核糖核苷酸还原酶M2在小脑髓母细胞瘤中的功能及机制

doi:10.3969/j.issn.1004-616x.2023.04.006

Abstract

Abstract: OBJECTIVE： To investigate biological functions and mechanism of ribonucleotide reductase subunit M2 (RRM2) in medulloblastoma. METHODS： Relationships between survival and the levels of RRM2 expression in GEO database (GSE85217) were analyzed. Expressions of RRM2 in medulloblastoma and normal cerebellar tissues were analyzed using immunohistochemistry and database. CCK-8 proliferation experiments，transwell experiments，and flow cytometry were used to study the effects of RRM2 on proliferation，migration，cell cycle，and apoptosis of medulloblastoma cell lines Daoy and D283. RNA sequencing (RNA-seq) was used to explore downstream molecular mechanisms. Paired t-test and independent sample t-test were used for statistical analysis. RESULTS： Through the analysis of GEO database，survival of medulloblastoma patients was worse in the RRM2-high group than that in low group (P<0.05). The results of immunohistochemistry and database showed that expressions of RRM2 were significantly higher in medulloblastoma than that in normal cerebellar tissues (P<0.05). Compared to the control groups，overexpressions of RRM2 promoted tumor cell proliferation and migration，while knockdown of RRM2 reduced tumor cell proliferation and migration. In addition，overexpressions of RRM2 significantly increased the proportions of cells in the S phase (P<0.05) and reduced apoptosis (P<0.05). After knockdown of RRM2，RNA-seq results showed that 3 454 genes were up-regulated and 3 332 genes were down-regulated. KEGG analysis showed that multiple signal pathways were affected，including FOXO，cell cycle，ribosome biosynthesis，etc. CONCLUSION： RRM2 was highly expressed in medulloblastoma and the expression was negatively related to prognosis. In addition，RRM2 expression promoted proliferation and migration of medulloblastoma cells and reduced apoptosis.

Key words: edulloblastoma, RRM2, proliferation, migration, apoptosis

CLC Number:

R730.2

ZHANG Qi, WU Jing, ZHANG Chenlu. The biological function and mechanism of ribonucleotide reductase subunit M2 in medulloblastoma[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2023, 35(4): 279-284,291.

References

[1] NORTHCOTT P A, ROBINSON G W, KRATZ C P, et al. Medulloblastoma[J]. Nat Rev Dis Primers, 2019, 5(1): 11.
[2] WANG J, GARANCHER A, RAMASWAMY V, et al. Medulloblastoma: from molecular subgroups to molecular targeted therapies[J]. Annu Rev Neurosci, 2018, 41: 207-232.
[3] NORDLUND P, REICHARD P. Ribonucleotide reductases[J]. Annu Rev Biochem, 2006, 75: 681-706.
[4] KRETSCHMER C, STERNER-KOCK A, SIEDENTOPF F, et al. Identification of early molecular markers for breast cancer[J]. Mol Cancer, 2011, 10(1): 15.
[5] GRADE M, HUMMON A B, CAMPS J, et al. A genomic strategy for the functional validation of colorectal cancer genes identifies potential therapeutic targets[J]. Int J Cancer, 2011, 128(5): 1069-1079.
[6] XU X, PAGE J L, SURTEES J A, et al. Broad overexpression of ribonucleotide reductase genes in mice specifically induces lung neoplasms[J]. Cancer Res, 2008, 68(8): 2652-2660.
[7] TAYLOR M D, NORTHCOTT P A, KORSHUNOV A, et al. Molecular subgroups of medulloblastoma: the current consensus[J]. Acta Neuropathol, 2012, 123(4): 465-472.
[8] HOVESTADT V, AYRAULT O, SWARTLING F J, et al. Medulloblastomics revisited: biological and clinical insights from thousands of patients[J]. Nat Rev Cancer, 2020, 20(1): 42-56.
[9] MAZZU Y Z, ARMENIA J, CHAKRABORTY G, et al. A novel mechanism driving poor-prognosis prostate cancer: overexpression of the DNA repair gene, ribonucleotide reductase small subunit M2(RRM2)[J]. Clin Cancer Res, 2019, 25(14): 4480-4492.
[10] AYE Y, LI M, LONG M J C, et al. Ribonucleotide reductase and cancer: biological mechanisms and targeted therapies[J]. Oncogene, 2015, 34(16): 2011-2021.
[11] PFISTER S X, MARKKANEN E, JIANG Y Y, et al. Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation[J]. Cancer Cell, 2015, 28(5): 557-568.
[12] ZHAN Y Q, JIANG L S, JIN X H, et al. Inhibiting RRM2 to enhance the anticancer activity of chemotherapy[J]. Biomedecine Pharmacother, 2021, 133: 110996.
[13] LI C, ZHENG J F, CHEN S, et al. RRM2 promotes the progression of human glioblastoma[J]. J Cell Physiol, 2018, 233(10): 6759-6767.
[14] HAN P, LIN Z R, XU L H, et al. Ribonucleotide reductase M2 subunit expression and prognostic value in nasopharyngeal carcinoma[J]. Mol Med Rep, 2015, 12(1): 401-409.
[15] LIU X, PENG J M, ZHOU Y Y, et al. Silencing RRM2 inhibits multiple myeloma bytargeting the Wnt/β-catenin signaling pathway[J]. Mol Med Rep, 2019, 20(3): 2159-2166.
[16] XIONG W, ZHANG B, YU H X, et al. RRM2 regulates sensitivity to sunitinib and PD-1 blockade in renal cancer by stabilizing ANXA1 and activating the AKT pathway[J]. Adv Sci, 2021, 8(18): e2100881.
[17] LIU Y, AO X, DING W, et al. Critical role of FOXO3a in carcinogenesis[J]. Mol Cancer, 2018, 17(1): 104.
[18] DAS T P, SUMAN S, ALATASSI H, et al. Inhibition of AKT promotes FOXO3a-dependent apoptosis in prostate cancer[J]. Cell Death Dis, 2016, 7(2): e2111.

