Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

Abstract

Increasing evidence has shown that the metabolism and clearance of molecular targeted agents, such as sorafenib, plays an important role in mediating the resistance of HCC cells to these agents. Metabolism of sorafenib is performed by oxidative metabolism, which is initially mediated by CYP3A4. Thus, targeting CYP3A4 is a promising approach to enhance the sensitivity of HCC cells to chemotherapeutic agents. In the present work, we examined the association between CYP3A4 and the prognosis of HCC patients receiving sorafenib. Using the online tool miRDB, we predicted that has-microRNA-4277 (miR-4277), an online miRNA targets the 3’UTR of the transcript of cyp3a4. Furthermore, overexpression of miR-4277 in HCC cells repressed the expression of CYP3A4 and reduced the elimination of sorafenib in HCC cells. Moreover, miR-4277 enhanced the sensitivity of HCC cells to sorafenib in vitro and in vivo. Therefore, our results not only expand our understanding of CYP3A4 regulation in HCC, but also provide evidence for the use of miR-4277 as a potential therapeutic in advanced HCC.

A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma

“…After 2-3 weeks of injection, the length and width of the nude mice's subcutaneous tumors were measured. and the tumor volume was calculated as follows: tumor volume = subcutaneous tumor length × width × width/2, when the volume of the subcutaneous tumor reached approximately 1000-1200 mm 3 , the construction of the immunodeficiency nude mouse subcutaneous tumor model was completed (42)(43)(44)(45)(46). The Warburg effect related factors or EMT related factors in the were examined following the methods descripted by Yin et al, 2019 (47).…”

“…The pharmacokinetic properties of Bay-876 were determined in subcutaneous tumor model following the methods described previously (21,(42)(43)(44)(45)(46)(47). Briefly, the BAY-876 solution or microcrystalline formulation was injected into the subcutaneous tumors and the tumor tissues were harvested at the indicated time points.…”

“…The antitumor effect of these formulations was measured by determining tumor volumes, tumor weights, or using microPET. The aerobic glycolysis of the tumor tissues were measured following the methods described by Yin et al (42). The body-weights or the liver-weights of Immunodeficiency rat were examined (24)(25)(26)(27).…”

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

“…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).…”

DataSheet_1.doc

“…In order to overcome the shortcomings of Sorafenib, newly molecular targeted drugs including Regorafenib, Lenvatinib and Cabozantinib have been approved for marketing one after another (78)(79)(80). Although it is currently believed that these drugs are generally superior to Sorafenib, these agents (lenvatinib, regorafenib, and carbozantinib) have the same chemical core structure (1-(4-(pyridin-4-yloxy)phenyl) urea) with sorafenib (81). Therefore, it is urgent to develop the novel research strategies.…”