DIRAS2 promotes radiation resistance in renal cell carcinoma via autophagy induction and MKK4-JNK1 pathway activation

被引：0
作者：
Cai, C. F. [1 ,2 ]
He, Y. [2 ]
Yue, D. [3 ]
Wang, Z. H. [1 ]
Guo, N. [1 ,4 ]
Tian, J. [1 ,4 ]
机构：
[1] Shandong Univ, Qilu Hosp, Cheeloo Coll Med, Dept Urol, Jinan 250014, Shandong, Peoples R China
[2] Shandong Univ, Qilu Hosp, Cheeloo Coll Med, Lab Basic Med Sci, Jinan 250014, Shandong, Peoples R China
[3] Jining Med Univ, Dept Urol, Affiliated Hosp, Jining 272000, Shandong, Peoples R China
[4] Shandong Univ, Qilu Hosp, Cheeloo Coll Med, Dept Organ Transplantat, Jinan 250014, Shandong, Peoples R China
来源：
INTERNATIONAL JOURNAL OF RADIATION RESEARCH | 2023年 / 21卷 / 04期
关键词：
Clear cell renal cell carcinoma; DIRAS2; autophagy; radiation resistance; RADIOTHERAPY; ROLES;
D O I：
10.61186/ijrr.21.4.805
中图分类号：
R8 [特种医学]; R445 [影像诊断学];
学科分类号：
1002 ; 100207 ; 1009 ;
摘要：
Background: To investigate the effect of DIRAS2 on the response to ionizing radiation (IR) and the related potential molecular mechanism in human ccRCC cells. Materials and Methods: In this paper, the expression levels of DIRAS2 in human ccRCC and paired normal tissues were obtained from the Oncomine platform and The Cancer Genome Atlas (TCGA) database, which was further validated by immunohistochemistry. DIRAS2-overexpression cell lines were constructed using a lentivirus-mediated gene expression system. A clonogenic assay was performed to evaluate cell radiation resistance. The effect of DIRAS2 on autophagy was determined by immunoblotting and immunofluorescence analysis. The expression of DIRAS2 and related signalling molecules was evaluated by immunoblotting. Results: Here, we found that the expression of DIRAS2 was upregulated in human ccRCC. Overexpression of DIRAS2 promoted radiation resistance in ccRCC cells and enhanced the levels of radiation-induced autophagy. Moreover, inhibition of autophagy by chloroquine (CQ) pretreatment largely eliminated the effect of DIRAS2 overexpression on radiation resistance. Finally, molecular mechanism investigation showed that DIRAS2 activated the mitogen-activated protein kinase (MAPK) kinase 4 (MKK4)-c-Jun NH2-terminal kinase 1 (JNK1)-Bcl-2 pathway. Conclusion: Taken together, these results indicated that DIRAS2 may confer radiation resistance to human RCC via autophagy induction through the MKK4-JNK1-Bcl-2 signalling pathway.
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收藏
页码：805 / 813
页数：10
相关论文
共 32 条
[1]   Requirement of clusterin expression for prosurvival autophagy in hypoxic kidney tubular epithelial cells [J].
Alnasser, Hatem A. ;
Guan, Qiunong ;
Zhang, Fan ;
Gleave, Martin E. ;
Nguan, Christopher Y. C. ;
Du, Caigan .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2016, 310 (02) :F160-F173
[2]   Signaling pathways in renal cell carcinoma [J].
Banumathy, Gowrishankar ;
Cairns, Paul .
CANCER BIOLOGY & THERAPY, 2010, 10 (07) :658-664
[3]   Radiation induces EIF2AK3/PERK and ERN1/IRE1 mediated pro-survival autophagy [J].
Chaurasia, Madhuri ;
Gupta, Swapnil ;
Das, Asmita ;
Dwarakanath, B. S. ;
Simonsen, Anne ;
Sharma, Kulbhushan .
AUTOPHAGY, 2019, 15 (08) :1391-1406
[4]   Targeting the HIF2-VEGF axis in renal cell carcinoma [J].
