脊索瘤分子调控机制的研究进展
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摘要
脊索瘤是起源于胚胎残余脊索组织的原发性恶性肿瘤。由于脊索瘤局部侵袭性高及化疗耐受性强,其复发率较高,预后较差。虽然相关研究发现原癌基因Brachyury等多个分子参与脊索瘤发生发展,然而其病因仍不明确。脊索瘤的治疗仍然是困扰临床医生的难题。近年来,新的分子标志物iASPP、SMARCB1及信号通路PI3K/AKT等被证实与脊索瘤的发生相关。确定关键分子及信号通路,一方面有助于深入了解脊索瘤的病因及发病机制,另一方面也为研发新的靶向药物以改善脊索瘤治疗现状奠定基础。本文从目前研究较多的关键分子、信号通路及表观遗传学等方面对脊索瘤分子调控机制的研究进展进行综述。
Chordoma is a rare primary malignant bone tumor derived from notochord remnants. Due to its strong local invasiveness and chemotherapy resistance, chordoma has a high local recurrence rate and poor prognosis. Although previous studies identified many molecules including brachyury as the oncogenes in chordoma, the pathogenesis of chordoma remains to be fully elucidated. The treatment of chordoma is still a challenge for the surgeons. In recent year, multiple novel biomarkers such as iASPP, SMARCB1 and signaling pathways like PI3K/AKT have been reported to be related with the pathogenesis of chordoma. Identifying crucial targets and signaling pathways is helpful to understand the pathogenesis of chordoma further, and lays a solid foundation to develop new drugs to improve the therapeutic effects of chordoma on the other hand. In this paper, we aim to review the recent advances in molecular regulation mechanism of chordoma.
Chordoma is a rare primary malignant bone tumor derived from notochord remnants. Due to its strong local invasiveness and chemotherapy resistance, chordoma has a high local recurrence rate and poor prognosis. Although previous studies identified many molecules including brachyury as the oncogenes in chordoma, the pathogenesis of chordoma remains to be fully elucidated. The treatment of chordoma is still a challenge for the surgeons. In recent year, multiple novel biomarkers such as iASPP, SMARCB1 and signaling pathways like PI3K/AKT have been reported to be related with the pathogenesis of chordoma. Identifying crucial targets and signaling pathways is helpful to understand the pathogenesis of chordoma further, and lays a solid foundation to develop new drugs to improve the therapeutic effects of chordoma on the other hand. In this paper, we aim to review the recent advances in molecular regulation mechanism of chordoma.
引文
[1]Walcott BP,Nahed BV,Mohyeldin A,et al.Chordoma:current concepts,management,and future directions[J].Lancet Oncol,2012,13(2):e69-76.
[2]Zhou Z,Wang X,Wu Z,et al.Epidemiological characteristics of primary spinal osseous tumors in Eastern China[J].World J Surg Oncol,2017,15(1):73.
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[5]Shah SR,David JM,Tippens ND,et al.Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer[J].Cell Rep,2017,21(2):495-507.
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[7]Wang K,Hu Q,Wang L,et al.T gene isoform expression pattern is significantly different between chordomas and notochords[J].Biochem Biophys Res Commun,2015,467(2):261-7.
[8]Yakkioui Y,Temel Y,Creytens D,et al.A comparison of cell-cycle markers in skull base and sacral chordomas[J].World Neurosurg,2014,82(1-2):e311-8.
[9]Mendoza M,Mandani G,Momand J.The MDM2 gene family[J].Biomol Concepts,2014,5(1):9-19.
[10]Naka T,Boltze C,Kuester D,et al.Alterations of G1-S checkpoint in chordoma:the prognostic impact of p53 overexpression[J].Cancer,2005,104(6):1255-63.
[11]Ma Y,Zhu B,Liu X,et al.iASPP overexpression is associated with clinical outcome in spinal chordoma and influences cellular proliferation,invasion,and sensitivity to cisplatin in vitro[J].Oncotarget,2017,8(40):68365-80.
[12]Liu JQ,Zhang QH,Wang ZL.Clinicopathological significance of p16,cyclin D1,Rb and MIB-1 levels in skull base chordoma and chondrosarcoma[J].World J Otorhinolaryngol Head Neck Surg,2015,1(1):50-6.
[13]Choy E,MacConaill LE,Cote GM,et al.Genotyping cancerassociated genes in chordoma identifies mutations in oncogenes and areas of chromosomal loss involving CDKN2A,PTEN,and SMARCB1[J].PLoS One,2014,9(7):e101283.
