Impact of O6-methylguanine-DNA methyltransferase expression on the drug resistance of clear cell renal cell carcinoma

Nan Ge; Liqiang Guo; Jie Zhang; Zhaomin Lin; Yan Li; Yuqiang Liu; Feng Kong; Xiaolei Fang; Shengtian Zhao

doi:10.1093/jjco/hyv095

Impact of O6-methylguanine-DNA methyltransferase expression on the drug resistance of clear cell renal cell carcinoma

Jpn J Clin Oncol. 2015 Sep;45(9):860-6. doi: 10.1093/jjco/hyv095. Epub 2015 Jul 16.

Authors

Nan Ge¹, Liqiang Guo¹, Jie Zhang¹, Zhaomin Lin², Yan Li³, Yuqiang Liu¹, Feng Kong², Xiaolei Fang¹, Shengtian Zhao⁴

Affiliations

¹ Department of Urology Surgery, The Second Hospital, Shandong University, Jinan.
² Central Research Laboratory, The Second Hospital, Shandong University, Jinan.
³ Department of Radiology, The Affiliated Hospital, Shandong University of Traditional Chinese Medicine, Jinan, PR China.
⁴ Department of Urology Surgery, The Second Hospital, Shandong University, Jinan zhaoshengtian@sdu.edu.cn.

PMID: 26185135
DOI: 10.1093/jjco/hyv095

Abstract

Objective: The deoxyribonucleic acid-repair protein O(6)-methylguanine-deoxyribonucleic acid methyltransferase is a major determinant of resistance of cells to various alkylating drugs. Its expression profile is different in different cancer types. Here, we studied the expression and function of O(6)-methylguanine-deoxyribonucleic acid methyltransferase in clear cell renal cell carcinoma.

Methods: The expression of O(6)-methylguanine-deoxyribonucleic acid methyltransferase was evaluated in clear cell renal cell carcinoma tissues and cell lines by quantitative real-time polymerase chain reaction and immunohistochemistry. The relationship between O(6)-methylguanine-deoxyribonucleic acid methyltransferase expression and clinicopathological characteristics was analyzed. To further investigate the function of O(6)-methylguanine-deoxyribonucleic acid methyltransferase in clear cell renal cell carcinoma resistance to alkylating agents, siRNA targeting O(6)-methylguanine-deoxyribonucleic acid methyltransferase were used to silence the O(6)-methylguanine-deoxyribonucleic acid methyltransferase expression.

Results: We found that O(6)-methylguanine-deoxyribonucleic acid methyltransferase is over-expressed in clear cell renal cell carcinoma tissues and cell lines. O(6)-methylguanine-deoxyribonucleic acid methyltransferase expression is related with tumor progression in clear cell renal cell carcinoma patients. Up-regulation of O(6)-methylguanine-deoxyribonucleic acid methyltransferase plays a critical role in primary resistance to alkylating agents.

Conclusions: The overexpression of O(6)-methylguanine-deoxyribonucleic acid methyltransferase contributes to resistance of clear cell renal cell carcinoma to standard chemotherapy. Our results have significance for understanding a new pathway of the development of drug resistance of clear cell renal cell carcinoma.

Keywords: MGMT; alkylating agents; clear cell renal cell carcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Antineoplastic Agents, Alkylating / pharmacology
Antineoplastic Agents, Alkylating / therapeutic use
Carcinoma, Renal Cell / drug therapy
Carcinoma, Renal Cell / metabolism
Carcinoma, Renal Cell / pathology*
Cell Line, Tumor
Cell Survival / drug effects
Drug Resistance, Neoplasm
Female
Humans
Immunohistochemistry
Kidney Neoplasms / drug therapy
Kidney Neoplasms / metabolism
Kidney Neoplasms / pathology*
Male
Middle Aged
O(6)-Methylguanine-DNA Methyltransferase / antagonists & inhibitors
O(6)-Methylguanine-DNA Methyltransferase / genetics
O(6)-Methylguanine-DNA Methyltransferase / metabolism*
RNA Interference
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Real-Time Polymerase Chain Reaction
Up-Regulation / drug effects

Substances

Antineoplastic Agents, Alkylating
RNA, Messenger
RNA, Small Interfering
O(6)-Methylguanine-DNA Methyltransferase