Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

邮发代号 80-967

2019 Impact Factor: 3.421

Frontiers of Medicine  2024, Vol. 18 Issue (5): 921-937   https://doi.org/10.1007/s11684-024-1082-6
  本期目录
Polymorphism in the Hsa-miR-4274 seed region influences the expression of PEX5 and enhances radiotherapy resistance in colorectal cancer
Qixuan Lu1, Ningxin Ren1, Hongxia Chen1, Shaosen Zhang1, Ruoqing Yan1, Mengjie Li1, Linlin Zheng1, Wen Tan1(), Dongxin Lin1,2()
. State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China
 全文: PDF(7700 KB)   HTML
Abstract

Identifying biomarkers for predicting radiotherapy efficacy is crucial for optimizing personalized treatments. We previously reported that rs1553867776 in the miR-4274 seed region can predict survival in patients with rectal cancer receiving postoperative chemoradiation therapy. Hence, to investigate the molecular mechanism of the genetic variation and its impact on the radiosensitivity of colorectal cancer (CRC), in this study, bioinformatics analysis is combined with functional experiments to confirm peroxisomal biogenesis factor 5 (PEX5) as a direct target of miR-4274. The miR-4274 rs1553867776 variant influences the binding of miR-4274 and PEX5 mRNA, which subsequently regulates PEX5 protein expression. The interaction between PEX5 and Ku70 was verified by co-immunoprecipitation and immunofluorescence. A xenograft tumor model was established to validate the effects of miR-4274 and PEX5 on CRC progression and radiosensitivity in vivo. The overexpression of PEX5 enhances radiosensitivity by preventing Ku70 from entering the nucleus and reducing the repair of ionizing radiation (IR)-induced DNA damage by the Ku70/Ku80 complex in the nucleus. In addition, the enhanced expression of PEX5 is associated with increased IR-induced ferroptosis. Thus, targeting this mechanism might effectively increase the radiosensitivity of CRC. These findings offer novel insights into the mechanism of cancer radioresistance and have important implications for clinical radiotherapy.

Key wordscolorectal cancer    polymorphism    miR-4274    PEX5    radiotherapy resistance
收稿日期: 2023-12-14      出版日期: 2024-10-29
Corresponding Author(s): Wen Tan,Dongxin Lin   
 引用本文:   
. [J]. Frontiers of Medicine, 2024, 18(5): 921-937.
Qixuan Lu, Ningxin Ren, Hongxia Chen, Shaosen Zhang, Ruoqing Yan, Mengjie Li, Linlin Zheng, Wen Tan, Dongxin Lin. Polymorphism in the Hsa-miR-4274 seed region influences the expression of PEX5 and enhances radiotherapy resistance in colorectal cancer. Front. Med., 2024, 18(5): 921-937.
 链接本文:  
https://academic.hep.com.cn/fmd/CN/10.1007/s11684-024-1082-6
https://academic.hep.com.cn/fmd/CN/Y2024/V18/I5/921
Fig.1  
Fig.2  
Fig.3  
Fig.4  
Fig.5  
Fig.6  
Fig.7  
1 RL Siegel, KD Miller, NS Wagle, A Jemal. Cancer statistics, 2023. CA Cancer J Clin 2023; 73(1): 17–48
https://doi.org/10.3322/caac.21763
2 E Dekker, PJ Tanis, JLA Vleugels, PM Kasi, MB Wallace. Colorectal cancer. Lancet 2019; 394(10207): 1467–1480
https://doi.org/10.1016/S0140-6736(19)32319-0
3 S Pucci, C Polidoro, A Joubert, F Mastrangeli, B Tolu, M Benassi, V Fiaschetti, L Greco, R Miceli, R Floris, G Novelli, A Orlandi, R Santoni. Ku70, Ku80, and sClusterin: acluster of predicting factors for response to neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2017; 97(2): 381–388
https://doi.org/10.1016/j.ijrobp.2016.10.018
4 W Liu, C Miao, S Zhang, Y Liu, X Niu, Y Xi, W Guo, J Chu, A Lin, H Liu, X Yang, X Chen, C Zhong, Y Ma, Y Wang, S Zhu, S Liu, W Tan, D Lin, C Wu. VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance. Signal Transduct Target Ther 2021; 6(1): 322
