LRP1B suppresses HCC progression through the NCSTN/PI3K/AKT signaling axis and affects doxorubicin resistance
作者机构：Department of Hepatobiliary SurgeryThe Second Hospital of Shandong UniversityJinanShandong 250033China Department of GeneralVisceraland Transplant SurgeryLudwig-Maximilians-University MunichMunich 81377Germany Department of Reproductive MedicineCentral Hospital Affiliated to Shandong First Medical UniversityJinanShandong 250013China Organ Transplant DepartmentQilu Hospital of Shandong UniversityJinanShandong 250012China Clinical Molecular Medicine Testing CenterThe First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China
出 版 物：《Genes & Diseases》 (基因与疾病(英文))
年 卷 期：2023年第10卷第5期
页 面：2082-2096页
核心收录：
学科分类：0710[理学-生物学] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：funded by the National Natural Science Foundation of China(No.81871653) the Natural Science Foundationof 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) Second Hospital of Shandong University Cultivation Funding(China)(No.2022YP45).
主 题：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 implications in hepatocellular carcinoma(HCC)and explore their possible mechanisms.The gene mutation 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 putative genes on proliferation,invasion,drug resistance,and other malignant biological behaviors 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 associated 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 resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.
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