表观遗传调控机制在犬肿瘤中的研究进展

doi:10.16431/j.cnki.1671-7236.2021.11.042

摘要/Abstract

摘要： 犬肿瘤性疾病是兽医临床上常发的一种疾病，其发病率较高，是造成世界范围内犬死亡的重要原因之一，由于其病理学分类、自发性、基因和信号通路等方面与人类肿瘤有相似之处，可作为人类肿瘤的研究模型。表观遗传是基于DNA序列没有发生改变的情况下所致基因功能和表达水平发生了可遗传的变化，主要通过基因转录或翻译过程的调控，影响其功能和特性。表观遗传改变主要包括DNA甲基化水平改变、组蛋白修饰、染色质重塑和非编码RNA调控等。DNA异常甲基化在犬的多种肿瘤中均有研究，包括犬白血病、淋巴瘤及黑色素瘤等，且犬与人类肿瘤的DNA异常甲基化模式相似。在肿瘤中组蛋白各种修饰酶表达失调，是抗肿瘤药物开发分子靶点研究的主要焦点，但目前在犬肿瘤中的研究较少。非编码RNA中microRNA与lncRNA是目前的研究热点，已有较多研究致力于开发针对非编码RNA的靶向研究药物，但目前在兽医领域应用较少。作者主要综述了犬肿瘤疾病的流行病学、DNA甲基化、组蛋白修饰、非编码RNA等表观遗传学变化在犬肿瘤中的研究进展，揭示表观遗传异常与犬肿瘤发生发展的关系，以期为开发犬肿瘤性疾病诊断、靶向治疗及预后的特异性标志物提供参考依据。

关键词: 犬; 肿瘤; 表观遗传调控; DNA甲基化

Abstract: The canine neoplastic disease is common in the veterinary clinic, which has a high incidence and is one of the important causes of dog death worldwide. Because canine tumors are similar to human tumors in their pathological classification, spontaneity, genes, and signal pathways, dogs with tumors can be used as research models for human tumors. Epigenetics refers to heritable changes in gene function and expression levels that occur without a change in DNA sequence, mainly through the regulation of gene transcription and translation process influence the functions and features. Epigenetic changes mainly include changes in DNA methylation level, histone modification, chromatin remolding, and regulation of non-coding RNA. Abnormal DNA methylation has been studied in a variety of canine tumors, including canine leukemia, lymphoma, and melanoma. Among these tumors, the abnormal DNA methylation patterns of canine and human tumors are similar. The dysregulation of the expression of a variety of histone-modifying enzymes in tumors is the research hotspot of molecular targets for the development of anti-tumor drugs, but there are currently few studies in canine tumors. microRNA and lncRNA are currently research focuses on non-coding RNA. Many researches had been devoted to the development of targeted research drugs for non-coding RNA, but currently, there are few applications in the veterinary field. In this paper, the epidemiology, DNA methylation, histone modification, noncoding RNA, and other epigenetic changes in canine cancer were reviewed to reveal the relationship between epigenetic abnormalities and the occurrence and development of canine tumor, and to provide a reference for the development of specific markers for the diagnosis, targeted therapy and prognosis of canine neoplastic diseases.

Key words: canine; tumor; epigenetic regulation; DNA methylation

中图分类号:

S858.292

任晓丽, 范玉营, 皇甫和平, 董青, 石冬梅, 刘云. 表观遗传调控机制在犬肿瘤中的研究进展[J]. 中国畜牧兽医, 2021, 48(11): 4319-4326.

REN Xiaoli, FAN Yuying, HUANGFU Heping, DONG Qing, SHI Dongmei, LIU Yun. Research Progress on Epigenetic Regulation Mechanism in Canine Tumor[J]. China Animal Husbandry and Veterinary Medicine, 2021, 48(11): 4319-4326.

