Prognostic value of PRMT2, TRAF2 and metastasis-related gene in renal clear cell carcinoma

doi:10.11958/20242358

Abstract

Abstract:

Objective To analyze the correlation between expression levels of protein arginine methyltransferase 2 (PRMT2)， TNF receptor associated factor 2 (TRAF2) and metastasis-related genes in clear cell renal cell carcinoma (ccRCC)and their evaluation value for prognosis. Methods A total of 110 patients with ccRCC were selected. The expression levels of PRMT2, TRAF2 protein and mRNA, and the expression of metastasis-related genes [N-cadherin (N-cad), E-cadherin (E-cad), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor C (VEGFC)]were detected in cancer tissue and paracancer tissue. Pearson correlation analysis was used to analyze the correlation between PRMT2, TRAF2 mRNA and metastasis-related genes, and the effect of PRMT2 and TRAF2 expression on the prognosis of ccRCC patients. Results The mRNA expression levels of PRMT2, TRAF2, N-cad, VEGFA and VEGFC were higher in ccRCC cancer tissue than those in adjacent tissue, and E-cad was lower in ccRCC cancer tissue than that in adjacent tissue (P<0.01). PRMT2 and TRAF2 mRNA were positively correlated with N-cad, VEGFA and VEGFC mRNA expression, and negatively correlated with E-cad mRNA expression in cancer tissue (P<0.01). The positive rates of PRMT2 protein and TRAF2 protein in ccRCC cancer tissue were higher than those in adjacent tissue (P<0.01). The positive rates of PRMT2 and TRAF2 protein in TNM stage III cancer tissue were higher than those in TNM stage I-II cancer tissue (P < 0.05). The 3-year progression-free survival rate of the PRMT2 and TRAF2 positive group was lower than that of the negative group (P<0.05). TNM stage III, PRMT2 positive and TRAF2 positive were risk factors affecting the progression-free survival prognosis of ccRCC patients (P<0.05). Conclusion The expression levels of PRMT2 and TRAF2 are up-regulated in ccRCC, which are related to the expression of metastasis-related genes and TNM stage of tumor, and can be used as the marker for evaluating the prognosis of ccRCC.

Key words: carcinoma, renal cell, protein-arginine N-methyltransferases, TNF receptor-associated factor 2, cadherins, vascular endothelial growth factors, prognosis

CLC Number:

