Abstract
LncRNA-PTENP1 was reported to promote multiple myeloma cancer stem cell proliferation, and the G allele of rs7853346 polymorphism in lncRNA-PTENP1 was demonstrated to enhance the effect of lncRNA-PTENP1. In this study, we aimed to study the potential effect of lncRNA-PTENP1 and CCR2 mRNA polymorphisms on cognitive impairment in glioma patients. In this study, 279 glioma patients were recruited and grouped according to their genotypes of rs7853346 in PTENP1 and rs1799864 in CCR1. Pathogenic parameters were collected from patients before radiotherapy (month 0) or at month 1 and month 3 after radiotherapy to study the effect of rs7853346 and rs1799864 on cognitive impairment. Sequence analysis, luciferase assay, real-time PCR, and Western blot were performed to study the regulatory relationships between lncRNA-PTENP1, miR-18b, and CCR2. The glioma patient groups exhibited no significant differences concerning basic characteristics. However, the CG&GG/GG genotype alleviated radiotherapy-induced cognitive impairment by exhibiting the highest MMSE among the four groups. On the contrary, parameters including the severity of depression, bladder control, global health status, itchy skin, and weakness of legs all showed no difference among different patient groups at month 0, month 1, and month 3. Also, a long-term positive effect of CG&GG/GG genotype on role functioning and social functioning was also observed after radiotherapy. Compared with patients carrying the CC genotype of rs7853346, the expression of lncRNA-PTENP1 was reduced while the miR-19b level was elevated in patients carrying the CG&GG genotypes of rs7853346. Moreover, the expression of CCR2 mRNA was the highest in the CC/GA&AA group and the lowest in the CG&GG/GG group. Subsequent sequence analysis and luciferase assay indicated that miR-19b could bind to lncRNA-PTENP1 and 3’UTR of CCR2 mRNA, and the knockdown of lncRNA-PTENP1 led to evident up-regulation of miR-19b and down-regulation of CCR2 mRNA/protein in a cellular model, thus verifying the presence of the lncRNA-PTENP1/miR-19b/CCR2 mRNA signaling pathway. In conclusion, by studying the changes in the key parameters of glioma patients who were subjected to radiotherapy, we concluded that the rs7853346 polymorphism in lncRNA-PTENP1 and the rs1799864 polymorphism in CCR2 could independently affect cognitive impairment, while a more significant combined effect on cognitive impairment was exerted in glioma patients via the signaling pathway of PTENP1/miR-19b/CCR2.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
Andonegui G, Zelinski EL, Schubert CL, Knight D, Craig LA, Winston BW, Spanswick SC, Petri B, Jenne CN, Sutherland JC, Nguyen R, Jayawardena N, Kelly MM, Doig CJ, Sutherland RJ, Kubes P (2018) Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment. JCI Insight 3:e99364
Batista PJ, Chang HY (2013) Long noncoding RNAs: cellular address codes in development and disease. Cell 152:1298–1307
Belarbi K, Jopson T, Arellano C, Fike JR, Rosi S (2013) CCR2 deficiency prevents neuronal dysfunction and cognitive impairments induced by cranial irradiation. Cancer Res 73:1201–1210
Booth G, Newham P, Barlow R, Raines S, Zheng B, Han S (2008) Gene expression profiles at different stages of collagen-induced arthritis. Autoimmunity 41:512–521
Chan RW, Lai FM, Li EK, Tam LS, Chow KM, Lai KB, Li PK, Szeto CC (2007) Intrarenal cytokine gene expression in lupus nephritis. Ann Rheum Dis 66:886–892
Chaudhry MA (2014) Radiation-induced microRNA: discovery, functional analysis, and cancer radiotherapy. J Cell Biochem 115:436–449
