Relevance of two genes in the multidrug resistance of hepatocellular carcinoma: in vivo and clinical studies.
OBJECTIVE
A former study evaluated the roles of four multidrug resistance-related proteins, namely multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), multidrug resistance-related protein (MRP1), and lung resistance-related protein (LRP), in the MDR mechanism of the multidrug resistant hepatoma HepG2/ADM cell line and proposed that up-regulated MDR1 and BCRP are responsible for the MDR of hepatocellular carcinoma. This work aims to confirm that assumption in vivo and in clinical specimens.


METHODS
First, the chemotherapeutic resistance of subcutaneous HepG2/ADM tumor and hepatocellular carcinoma samples post-transarterial chemoembolization (TACE) was determined by MTT, contrary to subcutaneous HepG2 tumor and hepatocellular carcinoma samples without TACE, respectively. Then, the mRNA and protein differential expression of the four genes between the MDR tissues and drug-sensitive tissues were quantitatively investigated by real-time RT-PCR and enhanced chemiluminescence western blot analysis, respectively.


RESULTS
1) mRNA expression of BCRP and MDR1 was respectively amplified 38.3 and 20.1 fold in tumors of HepG2/ADM mice compared to those of HepG2 mice, whereas they were respectively augmented for 14.6 and 9.3 times in TACE samples, contrary to the tumor tissues without TACE. 2) The protein presence of MDR1 and BCRP in MDR tumors was also significantly higher than those in the control group in vivo and in clinical specimens. 3) The mRNA expressions of MDR1 and BCRP were correlated to their protein levels.


CONCLUSIONS
The study showed that MDR1 and BCRP may be the most important factors for drug resistance in hepatocellular carcinoma. Moreover, the positive correlation between their mRNA and protein expression indicates the easy prediction of HCC MDR and possible inhibitive target of drug resistance at multi-levels.
Sun
Zhengang
Z
Department of Hepatobiliary Surgery Jingzhou Central Hospital, JingZhou, Hubei Province, China.
Zhao
Zizhuo
Z
Li
Gaopeng
G
Dong
Shengli
S
Huang
Zhiyong
Z
Ye
Lu
L
Liang
Huifang
H
Qu
Junyuan
J
Ai
Xi
X
Zhang
Wanguang
W
Chen
Xiaoping
X
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D016461:Chemoembolization, Therapeutic; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics; D000099187:Major Vault Protein
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1