R737.25

Figures/Tables 7

References 22

[1]	CIRILLO L, INNOCENTI S, BECHERUCCI F. Global epidemiology of kidney cancer[J]. Nephrol Dial Transplant, 2024, 39(6):920-928. doi:10.1093/ndt/gfae036.
[2]	吴亚蒙, 李亮亮, 王彦刚, 等. 血清APOC1和Klotho表达对肾癌后腹腔镜下肾部分切除术患者预后的预测价值[J]. 天津医药, 2025, 53(1):61-65.
	WU Y M, LI L L, WANG Y G, et al. Predictive value of serum APOC1 and Klotho expression for prognosis in patients undergoing laparoscopic partial nephrectomy for renal cancer[J]. Tianjin Med J, 2025, 53(1):61-65. doi:10.11958/20240969.
[3]	CHOWDHURY N, DRAKE C G. Kidney cancer:an overview of current therapeutic approaches[J]. Urol Clin North Am, 2020, 47(4):419-431. doi:10.1016/j.ucl.2020.07.009.
[4]	SAUTER C, MORIN T, GUIDEZ F, et al. Protein arginine methyltransferase 2 controls inflammatory signaling in acute myeloid leukemia[J]. Commun Biol, 2024, 7(1):753. doi:10.1038/s42003-024-06453-6.
[5]	JIE X, FONG W P, ZHOU R, et al. USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGF-β2 transcription[J]. Cell Death Differ, 2021, 28(7):2095-2111. doi:10.1038/s41418-021-00740-z.
[6]	FINGER Y, HABICH M, GERLICH S, et al. Proteasomal degradation induced by DPP9-mediated processing competes with mitochondrial protein import[J]. EMBO J, 2020, 39(19):e103889. doi:10.15252/embj.2019103889.
[7]	TANG Z, LI J, SHEN Q, et al. Contribution of upregulated dipeptidyl peptidase 9 (DPP9) in promoting tumoregenicity,metastasis and the prediction of poor prognosis in non-small cell lung cancer (NSCLC)[J]. Int J Cancer, 2017, 140(7):1620-1632. doi:10.1002/ijc.30571.
[8]	ROSELLINI M, MARCHETTI A, MOLLICA V, et al. Prognostic and predictive biomarkers for immunotherapy in advanced renal cell carcinoma[J]. Nat Rev Urol, 2023, 20(3):133-157. doi:10.1038/s41585-022-00676-0.
[9]	ZHAO J, BAI J, PENG F, et al. USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells[J]. Cell Death Dis, 2023, 14(1):40. doi:10.1038/s41419-022-05527-9.
[10]	杜蓓, 张民, 张建飞, 等. 脑胶质瘤组织去泛素化酶USP9X表达水平与病人生存预后的关系[J]. 中国临床神经外科杂志, 2023, 28(12):712-715.
	DU B, ZHANG M, ZHANG J F, et al. Relationship between the expression level of deubiquitinase Usp9x in brain glioma and the survival prognosis of patients[J]. Chinese Journal of Clinical Neurosurgery, 2023, 28 (12):712-715. doi:10.13798/j.issn.1009-153X.2023.12.011.
[11]	SEMENZA G L. Mechanisms of breast cancer stem cell specification and self-renewal mediated by hypoxia-inducible factor 1[J]. Stem Cells Transl Med, 2023, 12(12):783-790. doi:10.1093/stcltm/szad061.
[12]	XU X, WANG S, WANG H, et al. Hsa_circ_0008434 regulates USP9X expression by sponging miR-6838-5p to promote gastric cancer growth,migration and invasion[J]. BMC Cancer, 2021, 21(1):1289. doi:10.1186/s12885-021-09052-4.
[13]	LIU Q, AMINU B, ROSCOW O, et al. Targeting the ubiquitin signaling cascade in tumor microenvironment for cancer therapy[J]. Int J Mol Sci, 2021, 22(2):791. doi:10.3390/ijms22020791.
[14]	GUAN T, YANG X, LIANG H, et al. Deubiquitinating enzyme USP9X regulates metastasis and chemoresistance in triple-negative breast cancer by stabilizing Snail1[J]. J Cell Physiol, 2022, 237(7):2992-3000. doi:10.1002/jcp.30763.
[15]	LI H, ZHENG B. Overexpression of the ubiquitin-specific peptidase 9 X-Linked (USP9X) gene is associated with upregulation of cyclin D1 (CCND1) and downregulation of cyclin-dependent inhibitor kinase 1A (CDKN1A) in breast cancer tissue and cell lines[J]. Med Sci Monit, 2019, 25:4207-4216. doi:10.12659/MSM.914742.
[16]	LU H, LYU Y, TRAN L, et al. HIF-1 recruits NANOG as a coactivator for TERT gene transcription in hypoxic breast cancer stem cells[J]. Cell Rep, 2021, 36(13):109757. doi:10.1016/j.celrep.2021.109757.
[17]	ROLDÁN-ROMERO J M, VALDIVIA C, SANTOS M, et al. Deubiquitinase USP9X loss sensitizes renal cancer cells to mTOR inhibition[J]. Int J Cancer, 2023, 153(6):1300-1312. doi:10.1002/ijc.34575.
[18]	HOLLINGSWORTH L R, SHARIF H, GRISWOLD A R, et al. DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation[J]. Nature, 2021, 592(7856):778-783. doi:10.1038/s41586-021-03350-4.
[19]	BRUNETTI M, HOLTH A, PANAGOPOULOS I, et al. Expression and clinical role of the dipeptidyl peptidases DPP8 and DPP9 in ovarian carcinoma[J]. Virchows Arch, 2019, 474(2):177-185. doi:10.1007/s00428-018-2487-x.
[20]	CHANG K, CHEN Y, ZHANG X, et al. DPP9 stabilizes NRF2 to suppress ferroptosis and induce sorafenib resistance in clear cell renal cell carcinoma[J]. Cancer Res, 2023, 83(23):3940-3955. doi:10.1158/0008-5472.
[21]	HENDERSON J M, XIANG M, HUANG J C, et al. Dipeptidyl peptidase inhibition enhances CD8 T cell recruitment and activates intrahepatic inflammasome in a murine model of hepatocellular carcinoma[J]. Cancers (Basel), 2021, 13(21):5495-5503. doi:10.3390/cancers13215495.
[22]	BOLGI O, SILVA-GARCIA M, ROSS B, et al. Dipeptidyl peptidase 9 triggers BRCA2 degradation and promotes DNA damage repair[J]. EMBO Rep, 2022, 23(10):e54136. doi:10.15252/embr.202154136.

