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To investigate the mechanism of drug resistance occurring in hepatocellular carcinoma treated with sorafeinib from epigenetic perspective, and examine the effect of sensitivity of sorafeinib on hepatocellular carcinoma after in vita combination of epigenetic drug decitabine (DAC), so as to provide new ideas and methods for clinical treatment of hepatocellular carcinoma.
The GEPIA 2 database was used to retrieve information of 508 primary hepatocellular liver cancer patients, and the correlation between the expression of OATP1B3 and survival time was analyzed by Kaplan-Meier method. The methylation rate of SLCO1B3 promoter was detected by bisulfite methylation method. RT-qPCR and Western blot were used to detect the expression changes of cancer cell lines OATP1B3 before and after liver DAC treatment. RTCA-eSight experiment was performed to monitor the effect of sorafeinib in combination with DAC on the proliferation of hepatocellular carcinoma cells. Changes in the uptake of sorafeinib by hepatocellular carcinoma cells after the combination of the two drugs were detected by experimental LC-MS/MS.
The results of GEPIA2 database analysis showed that the overall survival rate of patients with hepatocellular carcinoma with high OATP1B3 expression was significantly higher than those with low expression. Bisulfite methylation sequencing showed that the promoter methylation rate of SLCO1B3 was higher in Hep3B and HepG2. RT-qPCR and Western blot showed that the mRNA and protein expressions of OATP1B3 in hepatocellular carcinoma cell lines Hep3B and HepG2 were relatively low, and the expression of OATP1B3 was upregulated after incubation with DAC. RTCA-eSight experiment showed that DAC combination treatment significantly enhanced the effect of sorafeinib on Hep3B and HepG2 inhibition. LC-MS/MS determination showed that the uptake of HEK293-OATP1B3 on sorafeinib was 2.10 times higher than that of HEK293-Wild. The uptake of sorafeinib by Hep3B and HepG2 was increased by 1.87-fold and 2.47-fold after being combined with DAC.
DAC can inhibit SLCO1B3 DNA methylation, up-regulate the expression of OATP1B3, improve the capacity of sorafenib transport, increase the accumulation of sorafenib in liver cancer cells, and enhance the sensitivity of liver cancer cells, so as to reverse the resistance of sorafenib.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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