参考文献

[1] DAWSON M A.The cancer epigenome:Concepts, challenges, and therapeutic opportunities[J]. Science, 2017, 355(6330):1147-1152.
[2] GRUNTZIG K, GRAF R, HASSIG M, et al. The Swiss canine cancer registry:A retrospective study on the occurrence of tumours in dogs in Switzerland from 1955 to 2008[J]. Journal of Comparative Pathology, 2015, 152(2-3):161-171.
[3] CHOI J W, YOON H Y, JEONG S W.Clinical outcomes of surgically managed spontaneous tumors in 114 client-owned dogs[J]. Immune Network, 2016, 16(2):116-125.
[4] GARDNER H L, FENGER J M, LONDON C A.Dogs as a model for cancer[J]. Annual Review of Animal Biosciences, 2016, 4:199-222.
[5] ABDELMEGEED S M, MOHAMMED S.Canine mammary tumors as a model for human disease[J]. Oncology Letters, 2018, 15(6):8195-8205.
[6] REBHUN R B, KENT M S, BORROFKA S A, et al. CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma[J]. Veterinary and Comparative Oncology, 2011, 9(1):38-44.
[7] POPHALI P A, MARINELLI L M, KETTERLING R P, et al. High level MYC amplification in B-cell lymphomas:Is it a marker of aggressive disease?[J]. Blood Cancer Journal, 2020, 10(1):5-13.
[8] CRUZ C J, MILNER R, ALLEMAN A R, et al. BCR-ABL translocation in a dog with chronic monocytic leukemia[J]. Veterinary Clinical Pathology, 2011, 40(1):40-47.
[9] FIGUEIREDO J F, CULVER S, BEHLING-KELLY E, et al. Acute myeloblastic leukemia with associated BCR-ABL translocation in a dog[J]. Veterinary Clinical Pathology, 2012, 41(3):362-368.
[10] ENGINLER S O, AKIS I, TOYDEMIR T S, et al. Genetic variations of BRCA1 and BRCA2 genes in dogs with mammary tumours[J]. Veterinary Research Communications, 2014, 38(1):21-27.
[11] SALEEM M, GHAZALI M B, WAHAB M, et al. The BRCA1 and BRCA2 genes in early-onset breast cancer patients[J]. Advances in Experimental Medicine and Biology, 2020, 1292:1-12.
[12] IQBAL N, IQBAL N.Human epidermal growth factor receptor 2(HER2) in cancers:Overexpression and therapeutic implications[J]. International Journal of Biological Macromolecules, 2014, 2014:852748.
[13] PASTOR N, EZQUERRA L J, SANTELLA M, et al. Prognostic significance of immunohistochemical markers and histological classification in malignant canine mammary tumours[J]. Veterinary and Comparative Oncology, 2020, 18(4):753-762.
[14] GREENBERG M, BOURC'HIS D.The diverse roles of DNA methylation in mammalian development and disease[J]. Nature Reviews Molecular Cell Biology, 2019, 20(10):590-607.
[15] EHRLICH M.DNA hypomethylation in cancer cells[J]. Epigenomics, 2009, 1(2):239-259.
[16] KULIS M, ESTELLER M.DNA methylation and cancer[J]. Advances in Human Genetics, 2010, 70:27-56.
[17] SKVORTSOVA K, STIRZAKER C, TABERLAY P.The DNA methylation landscape in cancer[J]. Essays in Biochemistry, 2019, 63(6):797-811.
[18] NOGUCHI S, MORI T, IGASE M, et al. A novel apoptosis-inducing mechanism of 5-aza-2'-deoxycitidine in melanoma cells:Demethylation of TNF-alpha and activation of FOXO1[J]. Cancer Letters, 2015, 369(2):344-353.
[19] NOGUCHI S, MORI T, NAKAGAWA T, et al. DNA methylation contributes toward silencing of antioncogenic microRNA-203 in human and canine melanoma cells[J]. Melanoma Research, 2015, 25(5):390-398.
[20] ISHIZAKI T, YAMAZAKI J, JELINEK J, et al. Genome-wide DNA methylation analysis identifies promoter hypermethylation in canine malignant melanoma[J]. Research in Veterinary Science, 2020, 132:521-526.
[21] FERRARESSO S, ARICO A, SANAVIA T, et al. DNA methylation profiling reveals common signatures of tumorigenesis and defines epigenetic prognostic subtypes of canine diffuse large B-cell lymphoma[J]. Scientific Reports, 2017, 7(1):11591-11601.
[22] SATO M, MOCHIZUKI H, GOTO-KOSHINO Y, et al. Prognostic significance of hypermethylation of death-associated protein kinase (DAPK) gene CpG island in dogs with high-grade B-cell lymphoma[J]. Veterinary and Comparative Oncology, 2018, 16(3):409-415.