https://doi.org/10.1038/s41392-021-00735-9
5 DP Bartel. Metazoan MicroRNAs. Cell 2018; 173(1): 20–51
https://doi.org/10.1016/j.cell.2018.03.006
6 DW Salzman, JB Weidhaas. SNPing cancer in the bud: microRNA and microRNA-target site polymorphisms as diagnostic and prognostic biomarkers in cancer. Pharmacol Ther 2013; 137(1): 55–63
https://doi.org/10.1016/j.pharmthera.2012.08.016
7 C Shen, T Yan, Z Wang, HC Su, X Zhu, X Tian, JY Fang, H Chen, J Hong. Variant of SNP rs1317082 at CCSlnc362 (RP11-362K14.5) creates a binding site for miR-4658 and diminishes the susceptibility to CRC. Cell Death Dis 2018; 9(12): 1177
https://doi.org/10.1038/s41419-018-1222-5
8 W Wang, C Yang, H Nie, X Qiu, L Zhang, Y Xiao, W Zhou, Q Zeng, X Zhang, Y Wu, J Liu, M Ying. LIMK2 acts as an oncogene in bladder cancer and its functional SNP in the microRNA-135a binding site affects bladder cancer risk. Int J Cancer 2019; 144(6): 1345–1355
https://doi.org/10.1002/ijc.31757
9 H Chen, L Yin, J Yang, N Ren, J Chen, Q Lu, Y Huang, Y Feng, W Wang, S Wang, Y Liu, Y Song, Y Li, J Jin, W Tan, D Lin. Genetic polymorphisms in genes regulating cell death and prognosis of patients with rectal cancer receiving postoperative chemoradiotherapy. Cancer Biol Med 2023; 20(4): 297–316
https://doi.org/10.20892/j.issn.2095-3941.2022.0711
10 Y Huang, Y Feng, H Ren, M Zhang, H Li, Y Qiao, T Feng, J Yang, W Wang, S Wang, Y Liu, Y Song, Y Li, J Jin, W Tan, D Lin. Associations of genetic variations in microRNA seed regions with acute adverse events and survival in patients with rectal cancer receiving postoperative chemoradiation therapy. Int J Radiat Oncol Biol Phys 2018; 100(4): 1026–1033
https://doi.org/10.1016/j.ijrobp.2017.12.256
11 N Landeros, AH Corvalan, M Musleh, LA Quiñones, NM Varela, P Gonzalez-Hormazabal. Novel risk associations between microRNA polymorphisms and gastric cancer in a Chilean population. Int J Mol Sci 2021; 23(1): 467
https://doi.org/10.3390/ijms23010467
12 M Shkurnikov, S Nikulin, S Nersisyan, A Poloznikov, S Zaidi, A Baranova, U Schumacher, D Wicklein, A Tonevitsky. LAMA4-regulating miR-4274 and its host gene SORCS2 play a role in IGFBP6-dependent effects on phenotype of basal-like breast cancer. Front Mol Biosci 2019; 6: 122
https://doi.org/10.3389/fmolb.2019.00122
13 S Liu, HL Zhang, J Li, ZP Ye, T Du, LC Li, YQ Guo, D Yang, ZL Li, JH Cao, BX Hu, YH Chen, GK Feng, ZM Li, R Deng, JJ Huang, XF Zhu. Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis. Redox Biol 2023; 62: 102677
https://doi.org/10.1016/j.redox.2023.102677
14 G Lei, C Mao, Y Yan, L Zhuang, B Gan. Ferroptosis, radiotherapy, and combination therapeutic strategies. Protein Cell 2021; 12(11): 836–857
https://doi.org/10.1007/s13238-021-00841-y
15 X Wang, Y Zhou, J Min, F Wang. Zooming in and out of ferroptosis in human disease. Front Med 2023; 17(2): 173–206
https://doi.org/10.1007/s11684-023-0992-z
16 Y Zou, WS Henry, EL Ricq, ET Graham, VV Phadnis, P Maretich, S Paradkar, N Boehnke, AA Deik, F Reinhardt, JK Eaton, B Ferguson, W Wang, J Fairman, HR Keys, V Dančík, CB Clish, PA Clemons, PT Hammond, LA Boyer, RA Weinberg, SL Schreiber. Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature 2020; 585(7826): 603–608
https://doi.org/10.1038/s41586-020-2732-8
17 R Ravindran, IOL Bacellar, X Castellanos-Girouard, HM Wahba, Z Zhang, JG Omichinski, L Kisley, SW Michnick. Peroxisome biogenesis initiated by protein phase separation. Nature 2023; 617(7961): 608–615
https://doi.org/10.1038/s41586-023-06044-1
18 X Chen, R Kang, G Kroemer, D Tang. Organelle-specific regulation of ferroptosis. Cell Death Differ 2021; 28(10): 2843–2856
https://doi.org/10.1038/s41418-021-00859-z