基因名称	引物序列（5′→3′）	产物大小/bp
PRMT2	上游：CCCAGAAGTGAATCGCAGGG	174
PRMT2	下游TGCAGTGGTTTGTCTCAGGATA	174
TRAF2	上游ACATTCCGGCAAACCATGTG	192
TRAF2	下游GGATGACTTTATCCGTCAGGGA	192
N-cad	上游GAGGAGCAGTTACGGTCTGTG	101
N-cad	下游TCCTTTCCTTAGCTGACACTTGT	101
E-cad	上游CGAGAGCTACACGTTCACGG	184
E-cad	下游GGGTGTCGAGGGAAAAATAGG	184
VEGFA	上游GGCTGGCAACATAACAGAGAA	173
VEGFA	下游CCCCACATCTATACACACCTCC	173
VEGFC	上游ATGTGTGTCCGTCTACAGATGT	125
VEGFC	下游GGAAGTGTGATTGGCAAAACTGA	125
GAPDH	上游TCCCTGGAGTTGCTACAGC	144
GAPDH	下游AGGCGGAGCACAGGTACTT	144

基因名称	引物序列（5′→3′）	产物大小/bp
PRMT2	上游：CCCAGAAGTGAATCGCAGGG	174
PRMT2	下游TGCAGTGGTTTGTCTCAGGATA	174
TRAF2	上游ACATTCCGGCAAACCATGTG	192
TRAF2	下游GGATGACTTTATCCGTCAGGGA	192
N-cad	上游GAGGAGCAGTTACGGTCTGTG	101
N-cad	下游TCCTTTCCTTAGCTGACACTTGT	101
E-cad	上游CGAGAGCTACACGTTCACGG	184
E-cad	下游GGGTGTCGAGGGAAAAATAGG	184
VEGFA	上游GGCTGGCAACATAACAGAGAA	173
VEGFA	下游CCCCACATCTATACACACCTCC	173
VEGFC	上游ATGTGTGTCCGTCTACAGATGT	125
VEGFC	下游GGAAGTGTGATTGGCAAAACTGA	125
GAPDH	上游TCCCTGGAGTTGCTACAGC	144
GAPDH	下游AGGCGGAGCACAGGTACTT	144

组别	PRMT2	TRAF2	N-cad
癌旁组织	0.84±0.22	1.02±0.33	1.14±0.32
癌组织	2.01±0.38	2.44±0.42	3.21±0.52
t	27.947^＊＊	27.883^＊＊	35.557^＊＊
组别	E-cad	VEGFA	VEGFC
癌旁组织	1.11±0.24	0.93±0.28	0.82±0.21
癌组织	0.68±0.15	2.85±0.36	3.91±0.50
t	15.935^＊＊	44.154^＊＊	59.760^＊＊

组别	PRMT2	TRAF2	N-cad
癌旁组织	0.84±0.22	1.02±0.33	1.14±0.32
癌组织	2.01±0.38	2.44±0.42	3.21±0.52
t	27.947^＊＊	27.883^＊＊	35.557^＊＊
组别	E-cad	VEGFA	VEGFC
癌旁组织	1.11±0.24	0.93±0.28	0.82±0.21
癌组织	0.68±0.15	2.85±0.36	3.91±0.50
t	15.935^＊＊	44.154^＊＊	59.760^＊＊

指标	PRMT2	TRAF2
N-cad	0.815^＊＊	0.761^＊＊
E-cad	-0.715^＊＊	-0.781^＊＊
VEGFA	0.701^＊＊	0.790^＊＊
VEGFC	0.697^＊＊	0.681^＊＊