同源盒基因转录反义RNA(HOTAIR)在乳腺癌临床诊疗中的研究进展
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摘要
同源盒基因转录反义RNA(HOTAIR)是第一个被发现具有反式转录调控作用的长链非编码RNA。作为反义RNA,HOTAIR本身并不编码蛋白质,而是以反式转录调控因子作用于不同染色体上的HOX基因簇,从而在基因组调控和肿瘤的发生、发展中起着重要作用。研究表明,HOTAIR与人类多种肿瘤(如乳腺癌、结直肠癌、肝癌、胰腺癌、喉癌等)的发生、发展及转移预后密切相关,高表达HOTAIR能抑制抑癌基因的表达,促进肿瘤复发转移,而下调HOTAIR表达则降低肿瘤细胞的转移侵袭能力。近年来研究逐渐证实,HOTAIR在乳腺癌组织、细胞系及其外周血中存在异常表达,并且这种表达失调有助于阐明乳腺癌的发生机制及耐药机制。临床研究则进一步表明,检测HOTAIR的表达水平不仅有助于提高乳腺癌的诊断敏感性和特异性,而且有助于促进临床上对乳腺癌的病情评估、预后判断、疗效评价和肿瘤复发转移的动态监测。此外,HOTAIR表达可能与乳腺癌不同激素受体类型的生物学行为相关。在乳腺癌治疗方面的探索研究则显示,通过设计HOTAIR促癌通路上的相应抗肿瘤药物或将能够为某些难治性乳腺癌的治疗带来曙光,比如他莫昔芬耐药乳腺癌。本文将对近几年上述研究进展进行综述。
HOX transcript antisense RNA( HOTAIR) is the first long chain non-coding RNA to be found with transcription regulation effect. As antisense RNA,HOTAIR itself does not encode proteins,but it acts as a transcription regulatory factor by effecting on different chromosomes of HOX gene cluster,thus playing an important role in the genomic control and development of tumor. Studies have shown that HOTAIR is dysregulated in several human cancers,such breast cancer,colorectal cancer,liver cancer,pancreatic cancer,laryngeal cancer,etc. High expression of HOTAIR can inhibit the expression of tumor suppressor genes,which will promote the tumor recurrence and metastasis,however down-regulated expression of HOTAIR will reduce the invasive ability of tumor cell. Researches in recent years have confirmed that HOTAIR expression is abnormal in breast cancer tissues,cell lines and peripheral blood,which is helpful to illuminate the mechanism of breast cancer development and the mechanism of drug resistance. Clinical studies further show that the detection of HOTAIR expression level is not only helpful to improve the diagnostic capability of breast cancer,but also helpful to promote clinical condition evaluation,prognosis judgment,curative effect evaluation and dynamic monitoring of tumor recurrence. In addition,HOTAIR expression may be related to biological behavior of breast cancer in different hormone receptor types. Exploration studies also shown that antitumor drugs designed according to carcinogenesis of HOTAIR will be able to bring light to the treatment of some refractory breast cancer,such as tamoxifen resistant breast cancer. This paper will review the research progress in recent years.
HOX transcript antisense RNA( HOTAIR) is the first long chain non-coding RNA to be found with transcription regulation effect. As antisense RNA,HOTAIR itself does not encode proteins,but it acts as a transcription regulatory factor by effecting on different chromosomes of HOX gene cluster,thus playing an important role in the genomic control and development of tumor. Studies have shown that HOTAIR is dysregulated in several human cancers,such breast cancer,colorectal cancer,liver cancer,pancreatic cancer,laryngeal cancer,etc. High expression of HOTAIR can inhibit the expression of tumor suppressor genes,which will promote the tumor recurrence and metastasis,however down-regulated expression of HOTAIR will reduce the invasive ability of tumor cell. Researches in recent years have confirmed that HOTAIR expression is abnormal in breast cancer tissues,cell lines and peripheral blood,which is helpful to illuminate the mechanism of breast cancer development and the mechanism of drug resistance. Clinical studies further show that the detection of HOTAIR expression level is not only helpful to improve the diagnostic capability of breast cancer,but also helpful to promote clinical condition evaluation,prognosis judgment,curative effect evaluation and dynamic monitoring of tumor recurrence. In addition,HOTAIR expression may be related to biological behavior of breast cancer in different hormone receptor types. Exploration studies also shown that antitumor drugs designed according to carcinogenesis of HOTAIR will be able to bring light to the treatment of some refractory breast cancer,such as tamoxifen resistant breast cancer. This paper will review the research progress in recent years.