19 Y Fujiki, K Okumoto, M Honsho, Y Abe. Molecular insights into peroxisome homeostasis and peroxisome biogenesis disorders. Biochim Biophys Acta Mol Cell Res 2022; 1869(11): 119330
https://doi.org/10.1016/j.bbamcr.2022.119330
20 H Yan, R Talty, O Aladelokun, M Bosenberg, CH Johnson. Ferroptosis in colorectal cancer: a future target. Br J Cancer 2023; 128(8): 1439–1451
https://doi.org/10.1038/s41416-023-02149-6
21 C Sticht, C De La Torre, A Parveen, N Gretz. miRWalk: An online resource for prediction of microRNA binding sites. PLoS One 2018; 13(10): e0206239
https://doi.org/10.1371/journal.pone.0206239
22 S Bandyopadhyay, R Mitra. TargetMiner: microRNA target prediction with systematic identification of tissue-specific negative examples. Bioinformatics 2009; 25(20): 2625–2631
https://doi.org/10.1093/bioinformatics/btp503
23 A Bhattacharya, JD Ziebarth, Y Cui. PolymiRTS Database 3.0: linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways. Nucleic Acids Res 2014; 42(Database issue): D86–D91
https://doi.org/10.1093/nar/gkt1028
24 MD Paraskevopoulou, G Georgakilas, N Kostoulas, IS Vlachos, T Vergoulis, M Reczko, C Filippidis, T Dalamagas, AG Hatzigeorgiou. DIANA-microT web server v5.0: service integration into miRNA functional analysis workflows. Nucleic Acids Res 2013; 41(W1): W169–W173
https://doi.org/10.1093/nar/gkt393
25 Y Chen, X Wang. miRDB: an online database for prediction of functional microRNA targets. Nucleic Acids Res 2020; 48(D1): D127–D131
https://doi.org/10.1093/nar/gkz757
26 V Agarwal, GW Bell, JW Nam, DP Bartel. Predicting effective microRNA target sites in mammalian mRNAs. eLife 2015; 4: e05005
https://doi.org/10.7554/eLife.05005
27 DS Chandrashekar, SK Karthikeyan, PK Korla, H Patel, AR Shovon, M Athar, GJ Netto, ZS Qin, S Kumar, U Manne, CJ Creighton, S Varambally. UALCAN: An update to the integrated cancer data analysis platform. Neoplasia 2022; 25: 18–27
https://doi.org/10.1016/j.neo.2022.01.001
28 T Li, J Fu, Z Zeng, D Cohen, J Li, Q Chen, B Li, XS Liu. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res 2020; 48(W1): W509–W514
https://doi.org/10.1093/nar/gkaa407
29 Y Zhou, B Zhou, L Pache, M Chang, AH Khodabakhshi, O Tanaseichuk, C Benner, SK Chanda. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019; 10(1): 1523
https://doi.org/10.1038/s41467-019-09234-6
30 S Huang, D Fantini, BJ Merrill, S Bagchi, G Guzman, P Raychaudhuri. DDB2 is a novel regulator of Wnt signaling in colon cancer. Cancer Res 2017; 77(23): 6562–6575
https://doi.org/10.1158/0008-5472.CAN-17-1570
31 S Burdak-Rothkamm, K Rothkamm, K McClelland, ST Al Rashid, KM Prise. BRCA1, FANCD2 and Chk1 are potential molecular targets for the modulation of a radiation-induced DNA damage response in bystander cells. Cancer Lett 2015; 356(2 2 Pt B): 454–461
https://doi.org/10.1016/j.canlet.2014.09.043
32 C Han, Z Liu, Y Zhang, A Shen, C Dong, A Zhang, C Moore, Z Ren, C Lu, X Cao, CL Zhang, J Qiao, YX Fu. Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling. Nat Immunol 2020; 21(5): 546–554
https://doi.org/10.1038/s41590-020-0641-5
33 N Sándor, B Schilling-Tóth, E Kis, L Fodor, F Mucsányi, G Sáfrány, H Hegyesi. TP53inp1 gene is implicated in early radiation response in human fibroblast cells. Int J Mol Sci 2015; 16(10): 25450–25465
https://doi.org/10.3390/ijms161025450
34 TU Bracker, A Sommer, I Fichtner, H Faus, B Haendler, H Hess-Stumpp. Efficacy of MS-275, a selective inhibitor of class I histone deacetylases, in human colon cancer models. Int J Oncol 2009; 35(4): 909–920
35 Genome Atlas Network Cancer. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487(7407): 330–337
https://doi.org/10.1038/nature11252
