LRP1B suppresses HCC progression through the NCSTN/PI3K/AKT signaling axis and affects doxorubicin resistance

作者全名："Zhai, Xiangyu; Xia, Zhijia; Du, Gang; Zhang, Xinlu; Xia, Tong; Ma, Delin; Li, Xiaosong; Jin, Bin; Zhang, Hao"

作者地址："[Zhai, Xiangyu; Du, Gang; Jin, Bin; Zhang, Hao] Shandong Univ, Hosp 2, Dept Hepatobiliary Surg, Jinan 250033, Shandong, Peoples R China; [Xia, Zhijia] Ludwig Maximilians Univ Munchen, Dept Gen Visceral & Transplant Surg, D-81377 Munich, Germany; [Zhang, Xinlu] Shandong First Med Univ, Cent Hosp, Dept Reprod Med, Jinan 250013, Shandong, Peoples R China; [Du, Gang; Xia, Tong; Ma, Delin; Jin, Bin; Zhang, Hao] Shandong Univ, Qilu Hosp, Organ Transplant Dept, Jinan 250012, Shandong, Peoples R China; [Li, Xiaosong] Chongqing Med Univ, Affiliated Hosp 1, Clin Mol Med Testing Ctr, Chongqing 400016, Peoples R China"

通信作者："Jin, B; Zhang, H (通讯作者)，Shandong Univ, Hosp 2, Dept Hepatobiliary Surg, Jinan 250033, Shandong, Peoples R China.; Jin, B; Zhang, H (通讯作者)，Shandong Univ, Qilu Hosp, Organ Transplant Dept, Jinan 250012, Shandong, Peoples R China.; Li, XS (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Clin Mol Med Testing Ctr, Chongqing 400016, Peoples R China."

来源：GENES & DISEASES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001037679800001

JCR分区：Q1

影响因子：6.9

年份：2023

卷号：10

期号：5

开始页：2082

结束页：2096

文献类型：Article

关键词：Doxorubicin; Hepatocellular carcinoma; LRP1B; PI3K; AKT pathway; Tumor mutation burden

摘要："Accumulating evidence supports the association of somatic mutations with tumor occurrence and development. We aimed to identify somatic mutations with important implica-tions in hepatocellular carcinoma (HCC) and explore their possible mechanisms. The gene mu-tation profiles of HCC patients were assessed, and the tumor mutation burden was calculated. Gene mutations closely associated with tumor mutation burden and patient overall survival were identified. In vivo and in vitro experiments were performed to verify the effects of pu-tative genes on proliferation, invasion, drug resistance, and other malignant biological behav-iors of tumor cells. Fourteen genes with a high mutation frequency were identified. The mutation status of 12 of these genes was closely related to the mutation burden. Among these 12 genes, LRP1B mutation was closely associated with patient prognosis. Nine genes were asso-ciated with immune cell infiltration. The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin. LRP1B could directly bind to NCSTN and affect its protein expression level, thereby regulating the PI3K/AKT pathway. Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resis-tance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives. 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/)."

基金机构："National Natural Science Foundation of China [81871653]; Natural Science Foundation of Chongqing, China; Chongqing Science and Health Joint Medical High-end Talent Project (China) [W0073]; Science and Technology Research Program of Chongqing Municipal Education Commission (China); CQMU Program for Youth Innovation in Future Medicine (China) [KJZDK202100402]; Second Hospital of Shandong University Cultivation Funding (China) [KJQN201900449]; [2022GDRC012]; [2022YP45]; [cstc2020jcyjmsxmX0159]"

基金资助正文："This study was funded by the National Natural Science Foundation of China (No. 81871653), the Natural Science Foundation of Chongqing, China (No. cstc2020jcyjmsxmX0159), Chongqing Science and Health Joint Medical High-end Talent Project (China) (No. 2022GDRC012), Science and Technology Research Program of Chongqing Municipal Education Commission (China) (No. KJZDK202100402 and KJQN201900449), CQMU Program for Youth Innovation in Future Medicine (China) (No. W0073) and Second Hospital of Shandong University Cultivation Funding (China) (No.2022YP45)."