引文
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[2]Serghiou S,Kyriakopoulou A,Ioannidis JP.Long noncoding RNAs as novel predictors of survival in human cancer:a systematic review and meta-analysis[J].Mol Cancer,2016,15(1):50-63.
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[5]Zhang L,Song X,Wang X,et al.Circulating DNA of HOTAIR in serum is a novel biomarker for breast cancer[J].Breast Cancer Res Treat,2015,152(1):199-208.
[6]Soudyab M,Iranpour M,Ghafouri-Fard S.The Role of Long Non-Coding RNAs in Breast Cancer[J].Arch Iran Med,2016,19(7):508-517.
[7]Yu X,Li Z.Long non-coding RNA HOTAIR:A novel oncogene(Review)[J].Mol Med Rep,2015,12(4):5611-5618.
[8]Zhang YY,Huang SH,Zhou HR,et al.Role of HOTAIR in the diagnosis and prognosis of acute leukemia[J].Oncol Rep,2016,36(6):3113-3122.
[9]Gupta RA,Shah N,Wang KC,et al.Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis[J].Nature,2010,464(7291):1071-1076.
[10]Battistelli C,Cicchini C,Santangelo L,et al.The Snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lnc RNAHOTAIR in epithelial-to-mesenchymal transition[J].Oncogene,2017,36(7):942-955.
[11]杨韬.Linc RNA HOTAIR诱导乳腺癌细胞上皮间质转化的研究[D].西安:第四军医大学,2012.
[12]Srensen KP,Thomassen M,Tan Q,et al.Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer[J].Breast Cancer Res Treat,2013,142(3):529-536.
[13]Tao S,He H,Chen Q.Estradiol induces HOTAIR levels via GPERmediated mi R-148a inhibition in breast cancer[J].J Transl Med,2015,13(4):131-138.
[14]张开炯,张毅,罗正莲,等.血浆长链非编码RNA HOTAIR是乳腺癌诊断的潜在生物标志物[J].南方医科大学学报,2016,36(4):488-492.
[15]Pádua Alves C,Fonseca AS,Muys BR,et al.Brief report:The linc RNA Hotair is required for epithelial-to-mesenchymal transition and stemness maintenance of cancer cell lines[J].Stem Cells,2013,31(12):2827-2832.
[16]Yao Y,Li J,Wang L.Large intervening non-coding RNA HOTAIR is an indicator of poor prognosis and therapeutic target in humancancers[J].Int J Mol Sci,2014,15(10):18985-18999.
[17]Chisholm KM,Wan Y,Li R,et al.Detection of Long Non-Coding RNA in Archival Tissue:Correlation with Polycomb Protein Expression in Primary and Metastatic Breast Carcinoma[J].PLoS One,2012,7(10):e47998.
[18]王昌亮,王礼泉,林明臻,等.长链非编码RNA-HOTAIR与乳腺癌腋窝淋巴结转移相关性研究[J].中国医学创新,2015,12(2):38-40,41.
[19]Lu L,Zhu G,Zhang C,et al.Association of large noncoding RNA HOTAIR expression and its downstream intergenic Cp G island methylation with survival in breast cancer[J].Breast Cancer Res Treat,2012,136(3):875-883.