Chen MK, Yeh KT, Chiou HL, Lin CW, Chung TT, Yang SF (2011) CCR2-64I gene polymorphism increase susceptibility to oral cancer. Oral Oncol 47:577–582
Connolly KA, Belt BA, Figueroa NM, Murthy A, Patel A, Kim M, Lord EM, Linehan DC, Gerber SA (2016) Increasing the efficacy of radiotherapy by modulating the CCR2/CCR5 chemokine axes. Oncotarget 7:86522–86535
Conti I, Rollins BJ (2004) CCL2 (monocyte chemoattractant protein-1) and cancer. Semin Cancer Biol 14:149–154
Cui FM, Li JX, Chen Q, Du HB, Zhang SY, Nie JH, Cao JP, Zhou PK, Hei TK, Tong J (2013) Radon-induced alterations in micro-RNA expression profiles in transformed BEAS2B cells. J Toxicol Environ Health A 76:107–119
Dong Y, Shen X, He M, Wu Z, Zheng Q, Wang Y, Chen Y, Wu S, Cui J, Zeng Z (2016) Activation of the JNK-c-Jun pathway in response to irradiation facilitates Fas ligand secretion in hepatoma cells and increases hepatocyte injury. J Exp Clin Cancer Res 35:114
Franciszkiewicz K, Boissonnas A, Boutet M, Combadiere C, Mami-Chouaib F (2012) Role of chemokines and chemokine receptors in shaping the effector phase of the antitumor immune response. Cancer Res 72:6325–6332
Ge Y, He Y, Jiang M, Luo D, Huan X, Wang W, Zhang D, Yang L, Zhou J (2017) Polymorphisms in lncRNA PTENP1 and the risk of gastric cancer in a chinese population. Dis Mark 2017:6807452
Gruber AR, Lorenz R, Bernhart SH, Neubock R, Hofacker IL (2008) The Vienna RNA websuite. Nucleic Acids Res 36:W70-74
Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, Yatabe Y, Kawahara K, Sekido Y, Takahashi T (2005) A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res 65:9628–9632
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM (2005) A microRNA polycistron as a potential human oncogene. Nature 435:828–833
Heimdal JH, Olsnes C, Olofsson J, Aarstad HJ (2001) Monocyte and monocyte-derived macrophage secretion of MCP-1 in co-culture with autologous malignant and benign control fragment spheroids. Cancer Immunol Immunother 50:300–306
Hollander MC, Blumenthal GM, Dennis PA (2011) PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 11:289–301
Kalbasi A, Komar C, Tooker GM, Liu M, Lee JW, Gladney WL, Ben-Josef E, Beatty GL (2017) Tumor-derived CCL2 mediates resistance to radiotherapy in pancreatic ductal adenocarcinoma. Clin Cancer Res 23:137–148
Lan T, Li C, Yang G, Sun Y, Zhuang L, Ou Y, Li H, Wang G, Kisseleva T, Brenner D, Guo J (2018) Sphingosine kinase 1 promotes liver fibrosis by preventing miR-19b-3p-mediated inhibition of CCR2. Hepatology 68:1070–1086
Li J, Yang S, Yan W, Yang J, Qin YJ, Lin XL, Xie RY, Wang SC, Jin W, Gao F, Shi JW, Zhao WT, Jia JS, Shen HF, Ke JR, Liu B, Zhao YQ, Huang WH, Yao KT, Li DJ, Xiao D (2015) MicroRNA-19 triggers epithelial-mesenchymal transition of lung cancer cells accompanied by growth inhibition. Lab Invest 95:1056–1070
Li RK, Gao J, Guo LH, Huang GQ, Luo WH (2017) PTENP1 acts as a ceRNA to regulate PTEN by sponging miR-19b and explores the biological role of PTENP1 in breast cancer. Cancer Gene Ther 24:309–315
Liang H, Deng L, Hou Y, Meng X, Huang X, Rao E, Zheng W, Mauceri H, Mack M, Xu M, Fu YX, Weichselbaum RR (2017) Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat Commun 8:1736
Liss C, Fekete MJ, Hasina R, Lam CD, Lingen MW (2001) Paracrine angiogenic loop between head-and-neck squamous-cell carcinomas and macrophages. Int J Cancer 93:781–785
Monje ML, Palmer T (2003) Radiation injury and neurogenesis. Curr Opin Neurol 16:129–134
Monje ML, Mizumatsu S, Fike JR, Palmer TD (2002) Irradiation induces neural precursor-cell dysfunction. Nat Med 8:955–962
Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765
