Oxyberberine sensitizes liver cancer cells to sorafenib via inhibiting NOTCH1-USP7-c-Myc pathway

作者全名："Sun, Liangbo; He, Meng; Li, Feng; Wu, Di; Zheng, Ping; Zhang, Cong; Liu, Yang; Liu, Dong; Shan, Meihua; Yang, Mingzhen; Ma, Yuanhang; Lian, Jiqin; Xiong, Haojun"

作者地址："[Sun, Liangbo; Li, Feng; Wu, Di; Zheng, Ping; Xiong, Haojun] Third Mil Med Univ, Army Med Univ, Key Lab Hepatobiliary & Pancreat Surg,Inst Hepatob, Chongqing, Peoples R China; [Sun, Liangbo; He, Meng; Liu, Dong; Shan, Meihua; Yang, Mingzhen; Lian, Jiqin] Third Mil Med Univ, ThirdMil Med Univ, Dept Clin Biochem, Chongqing, Peoples R China; [Li, Feng] Chongqing Med Univ, Affiliated Hosp 3, Dept Hepatobiliary & Pancreat Surg, Chongqing, Peoples R China; [Zhang, Cong; Liu, Yang] Third Mil Med Univ, ThirdMilitary Med Univ, Coll Basic Med, Dept Lab Anim Sci, Chongqing, Peoples R China; [Ma, Yuanhang] Third Mil Med Univ, Mil Med Univ 3, Dept Gen Surg, Xinqiao Hosp, Chongqing, Peoples R China; [Ma, Yuanhang] Army Med Univ, Xinqiao Hosp, Dept Gen Surg, 83 Xinqiao St, Chongqing 400038, Peoples R China; [Lian, Jiqin] Army Med Univ, Dept Clin Biochem, 30 Gaotanyan, Chongqing 400038, Peoples R China; [Xiong, Haojun] Army Med Univ, Southwest Hosp, Inst Hepatobiliary Surg, Chongqing 400038, Peoples R China"

通信作者："Ma, YH (通讯作者)，Army Med Univ, Xinqiao Hosp, Dept Gen Surg, 83 Xinqiao St, Chongqing 400038, Peoples R China.; Lian, JQ (通讯作者)，Army Med Univ, Dept Clin Biochem, 30 Gaotanyan, Chongqing 400038, Peoples R China.; Xiong, HJ (通讯作者)，Army Med Univ, Southwest Hosp, Inst Hepatobiliary Surg, Chongqing 400038, Peoples R China."

来源：HEPATOLOGY COMMUNICATIONS

ESI学科分类：　

WOS号：WOS:001196650900001

JCR分区：Q1

影响因子：5.1

年份：2024

卷号：8

期号：4

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Background:Sorafenib is the first-line therapy for patients with advanced-stage HCC, but its clinical cure rate is unsatisfactory due to adverse reactions and drug resistance. Novel alternative strategies to overcome sorafenib resistance are urgently needed. Oxyberberine (OBB), a major metabolite of berberine in vivo, exhibits potential antitumor potency in various human malignancies, including liver cancer. However, it remains unknown whether and how OBB sensitizes liver cancer cells to sorafenib.Methods:Cell viability, trypan blue staining and flow cytometry assays were employed to determine the synergistic effect of OBB and sorafenib on killing HCC cells. PCR, western blot, co-immunoprecipitation and RNA interference assays were used to decipher the mechanism by which OBB sensitizes sorafenib. HCC xenograft models and clinical HCC samples were utilized to consolidate our findings.Results:We found for the first time that OBB sensitized liver cancer cells to sorafenib, enhancing its inhibitory effect on cell growth and induction of apoptosis in vitro. Interestingly, we observed that OBB enhanced the sensitivity of HCC cells to sorafenib by reducing ubiquitin-specific peptidase 7 (USP7) expression, a well-known tumor-promoting gene. Mechanistically, OBB inhibited notch homolog 1-mediated USP7 transcription, leading to the downregulation of V-Myc avian myelocytomatosis viral oncogene homolog (c-Myc), which synergized with sorafenib to suppress liver cancer. Furthermore, animal results showed that cotreatment with OBB and sorafenib significantly inhibited the tumor growth of liver cancer xenografts in mice.Conclusions:These results indicate that OBB enhances the sensitivity of liver cancer cells to sorafenib through inhibiting notch homolog 1-USP7-c-Myc signaling pathway, which potentially provides a novel therapeutic strategy for liver cancer to improve the effectiveness of sorafenib."

基金机构："National Natural Science Foundation of China [31900449, 82073300]; Chongqing Natural Science Foundation [CSTB2023NSCQ-MSX-0590, CSTB2023-NSCQ-MSX0651]; Youth Training Program of Army Medical University [2022XQN05]"

基金资助正文："This study was supported by the National Natural Science Foundation of China (31900449) and the Chongqing Natural Science Foundation (CSTB2023NSCQ-MSX-0590) to Haojun Xiong, the National Natural Science Foundation of China (82073300) to Jiqin Lian, the Chongqing Natural Science Foundation (CSTB2023-NSCQ-MSX0651), and the Youth Training Program of Army Medical University (2022XQN05) to Liangbo Sun."