[20]Li J,Wen W,Zhao S,et al.Prognostic role of HOTAIR in four estrogen-dependent malignant tumors:a meta-analysis[J].Onco Targets Ther,2015,8(6):1471-1482.
[21]Wang YL,Overstreet AM,Chen MS,et al.Combined inhibition of EGFR and c-ABL suppresses the growth of triple-negative breast cancer growth through inhibition of HOTAIR[J].Oncotarget,2015,6(13):11150-11161.
[22]Chen J,Lin C,Yong W,et al.Calycosin and genistein induce apoptosis by inactivation of HOTAIR/p-Akt signaling pathway in human breastcancer MCF-7 cells[J].Cell Physiol Biochem,2015,35(2):722-728.
[23]Yang X,Luo E,Liu X,et al.Delphinidin-3-glucoside suppresses breast carcinogenesis by inactivating the Akt/HOTAIR signaling pathway[J].BMC Cancer,2016,16:423.
[24]Nagini S.Breast Cancer:Current Molecular Therapeutic Targets and New Players[J].Anticancer Agents Med Chem,2017,17(2):152-163.
[25]Bhan A,Hussain I,Ansari KI,et al.Antisense transcript long noncoding RNA(lnc RNA)HOTAIR is transcriptionally induced by estradiol[J].J Mol Biol,2013,425(19):3707-3722.
[26]Bhan A,Mandal SS.Estradio-Induced Transcriptional Regulation of Long Non-Coding RNA,HOTAIR[J].Methods Mol Biol,2016,1366:395-412.
[27]Xue X,Yang YA,Zhang A.Lnc RNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer[J].Oncogene,2016,35(21):2746-2755.
[28]G9kmen-Polar Y,Vladislav IT,Neelamraju Y,et al.Prognostic impact of HOTAIR expression is restricted to ER-negative breast cancers[J].Sci Rep,2015,5:8765.
[29]Meredith EK,Balas MM,Sindy K,et al.An RNA matchmaker protein regulates the activity of the long noncoding RNA HOTAIR[J].RNA,2016,22(7):995-1010.
[2]Serghiou S,Kyriakopoulou A,Ioannidis JP.Long noncoding RNAs as novel predictors of survival in human cancer:a systematic review and meta-analysis[J].Mol Cancer,2016,15(1):50-63.
[3]Bayram S,Sümbül AT,Dada E.A functional HOTAIR rs12826786 C>T polymorphism is associated with breast can cer susceptibility and poorclinicopathological characteristics in a Turkish population:a hospital-based case-control study[J].Tumour Biol,2016,37(4):5577-5584.
[4]Hajjari M,Salavaty A.HOTAIR:an oncogenic long non-coding RNA in different cancers[J].Cancer Biol Med,2015,12(1):1-9.
[5]Zhang L,Song X,Wang X,et al.Circulating DNA of HOTAIR in serum is a novel biomarker for breast cancer[J].Breast Cancer Res Treat,2015,152(1):199-208.
[6]Soudyab M,Iranpour M,Ghafouri-Fard S.The Role of Long Non-Coding RNAs in Breast Cancer[J].Arch Iran Med,2016,19(7):508-517.
[7]Yu X,Li Z.Long non-coding RNA HOTAIR:A novel oncogene(Review)[J].Mol Med Rep,2015,12(4):5611-5618.
[8]Zhang YY,Huang SH,Zhou HR,et al.Role of HOTAIR in the diagnosis and prognosis of acute leukemia[J].Oncol Rep,2016,36(6):3113-3122.
[9]Gupta RA,Shah N,Wang KC,et al.Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis[J].Nature,2010,464(7291):1071-1076.
[10]Battistelli C,Cicchini C,Santangelo L,et al.The Snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lnc RNAHOTAIR in epithelial-to-mesenchymal transition[J].Oncogene,2017,36(7):942-955.
