Transcriptional regulation of NDUFA4L2 by NFIB induces sorafenib resistance by decreasing reactive oxygen species in hepatocellular carcinoma

作者全名："Zhou, Li; Mao, Lin-Hong; Li, Xia; Wang, Qing-Liang; Chen, Si-Yuan; Chen, Zhi-Ji; Lei, Jing; Liu, Hong-Tao; Liao, Si-Qi; Ran, Tao; Li, Xiao-Qin; Zhou, Zhi-Hang; He, Song"

作者地址："[Zhou, Li; Mao, Lin-Hong; Li, Xia; Chen, Si-Yuan; Chen, Zhi-Ji; Lei, Jing; Liu, Hong-Tao; Liao, Si-Qi; Ran, Tao; Li, Xiao-Qin; Zhou, Zhi-Hang; He, Song] Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing, Peoples R China; [Mao, Lin-Hong] Chengdu Second Peoples Hosp, Dept Gastroenterol, Chengdu, Sichuan, Peoples R China; [Wang, Qing-Liang] Chongqing Med Univ, Affiliated Hosp 2, Dept Pathol, Chongqing, Peoples R China; [Zhou, Zhi-Hang; He, Song] Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing 400010, Peoples R China"

通信作者："Zhou, ZH; He, S (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing 400010, Peoples R China."

来源：CANCER SCIENCE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000892047800001

JCR分区：Q1

影响因子：5.7

年份：2023

卷号：114

期号：3

开始页：793

结束页：805

文献类型：Article

关键词：HCC; NFIB; ROS; sorafenib

摘要："Sorafenib is one a first-line therapeutic drugs for advanced hepatocellular carcinoma (HCC). However, only 30% of patients benefit from sorafenib due to drug resistance. We and other groups have revealed that nuclear factor I B (NFIB) regulates liver regeneration and carcinogenesis, but its role in drug resistance is poorly known. We found that NFIB was more upregulated in sorafenib-resistant SMMC-7721 cells compared to parental cells. NFIB knockdown not only sensitized drug-resistant cells to sorafenib but also inhibited the proliferation and invasion of these cells. Meanwhile, NFIB promoted the proliferation and invasion of HCC cells in vitro and facilitated tumor growth and metastasis in vivo. Knocking down NFIB synergetically inhibited tumor growth with sorafenib. Mechanically, gene expression profiling and subsequent verification experiments proved that NFIB could bind with the promoter region of a complex I inhibitor NDUFA4L2 and promote its transcription. Transcriptional upregulation of NDUFA4L2 by NFIB could thus inhibit the sorafenib-induced reactive oxygen species accumulation. Finally, we found that NFIB was highly expressed in HCC tissues, and high NFIB expression level was associated with macrovascular invasion, advanced tumor stage, and poor prognosis of HCC patients (n = 156). In summary, we demonstrated that NFIB could transcriptionally upregulate NDUFA4L2 to enhance both intrinsic and acquired sorafenib resistance of HCC cells by reducing reactive oxygen species induction."

基金机构："National Natural Science Foundation of China [81972285, 82203791]; Natural Science Foundation of Chongqing [CSTB2022NSCQ-MSX1038, CSTB2022NSCQ-MSX1010]; Senior Medical Talents Program of Chongqing for Young and Middle- aged; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University [13-002- 011, 1 3 - 0 0 4 -009]"

基金资助正文："National Natural Science Foundation of China, Grant/Award Number: 81972285 and 82203791; Natural Science Foundation of Chongqing, Grant/Award Number: CSTB2022NSCQ-MSX1038 and CSTB2022NSCQ-MSX1010; Senior Medical Talents Program of Chongqing for Young and Middle- aged and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University, Grant/Award Number: 13-002- 011 and 1 3 - 0 0 4 -009"