The biological function and mechanism of ribonucleotide reductase subunit M2 in medulloblastoma

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	SHI Jianhong, CHEN Dingxiong, LU Xiaotong, HAO Jiajie, CAI Yan, WANG Mingrong, ZHANG Yu. Inhibitory effect of ICG-001 on proliferation of esophageal squamous carcinoma cells and its molecular mechanisms [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2023, 35(3): 187-191,196.
[2]	FENG Dan, FAN Zhilu, WANG Yinong, LI Sai, GUO Jing, CAI Yan, ZHANG Yu, WEI Wenqiang, WANG Mingrong, HAO Jiajie. P4HA2 promotes proliferation of esophageal squamous carcinoma cells via activating the EGFR/AKT/S6 signaling pathway [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2023, 35(2): 87-94,101.
[3]	CHEN Shuang, PENG Zhongrui, WU Zhenwen, GUO Dongbei, SUN Meijun, LI Lei. Protective effects of angelica keiskei chalcones on acute alcoholic liver injury in mice [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2023, 35(2): 95-101.
[4]	ZHANG Junjun, LIANG Leping. Effect of PTEN C-tail on migration and proliferation of nasopharyngeal carcinoma cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(6): 434-438.
[5]	BI Jiaxin, WANG Xiaoxue, ZHAO Ruohan, HAN Xu, SONG Jie. Down-expression of CENP-T and variation of its promoter region in BRCA [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(5): 327-334.
[6]	QI Jiankao, TANG Xiao, SUN Shihui, KOU Yanfang, CUI Zhiqin. Growth inhibition of non-small cell lung cancers by Zaoci decotion in combination with cisplatin and gemcitabine [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(5): 366-372,403.
[7]	ZHANG Yue, WANG Yaoyi, WU Xueliang, ZHANG Zhisheng, YANG Xiuming, JIANG Yang, QIAO Zhifei, LIANG Wanping, XUE Jun. The combination of ¹²⁵I particles and AZD1152 efficiently inhibited proliferation and promoted apoptosis of a triple negative breast cancer cell line [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(4): 295-299,306.
[8]	ZHAO Chenqian, XU Anqi, AI Duo, KONG Deqin, ZHANG Xiaodi, LI Wenli, HAI Chunxu, LIU Jiangzheng. Effects of Mito-TEMPO treatment on nitrogen mustard-induced cytotoxicity in BEAS-2B cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(3): 161-168.
[9]	CHEN Dingxiong, ZHU Yiqing, SHI Jianhong, CAI Yan, HAO Jiajie, WANG Mingrong, LIANG Jianwei, ZHANG Yu. DNAJB6b enhanced invasion and migration abilities of colorectal cancer cells by activating the AKT pathway [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(3): 178-183.
[10]	ZHANG Qi, LIU Yujun, ZHUANG Xibing, QIAO Tiankui. Fuzi extracts on proliferation and radiosensitization of lung cancer A549 cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(3): 227-232.
[11]	LI Boru, QIN Shuangjian, CAI Ying, LI Runbing, GUAN Lan, XIAO Fang, ZENG Ming, XU Xinyun. Effects of PM_2.5 on invasion and migration abilities in three types of cancer cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(2): 124-128,133.
[12]	ZHAO Yan, SUN Zhenxiao. Metformin inhibitd proliferation and migration of human breast cancer cell in vitro [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(1): 35-39.
[13]	WANG Xiaozhou, LI Hongshi, YU Xi, WEI Ning, WANG Ziying, HE Lijie. Effects of sinomenine on proliferation and invasion of HPV-positive cervical cancer SiHa cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(6): 442-445.
[14]	YANG Xingxiao, ZHANG Xueyuan, ZOU Naiyi, SHAN Bao'en, MA Ming, ZHU Shuchai. Effects of HMGB1 silencing on migration, invasion and radiosensitivity of esophageal squamous cell carcinoma cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(5): 327-333.
[15]	LI Boru, QIN Shuangjian, GUAN Lan, LI Runbing, CAI Ying, PU Jiening, ZENG Ming, XIAO Fang, XU Xinyun. Effects of PM_2.5 on oxidative damage and apoptosis in HK-2 cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(5): 360-364.