MDM2 Binding Protein Induces the Resistance of Hepatocellular Carcinoma Cells to Molecular Targeting Agents via Enhancing the Transcription Factor Activity of the Pregnane X Receptor

Abstract

The MDM2 binding protein (MTBP) has been considered an important regulator of human malignancies. In this study, we demonstrate that the high level of MTBP’s endogenous expression is correlated with poor prognosis of advanced hepatocellular carcinoma (HCC) patients who received sorafenib. MTBP interacted with the Pregnane X receptor (PXR) and enhanced the transcription factor activity of PXR. Moreover, MTBP enhanced the accumulation of PXR in HCC cells’ nuclear and the recruitment of PXR to its downstream gene’s (cyp3a4’s) promoter region. Mechanically, the knockdown of MTBP in MHCC97-H cells with high levels of MTBP decelerated the clearance or metabolism of sorafenib in HCC cells and led to the resistance of HCC cells to sorafenib. Whereas overexpression of MTBP in in MHCC97-L cells with low levels of MTBP showed the opposite trend. By establishing the interaction between MTBP and PXR, our results indicate that MTBP could function as a co-activator of PXR and could be a promising therapeutic target to enhance the sensitivity of HCC cells to molecular targeting agents.

Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

“…For the survival analysis, the endogenous expression of FBI-1 or HIF-1α was examined by qPCR, and the patients were divided into two groups, namely, the FBI-1/HIF-1α high group or the FBI-1/HIF-1α low group, according to the median values ( 31 , 32 ). Survival analysis is carried out in combination with the clinical information of the patients, and the clinical significance of the expression of FBI-1 or HIF-1α is determined by the survival curves, the overall survival (OS), or the time to progress (TTP) of patients in the high and low expression groups ( 33 , 34 ).…”

“…FBI-1/HIF-1a low group, according to the median values (31,32). Survival analysis is carried out in combination with the clinical information of the patients, and the clinical significance of the expression of FBI-1 or HIF-1a is determined by the survival curves, the overall survival (OS), or the time to progress (TTP) of patients in the high and low expression groups (33,34).…”

Inhibition of SREBP-1 Activation by a Novel Small-Molecule Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Tissue to Radiofrequency Ablation

“…For the animal experiments (the usage of nude mice) were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of China Medical University. MHCC97-H cells were cultured and injected into nude mice (4-6 weeks; Si-Bei-Fu Corporation, Beijing, China) to form subcutaneous tumors (35,36). The volume of each subcutaneous tumor was measured as width × width × length/ 2.…”

“…MHCC97-H cells were cultured and treated with the indicated concentration (30, 10, 3, 1, 0.03, 0.01, or 0.003 mmol/L) of SI-1, botulin, or fatostatin. Tumor tissues were harvested for the subcutaneous tumor model (35,36). The total RNA of cells or tumor tissues was extracted and reverse-transcribed into complimentary (c)DNA according to manufacturer (Thermo Fisher Scientific, Waltham, MA, USA) instructions and the methods described in our previous publications.…”

Novel Nanocrystal Injection of Insoluble Drug Anlotinib and Its Antitumor Effects on Hepatocellular Carcinoma

“…Since their approval, regorafenib, lenvatinib, and cabozantinib have been used for advanced HCC treatment (15)(16)(17)(18). The results of clinical trials seem to show that the new molecularly targeted drugs such as regorafenib, lenvatinib, and cabozantinib are superior to sorafenib, but the structures of these four compounds have similar chemical structure patterns, all these drugs are modifications of a basic 1-(4-(pyridin-4-yloxy)phenyl) urea structure (15)(16)(17)(18)(19)(20). Therefore, new drug candidates for treatment are needed.…”