[11]杨韬.Linc RNA HOTAIR诱导乳腺癌细胞上皮间质转化的研究[D].西安:第四军医大学,2012.
[12]Srensen KP,Thomassen M,Tan Q,et al.Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer[J].Breast Cancer Res Treat,2013,142(3):529-536.
[13]Tao S,He H,Chen Q.Estradiol induces HOTAIR levels via GPERmediated mi R-148a inhibition in breast cancer[J].J Transl Med,2015,13(4):131-138.
[14]张开炯,张毅,罗正莲,等.血浆长链非编码RNA HOTAIR是乳腺癌诊断的潜在生物标志物[J].南方医科大学学报,2016,36(4):488-492.
[15]Pádua Alves C,Fonseca AS,Muys BR,et al.Brief report:The linc RNA Hotair is required for epithelial-to-mesenchymal transition and stemness maintenance of cancer cell lines[J].Stem Cells,2013,31(12):2827-2832.
[16]Yao Y,Li J,Wang L.Large intervening non-coding RNA HOTAIR is an indicator of poor prognosis and therapeutic target in humancancers[J].Int J Mol Sci,2014,15(10):18985-18999.
[17]Chisholm KM,Wan Y,Li R,et al.Detection of Long Non-Coding RNA in Archival Tissue:Correlation with Polycomb Protein Expression in Primary and Metastatic Breast Carcinoma[J].PLoS One,2012,7(10):e47998.
[18]王昌亮,王礼泉,林明臻,等.长链非编码RNA-HOTAIR与乳腺癌腋窝淋巴结转移相关性研究[J].中国医学创新,2015,12(2):38-40,41.
[19]Lu L,Zhu G,Zhang C,et al.Association of large noncoding RNA HOTAIR expression and its downstream intergenic Cp G island methylation with survival in breast cancer[J].Breast Cancer Res Treat,2012,136(3):875-883.
[20]Li J,Wen W,Zhao S,et al.Prognostic role of HOTAIR in four estrogen-dependent malignant tumors:a meta-analysis[J].Onco Targets Ther,2015,8(6):1471-1482.
[21]Wang YL,Overstreet AM,Chen MS,et al.Combined inhibition of EGFR and c-ABL suppresses the growth of triple-negative breast cancer growth through inhibition of HOTAIR[J].Oncotarget,2015,6(13):11150-11161.
[22]Chen J,Lin C,Yong W,et al.Calycosin and genistein induce apoptosis by inactivation of HOTAIR/p-Akt signaling pathway in human breastcancer MCF-7 cells[J].Cell Physiol Biochem,2015,35(2):722-728.
[23]Yang X,Luo E,Liu X,et al.Delphinidin-3-glucoside suppresses breast carcinogenesis by inactivating the Akt/HOTAIR signaling pathway[J].BMC Cancer,2016,16:423.
[24]Nagini S.Breast Cancer:Current Molecular Therapeutic Targets and New Players[J].Anticancer Agents Med Chem,2017,17(2):152-163.
[25]Bhan A,Hussain I,Ansari KI,et al.Antisense transcript long noncoding RNA(lnc RNA)HOTAIR is transcriptionally induced by estradiol[J].J Mol Biol,2013,425(19):3707-3722.
[26]Bhan A,Mandal SS.Estradio-Induced Transcriptional Regulation of Long Non-Coding RNA,HOTAIR[J].Methods Mol Biol,2016,1366:395-412.
[27]Xue X,Yang YA,Zhang A.Lnc RNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer[J].Oncogene,2016,35(21):2746-2755.
[28]G9kmen-Polar Y,Vladislav IT,Neelamraju Y,et al.Prognostic impact of HOTAIR expression is restricted to ER-negative breast cancers[J].Sci Rep,2015,5:8765.
[29]Meredith EK,Balas MM,Sindy K,et al.An RNA matchmaker protein regulates the activity of the long noncoding RNA HOTAIR[J].RNA,2016,22(7):995-1010.