[23] YAMAZAKI J, JELINEK J, HISAMOTO S, et al. Dynamic changes in DNA methylation patterns in canine lymphoma cell lines demonstrated by genome-widequantitativeDNA methylation analysis[J]. The Veterinary Journal, 2018, 231:48-54.
[24] BIONDI L R, TEDARDI M V, GENTILE L B, et al. Quantification of global DNA methylation in canine mammary gland tumors via immunostaining of 5-methylcytosine:Histopathological and clinical correlations[J]. Frontiers in Veterinary Science, 2021, 8:628241.
[25] BRANDAO Y O, TOLEDO M B, CHEQUIN A, et al. DNA methylation status of the estrogen receptor alpha gene in canine mammary tumors[J]. Veterinary Pathology, 2018, 55(4):510-516.
[26] OTTAVIANO Y L, ISSA J P, PARL F F, et al. Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells[J]. Cancer Research, 1994, 54(10):2552-2555.
[27] ZORZAN E, HANSSENS K, GIANTIN M, et al. Mutational hotspot of TET2, IDH1, IDH2, SRSF2, SF3B1, KRAS, and NRAS from human systemic mastocytosis are not conserved in canine mast cell tumors[J]. PLoS One, 2015, 10(11):e0142450.
[28] TEFFERI A, LEVINE R L, LIM K H, et al. Frequent TET2 mutations in systemic mastocytosis:Clinical, KITD816V and FIP1L1-PDGFRA correlates[J]. Leukemia, 2009, 23(5):900-904.
[29] MCDONALD J T, KRITHARIS A, BEHESHTI A, et al. Correction:Comparative oncology DNA sequencing of canine T cell lymphoma via human hotspot panel[J]. Oncotarget, 2018, 9(70):22693-22702.
[30] LUGER K, MADER A W, RICHMOND R K, et al. Crystal structure of the nucleosome core particle at 2.8 A resolution[J]. Nature, 1997, 389(6648):251-260.
[31] KEBEDE A F, SCHNEIDER R, DAUJAT S.Novel types and sites of histone modifications emerge as players in the transcriptional regulation contest[J]. FEBS Journal, 2015, 282(9):1658-1674.
[32] LAWRENCE M, DAUJAT S, SCHNEIDER R.Lateral thinking:How histone modifications regulate gene expression[J]. Trends in Genetics, 2016, 32(1):42-56.
[33] FRAGA M F, BALLESTAR E, VILLAR-GAREA A, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer[J]. Nature Genetics, 2005, 37(4):391-400.
[34] HASSELL K N.Histone deacetylases and their inhibitors in cancer epigenetics[J]. Diseases, 2019, 7(4):57-69.
[35] WAN Y, LIU J, CHAN K M.Histone H3 mutations in cancer[J]. Current Pharmacology Reports, 2018, 4(4):292-300.
[36] YANG L, QIU Q, TANG M, et al. Purinostat mesylate is a uniquely potent and selective inhibitor of HDACs for the treatment of BCR-ABL-induced B-cell acute lymphoblastic leukemia[J]. Clinical Cancer Research, 2019, 25(24):7527-7539.
[37] ETO S, SAEKI K, YOSHITAKE R, et al. Anti-tumor effects of the histone deacetylase inhibitor vorinostat on canine urothelial carcinoma cells[J]. PLoS One, 2019, 14(6):e0218382.
[38] CAO Z, WU W, WEI H, et al. Downregulation of histone-lysine N-methyltransferase EZH2 inhibits cell viability and enhances chemosensitivity in lung cancer cells[J]. Oncology Letters, 2021, 21(1):26-35.
[39] JAN S, DAR M I, WANI R, et al. Targeting EHMT2/G9a for cancer therapy:Progress and perspective[J]. European Journal of Clinical Pharmacology, 2021, 893:173827.
[40] SAKTHIKUMAR S, ELVERS I, KIM J, et al. SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma[J]. Cancer Research, 2018, 78(13):3421-3431.
[41] GARDNER H L, SIVAPRAKASAM K, BRIONES N, et al. Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2[J]. Communications Biology, 2019, 2(266):266-278.
[42] LIU D, XIONG H, ELLIS A E, et al. Molecular homology and difference between spontaneous canine mammary cancer and human breast cancer[J]. Cancer Research, 2014, 74(18):5045-5056.
[43] MACIOTTA S, MEREGALLI M, TORRENTE Y.The involvement of microRNAs in neurodegenerative diseases[J]. Frontiers in Cellular Neuroscience, 2013, 7:265-281.