Navarro A, Marrades RM, Vinolas N, Quera A, Agusti C, Huerta A, Ramirez J, Torres A, Monzo M (2009) MicroRNAs expressed during lung cancer development are expressed in human pseudoglandular lung embryogenesis. Oncology 76:162–169
Olive V, Bennett MJ, Walker JC, Ma C, Jiang I, Cordon-Cardo C, Li QJ, Lowe SW, Hannon GJ, He L (2009) miR-19 is a key oncogenic component of mir-17-92. Genes Dev 23:2839–2849
Pellmar TC, Schauer DA, Zeman GH (1990) Time- and dose-dependent changes in neuronal activity produced by X radiation in brain slices. Radiat Res 122:209–214
Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP (2010) A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465:1033–1038
Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem 81:145–166
Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, Fike JR (2004) Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol 188:316–330
Shi TY, Chen XJ, Zhu ML, Wang MY, He J, Yu KD, Shao ZM, Sun MH, Zhou XY, Cheng X, Wu X, Wei Q (2013) A pri-miR-218 variant and risk of cervical carcinoma in Chinese women. BMC Cancer 13:19
Takahashi M, Galligan C, Tessarollo L, Yoshimura T (2009) Monocyte chemoattractant protein-1 (MCP-1), not MCP-3, is the primary chemokine required for monocyte recruitment in mouse peritonitis induced with thioglycollate or zymosan A. J Immunol 183:3463–3471
Tang Y, Cui Y, Li Z, Jiao Z, Zhang Y, He Y, Chen G, Zhou Q, Wang W, Zhou X, Luo J, Zhang S (2016) Radiation-induced miR-208a increases the proliferation and radioresistance by targeting p21 in human lung cancer cells. J Exp Clin Cancer Res 35:7
Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ, Newman J, Bronson RT, Crowley D, Stone JR, Jaenisch R, Sharp PA, Jacks T (2008) Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 132:875–886
Verhaegh GW, Verkleij L, Vermeulen SH, den Heijer M, Witjes JA, Kiemeney LA (2008) Polymorphisms in the H19 gene and the risk of bladder cancer. Eur Urol 54:1118–1126
Wu PH, Coultrap S, Pinnix C, Davies KD, Tailor R, Ang KK, Browning MD, Grosshans DR (2012) Radiation induces acute alterations in neuronal function. PLoS ONE 7:e37677
Wu C, Cao Y, He Z, He J, Hu C, Duan H, Jiang J (2014) Serum levels of miR-19b and miR-146a as prognostic biomarkers for non-small cell lung cancer. Tohoku J Exp Med 232:85–95
Xin C, Li JL, Zhang YX, Yu ZH (2018) Polymorphisms in lncRNA PTENP1 and the risk of oral squamous cell carcinoma in a Chinese population. Eur Rev Med Pharmacol Sci 22:5583–5587
Yu G, Yao W, Gumireddy K, Li A, Wang J, Xiao W, Chen K, Xiao H, Li H, Tang K, Ye Z, Huang Q, Xu H (2014) Pseudogene PTENP1 functions as a competing endogenous RNA to suppress clear-cell renal cell carcinoma progression. Mol Cancer Ther 13:3086–3097
Zhang Y, Xu C (2019) G allele of rs7853346 polymorphism in PTENP1 enhances the proliferation of multiple myeloma cancer stem cells by promoting the expression of PTENP1 and its downstream signaling molecules. J Cell Biochem 120:19738–19748
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SY and LXD planned the study, SY, ZZF, YQZ, BHF, and XH collected the literature and data. SY and LXD composed the manuscript, and all the other co-authors approved the final manuscript.
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Yang, S., Fu, Zz., Zhang, Yq. et al. Rs7853346 Polymorphism in lncRNA-PTENP1 and rs1799864 Polymorphism in CCR2 are Associated with Radiotherapy-Induced Cognitive Impairment in Subjects with Glioma Via Regulating PTENP1/miR-19b/CCR2 Signaling Pathway. Biochem Genet 60, 1159–1176 (2022). https://doi.org/10.1007/s10528-021-10145-9
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DOI: https://doi.org/10.1007/s10528-021-10145-9