Deficiency of 53BP1 inhibits the radiosensitivity of colorectal cancer

被引：15

作者：

Xiao, Yong ^{[1
]}

Zheng, Xiumei ^{[1
]}

Huang, Ai ^{[1
]}

Liu, Tao ^{[1
]}

Zhang, Tao ^{[1
]}

Ma, Hong ^{[1
]}

机构：

[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Ctr Canc, 1277 Jiefang Ave, Wuhan 430022, Hubei, Peoples R China

来源：

INTERNATIONAL JOURNAL OF ONCOLOGY | 2016年 / 49卷 / 04期

关键词：

53BP1; ATM-CHK2-p53; pathway; colorectal cancer; DNA damage repair; radiosensitivity; DNA-DAMAGE RESPONSE; HAPLOINSUFFICIENT TUMOR-SUPPRESSOR; ONCOGENE-INDUCED SENESCENCE; GENOMIC INSTABILITY; IONIZING-RADIATION; BRCA1; DEFICIENCY; RADIOTHERAPY; EXPRESSION; CELLS; P53;

D O I：

10.3892/ijo.2016.3629

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The present study aimed to observe the influence of p53 binding protein 1 (53BP1) silencing on the radiosensitivity of colorectal cancer (CRC) cells and investigated the potential underlying mechanisms. The differences in radiosensitivity among four CRC cells were detected by the clone formation assay, while the expression of their 53BP1 was detected by the western blot analysis. HCT116 cells with relatively high expression of 53BP1 were selected to silence the expression of 53BP1 by shRNA intervention. The influence on proliferation, apoptosis, and cell cycle distribution was detected by immunofluorescent staining of Ki-67 and flow cytometry. The expression of relevant proteins in the apoptotic pathway ATM-CHK2-p53 was further analyzed by western blot analysis. The expression of 53BP1 was found to be closely related to the radiosensitivity of the CRC cells. Decreased expression of 53BP1 led to the tolerance of HCT116 cells to radiation. The detection of tumor proliferation, apoptosis, and cell cycle showed that decreased expression of 53BP1 resulted in an increased S-phase percentage of HCT116 cells, an increased proliferating rate, and a decreased apoptotic rate after radiation. The analysis of the molecular pathway showed that the reduced expression of 53BP1 decreased the protein expression of ATM, CHK2, and the phosphorylated products associated with the p53 apoptotic pathway. In conclusion, decreased expression of 53BP1 leads to radiotolerance of CRC cells, and the underlying mechanism is probably related to the decreased expression of relevant proteins in the ATM-CHK2-p53 pathway, which affects cell cycle, apoptosis and proliferation.

引用

页码：1600 / 1608

页数：9

共 30 条

[1] 53BP1 expression is a modifier of the prognostic value of lymph node ratio and CA 19-9 in pancreatic adenocarcinoma [J].

Ausborn, Natalie L. ;

Wang, Tong ;

Wentz, Sabrina C. ;

Washington, Mary Kay ;

Merchant, Nipun B. ;

Zhao, Zhiguo ;

Shyr, Yu ;

Chakravarthy, Anuradha Bapsi ;

Xia, Fen .

BMC CANCER, 2013, 13

[2] DNA damage response mediators MDC1 and 53BP1:: constitutive activation and aberrant loss in breast and lung cancer, but not in testicular germ cell tumours [J].

Bartkova, J. ;

Horejsi, Z. ;

Sehested, M. ;

Nesland, J. M. ;

Rajpert-De Meyts, E. ;

Skakkebaek, N. E. ;

Stucki, M. ;

Jackson, S. ;

Lukas, J. ;

Bartek, J. .

ONCOGENE, 2007, 26 (53) :7414-7422

[3] Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints [J].

Bartkova, Jirina ;

Rezaei, Nousin ;

Liontos, Michalis ;

Karakaidos, Panagiotis ;

Kletsas, Dimitris ;

Issaeva, Natalia ;

Vassiliou, Leandros-Vassilios F. ;

Kolettas, Evangelos ;

Niforou, Katerina ;

Zoumpourlis, Vassilis C. ;

Takaoka, Munenori ;

Nakagawa, Hiroshi ;

Tort, Frederic ;

Fugger, Kasper ;

Johansson, Fredrik ;

Sehested, Maxwell ;

Andersen, Claus L. ;

Dyrskjot, Lars ;

Orntoft, Torben ;

Lukas, Jiri ;

Kittas, Christos ;

Helleday, Thomas ;

Halazonetis, Thanos D. ;

Bartek, Jiri ;

Gorgoulis, Vassilis G. .

NATURE, 2006, 444 (7119) :633-637

[4]

Bi JP, 2015, INT J CLIN EXP PATHO, V8, P6070

[5] 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers [J].

Bouwman, Peter ;

Aly, Amal ;

Escandell, Jose M. ;

Pieterse, Mark ;

Bartkova, Jirina ;

van der Gulden, Hanneke ;

Hiddingh, Sanne ;

Thanasoula, Maria ;

Kulkarni, Atul ;

Yang, Qifeng ;

Haffty, Bruce G. ;

Tommiska, Johanna ;

Blomqvist, Carl ;

Drapkin, Ronny ;

Adams, David J. ;

Nevanlinna, Heli ;

Bartek, Jiri ;

Tarsounas, Madalena ;

Ganesan, Shridar ;

Jonkers, Jos .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2010, 17 (06) :688-U56

[6] A Selective Requirement for 53BP1 in the Biological Response to Genomic Instability Induced by Brca1 Deficiency [J].

Cao, Liu ;

Xu, Xioaling ;

Bunting, Samuel F. ;

Liu, Jie ;

Wang, Rui-Hong ;

Cao, Longyue L. ;

Wu, J. Julie ;

Peng, Tie-Nan ;

Chen, Junjie ;

Nussenzweig, Andre ;

Deng, Chu-Xia ;

Finkel, Toren .

MOLECULAR CELL, 2009, 35 (04) :534-541

[7] Lysine methylation-dependent binding of 53BP1 to the pRb tumor suppressor [J].

Carr, Simon M. ;

Munro, Shonagh ;

Zalmas, Lykourgos-Panagiotis ;

Fedorov, Oleg ;

Johansson, Catrine ;

Krojer, Tobias ;

Sagum, Cari A. ;

Bedford, Mark T. ;

Oppermann, Udo ;

La Thangue, Nicholas B. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (31) :11341-11346

[8] FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage [J].

Chung, Young Min ;

Park, See-Hyoung ;

Tsai, Wen-Bin ;

Wang, Shih-Ya ;

Ikeda, Masa-Aki ;

Berek, Jonathan S. ;

Chen, David J. ;

Hu, Mickey C. -T. .

NATURE COMMUNICATIONS, 2012, 3

[9] 53BP1 deficiency in intestinal enterocytes does not alter the immediate response to ionizing radiation, but leads to increased nuclear area consistent with polyploidy [J].

Clarke, A. R. ;

Jones, N. ;

Pryde, F. ;

Adachi, Y. ;

Sansom, O. J. .

ONCOGENE, 2007, 26 (43) :6349-6355

[10] Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication [J].

Di Micco, Raffaella ;

Fumagalli, Marzia ;

Cicalese, Angelo ;

Piccinin, Sara ;

Gasparini, Patrizia ;

Luise, Chiara ;

Schurra, Catherine ;

Garre, Massimiliano ;

Nuciforo, Paolo Giovanni ;

Bensimon, Aaron ;

Maestro, Roberta ;

Pelicci, Pier Giuseppe ;

di Fagagna, Fabrizio d'Adda .

NATURE, 2006, 444 (7119) :638-642

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