[44] ZHOU S S, JIN J P, WANG J Q, et al. miRNAS in cardiovascular diseases:Potential biomarkers, therapeutic targets and challenges[J]. Acta Pharmacologica Sinica, 2018, 39(7):1073-1084.
[45] PENG Y, CROCE C M.The role of microRNAs in human cancer[J]. Signal Transduction and Targeted Therapy, 2016, 8(1):15004-15013.
[46] BOGGS R M, WRIGHT Z M, STICKNEY M J, et al. microRNA expression in canine mammary cancer[J]. Mammalian Genome, 2008, 19(7-8):561-569.
[47] STARKEY M P, COMPSTON-GARNETT L, MALHO P, et al. Metastasis-associated microRNA expression in canine uveal melanoma[J]. Veterinary and Comparative Oncology, 2018, 16(1):81-89.
[48] BULKOWSKA M, RYBICKA A, SENSES K M, et al. microRNA expression patterns in canine mammary cancer show significant differences between metastatic and non-metastatic tumours[J]. BMC Cancer, 2017, 17(1):278-294.
[49] FENGER J M, BEAR M D, VOLINIA S, et al. Overexpression of miR-9 in mast cells is associated with invasive behavior and spontaneous metastasis[J]. BMC Cancer, 2014, 14(84):84-99.
[50] FENGER J M, ROBERTS R D, IWENOFU O H, et al. miR-9 is overexpressed in spontaneous canine osteosarcoma and promotes a metastatic phenotype including invasion and migration in osteoblasts and osteosarcoma cell lines[J]. BMC Cancer, 2016, 16(1):784-802.
[51] LOPEZ C M, YU P Y, ZHANG X, et al. miR-34a regulates the invasive capacity of canine osteosarcoma cell lines[J]. PLoS One, 2018, 13(1):e0190086.
[52] DAILEY D D, HESS A M, BOUMA G J, et al. microRNA expression changes and integrated pathways associated with poor outcome in canine osteosarcoma[J]. Frontiers in Veterinary Science, 2021, 8:637622.
[53] ALBONICO F, MORTARINO M, AVALLONE G, et al. The expression ratio of miR-17-5p and miR-155 correlates with grading in canine splenic lymphoma[J]. Veterinary Immunology and Immunopathology, 2013, 155(1-2):117-123.
[54] BORRESEN B, NIELSEN L N, JESSEN L R, et al. Circulating let-7g is down-regulated in Bernese Mountain dogs with disseminated histiocytic sarcoma and carcinomas-A prospective study[J]. Veterinary and Comparative Oncology, 2017, 15(2):525-533.
[55] FUJIWARA-IGARASHI A, IGARASHI H, MIZUTANI N, et al. Expression profile of circulating serum microRNAs in dogs with lymphoma[J]. The Veterinary Journal, 2015, 205(2):317-321.
[56] CRAIG K, WOOD G A, KELLER S M, et al. microRNA profiling in canine multicentric lymphoma[J]. PLoS One, 2019, 14(12):e0226357.
[57] JAIN M, INGOLE S D, DESHMUKH R S, et al. CEA, CA 15-3, and miRNA expression as potential biomarkers in canine mammary tumors[J]. Chromosome Research, 2021, 29(2):175-188.
[58] KENT M S, ZWINGENBERGER A, WESTROPP J L, et al. microRNA profiling of dogs with transitional cell carcinoma of the bladder using blood and urine samples[J]. BMC Veterinary Research, 2017, 13(1):339-351.
[59] FISH E J, IRIZARRY K J, DEINNOCENTES P, et al. Malignant canine mammary epithelial cells shed exosomes containing differentially expressed microRNA that regulate oncogenic networks[J]. BMC Cancer, 2018, 18(1):832.
[60] ASADA H, TOMIYASU H, UCHIKAI T, et al. Comprehensive analysis of miRNA and protein profiles within exosomes derived from canine lymphoid tumour cell lines[J]. PLoS One, 2019, 14(4):e0208567.
[61] QIAO Z, YANG D, LIU L, et al. Genome-wide identification and characterization of long non-coding RNAs in MDCK cell lines with high and low tumorigenicities[J]. Genomics, 2020, 112(2):1077-1086.
[62] CHEN L, QIAN X, WANG Z, et al. The HOTAIR lncRNA:A remarkable oncogenic promoter in human cancer metastasis[J]. Oncology Letters, 2021, 21(4):302-309.
[63] GUPTA R A, SHAH N, WANG K C, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis[J]. Nature, 2010, 464(7291):1071-1076.
[64] VERMA A, JIANG Y, DU W, et al. Transcriptome sequencing reveals thousands of novel long non-coding RNAs in B cell lymphoma[J]. Genome Medicine, 2015, 1(7):110-126.