36 D Huang, C Du, D Ji, J Xi, J Gu. Overexpression of LAMC2 predicts poor prognosis in colorectal cancer patients and promotes cancer cell proliferation, migration, and invasion. Tumour Biol 2017; 39(6): 1010428317705849
https://doi.org/10.1177/1010428317705849
37 AM Vasilogianni, ZM Al-Majdoub, B Achour, SA Peters, A Rostami-Hodjegan, J Barber. Proteomic quantification of receptor tyrosine kinases involved in the development and progression of colorectal cancer liver metastasis. Front Oncol 2023; 13: 1010563
https://doi.org/10.3389/fonc.2023.1010563
38 Y Liu, Y Deguchi, R Tian, D Wei, L Wu, W Chen, W Xu, M Xu, F Liu, S Gao, JC Jaoude, SP Chrieki, MJ Moussalli, M Gagea, J Morris, RR Broaddus, X Zuo, I Shureiqi. Pleiotropic effects of PPARD accelerate colorectal tumorigenesis, progression, and invasion. Cancer Res 2019; 79(5): 954–969
https://doi.org/10.1158/0008-5472.CAN-18-1790
39 B Köse, RV Laar, HV Beekhuizen, FV Kemenade, AT Baykal, T Luider, C Güzel. Quantitative proteomic analysis of MCM3 in ThinPrep samples of patients with cervical preinvasive cancer. Int J Mol Sci 2023; 24(13): 10473
https://doi.org/10.3390/ijms241310473
40 J Lou, L Wei, H Wang. SCNN1A overexpression correlates with poor prognosis and immune infiltrates in ovarian cancer. Int J Gen Med 2022; 15: 1743–1763
https://doi.org/10.2147/IJGM.S351976
41 WL Cheng, PH Feng, KY Lee, KY Chen, WL Sun, N Van Hiep, CS Luo, SM Wu. The role of EREG/EGFR pathway in tumor progression. Int J Mol Sci 2021; 22(23): 12828
https://doi.org/10.3390/ijms222312828
42 H Sui, M Hao, W Chang, T Imamichi. The role of Ku70 as a cytosolic DNA sensor in innate immunity and beyond. Front Cell Infect Microbiol 2021; 11: 761983
https://doi.org/10.3389/fcimb.2021.761983
43 MD Yang, CW Tsai, WS Chang, YA Tsou, CN Wu, DT Bau. Predictive role of XRCC5/XRCC6 genotypes in digestive system cancers. World J Gastrointest Oncol 2011; 3(12): 175–181
https://doi.org/10.4251/wjgo.v3.i12.175
44 P Liao, W Wang, W Wang, I Kryczek, X Li, Y Bian, A Sell, S Wei, S Grove, JK Johnson, PD Kennedy, M Gijón, YM Shah, W Zou. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell 2022; 40(4): 365–378.e6
https://doi.org/10.1016/j.ccell.2022.02.003
45 J Quan, AM Bode, X Luo. ACSL family: The regulatory mechanisms and therapeutic implications in cancer. Eur J Pharmacol 2021; 909: 174397
https://doi.org/10.1016/j.ejphar.2021.174397
46 G Lei, Y Zhang, P Koppula, X Liu, J Zhang, SH Lin, JA Ajani, Q Xiao, Z Liao, H Wang, B Gan. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res 2020; 30(2): 146–162
https://doi.org/10.1038/s41422-019-0263-3
47 X Lang, MD Green, W Wang, J Yu, JE Choi, L Jiang, P Liao, J Zhou, Q Zhang, A Dow, AL Saripalli, I Kryczek, S Wei, W Szeliga, L Vatan, EM Stone, G Georgiou, M Cieslik, DR Wahl, MA Morgan, AM Chinnaiyan, TS Lawrence, W Zou. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov 2019; 9(12): 1673–1685
https://doi.org/10.1158/2159-8290.CD-19-0338
48 M Cai, X Sun, W Wang, Z Lian, P Wu, S Han, H Chen, P Zhang. Disruption of peroxisome function leads to metabolic stress, mTOR inhibition, and lethality in liver cancer cells. Cancer Lett 2018; 421: 82–93
https://doi.org/10.1016/j.canlet.2018.02.021
49 H Zhu, Y Lin, D Lu, S Wang, Y Liu, L Dong, Q Meng, J Gao, Y Wang, N Song, Y Suo, L Ding, P Wang, B Zhang, D Gao, J Fan, Q Gao, H Zhou. Proteomics of adjacent-to-tumor samples uncovers clinically relevant biological events in hepatocellular carcinoma. Natl Sci Rev 2023; 10(8): nwad167
https://doi.org/10.1093/nsr/nwad167
[1] FMD-24024-OF-TW_suppl_1 Download
[2] FMD-24024-OF-TW_suppl_2 Download
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed