provide a new direction for combination chemotherapy to overcome gemcitabine resistance, which frequently occurs during chemotherapy for pancreatic cancer.