Choueiri, Toni K. ;
Kaelin, William G., Jr. .
NATURE MEDICINE, 2020, 26 (10) :1519-1530
[5]   Comprehensivemolecular characterization of clear cell renal cell carcinoma [J].
Creighton, Chad J. ;
Morgan, Margaret ;
Gunaratne, Preethi H. ;
Wheeler, David A. ;
Gibbs, Richard A. ;
Robertson, A. Gordon ;
Chu, Andy ;
Beroukhim, Rameen ;
Cibulskis, Kristian ;
Signoretti, Sabina ;
Vandin, Fabio ;
Wu, Hsin-Ta ;
Raphael, Benjamin J. ;
Verhaak, Roel G. W. ;
Tamboli, Pheroze ;
Torres-Garcia, Wandaliz ;
Akbani, Rehan ;
Weinstein, John N. ;
Reuter, Victor ;
Hsieh, James J. ;
Brannon, A. Rose ;
Hakimi, A. Ari ;
Jacobsen, Anders ;
Ciriello, Giovanni ;
Reva, Boris ;
Ricketts, Christopher J. ;
Linehan, W. Marston ;
Stuart, Joshua M. ;
Rathmell, W. Kimryn ;
Shen, Hui ;
Laird, Peter W. ;
Muzny, Donna ;
Davis, Caleb ;
Morgan, Margaret ;
Xi, Liu ;
Chang, Kyle ;
Kakkar, Nipun ;
Trevino, Lisa R. ;
Benton, Susan ;
Reid, Jeffrey G. ;
Morton, Donna ;
Doddapaneni, Harsha ;
Han, Yi ;
Lewis, Lora ;
Dinh, Huyen ;
Kovar, Christie ;
Zhu, Yiming ;
Santibanez, Jireh ;
Wang, Min ;
Hale, Walker .
NATURE, 2013, 499 (7456) :43-+
[6]   Radiotherapy for renal-cell carcinoma [J].
De Meerleer, Gert ;
Khoo, Vincent ;
Escudier, Bernard ;
Joniau, Steven ;
Bossi, Alberto ;
Ost, Piet ;
Briganti, Alberto ;
Fonteyne, Valerie ;
Van Vulpen, Marco ;
Lumen, Nicolaas ;
Spahn, Martin ;
Mareel, Marc .
LANCET ONCOLOGY, 2014, 15 (04) :E170-E177
[7]   Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy [J].
Eng, Christina H. ;
Wang, Zuncai ;
Tkach, Diane ;
Toral-Barza, Lourdes ;
Ugwonali, Savuth ;
Liu, Shanming ;
Fitzgerald, Stephanie L. ;
George, Elizabeth ;
Frias, Elizabeth ;
Cochran, Nadire ;
De Jesus, Rowena ;
McAllister, Gregory ;
Hoffman, Gregory R. ;
Bray, Kevin ;
Lemon, LuAnna ;
Lucas, Judy ;
Fantin, Valeria R. ;
Abraham, Robert T. ;
Murphy, Leon O. ;
Nyfeler, Beat .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2016, 113 (01) :182-187
[8]   Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 [J].
Ferlay, Jacques ;
Soerjomataram, Isabelle ;
Dikshit, Rajesh ;
Eser, Sultan ;
Mathers, Colin ;
Rebelo, Marise ;
Parkin, Donald Maxwell ;
Forman, David ;
Bray, Freddie .
INTERNATIONAL JOURNAL OF CANCER, 2015, 136 (05) :E359-E386
[9]   Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy [J].
Galluzzi, Lorenzo ;
Bravo-San Pedro, Jose Manuel ;
Demaria, Sandra ;
Formenti, Silvia Chiara ;
Kroemer, Guido .
NATURE REVIEWS CLINICAL ONCOLOGY, 2017, 14 (04) :247-258
[10]  
Gasper Raphael, 2010, Small GTPases, V1, P133, DOI 10.4161/sgtp.1.3.14742
1234