[14]Chen H,Garbutt CC,Spentzos D,et al.Expression and Therapeutic Potential of SOX9 in Chordoma[J].Clin Cancer Res,2017,23(17):5176-86.
[15]Li M,Zhai Y,Bai J,et al.SNF5 as a prognostic factor in skull base chordoma[J].J Neurooncol,2018,137(1):139-46.
[16]Antonelli M,Raso A,Mascelli S,et al.SMARCB1/INI1Involvement in Pediatric Chordoma:A Mutational and Immunohistochemical Analysis[J].Am J Surg Pathol,2017,41(1):56-61.
[17]Owosho AA,Zhang L,Rosenblum MK,et al.High sensitivity of FISH analysis in detecting homozygous SMARCB1 deletions in poorly differentiated chordoma:a clinicopathologic and molecular study of nine cases[J].Genes Chromosomes Cancer,2018,57(2):89-95.
[18]Cha YJ,Hong CK,Kim DS,et al.Poorly differentiated chordoma with loss of SMARCB1/INI1 expression in pediatric patients:A report of two cases and review of the literature[J].Neuropathology,2018,38(1):47-53.
[19]Scheipl S,Barnard M,Cottone L,et al.EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen[J].J Pathol,2016,239(3):320-34.
[20]Magnaghi P,Salom B,Cozzi L,et al.Afatinib is a new therapeutic approach in chordoma with a unique ability to target EGFR and Brachyury[J].Mol Cancer Ther,2018,17(3):603-13.
[21]Tosuner Z,Bozkurt SU,Kilic T,et al.The Role of EGFR,Hepatocyte Growth Factor Receptor(c-Met),c-ErbB2(HER2-neu)and Clinicopathological Parameters in the Pathogenesis and Prognosis of Chordoma[J].Turk Patoloji Derg,2017,33(2):112-20.
[22]Chen K,Mo J,Zhou M,et al.Expression of PTEN and mTORin sacral chordoma and association with poor prognosis[J].Med Oncol,2014,31(4):886.
[23]Wu Z,Wang L,Guo Z,et al.Experimental study on differences in clivus chordoma bone invasion:an iTRAQ-based quantitative proteomic analysis[J].PLoS One,2015,10(3):e119523.
[24]Hu Y,Mintz A,Shah SR,et al.The FGFR/MEK/ERK/brachyury pathway is critical for chordoma cell growth and survival[J].Carcinogenesis,2014,35(7):1491-9.
[25]Choudhry Z,Rikani AA,Choudhry AM,et al.Sonic hedgehog signalling pathway:a complex network[J].Ann Neurosci,2014,21(1):28-31.
[26]Cates JM,Itani DM,Coffin CM,et al.The sonic hedgehog pathway in chordoid tumours[J].Histopathology,2010,56(7):978-9.
[27]Chen K,Chen H,Zhang K,et al.MicroRNA profiling and bioinformatics analyses reveal the potential roles of microRNAs in chordoma[J].Oncol Lett,2017,14(5):5533-9.
[28]Marucci G,Morandi L,Mazzatenta D,et al.MGMT promoter methylation status in clival chordoma[J].J Neurooncol,2014,118(2):271-6.
[29]Alholle A,Brini AT,Bauer J,et al.Genome-wide DNAmethylation profiling of recurrent and non-recurrent chordomas[J].Epigenetics,2015,10(3):213-20.
[30]Osaka E,Yang X,Shen JK,et al.MicroRNA-1(miR-1)inhibits chordoma cell migration and invasion by targeting slug[J].JOrthop Res,2014,32(8):1075-82.
[31]Zhang Y,Schiff D,Park D,et al.MicroRNA-608 and microRNA-34a regulate chordoma malignancy by targeting EGFR,Bcl-xLand MET[J].PLoS One,2014,9(3):e91546.
[32]Wei W,Zhang Q,Wang Z,et al.miR-219-5p inhibits proliferation and clonogenicity in chordoma cells and is associated with tumor recurrence[J].Oncol Lett,2016,12(6):4568-76.
[33]Zou MX,Huang W,Wang XB,et al.Reduced expression of mi RNA-1237-3p associated with poor survival of spinal chordoma patients[J].Eur Spine J,2015,24(8):1738-46.
[34]Osaka E,Kelly AD,Spentzos D,et al.MicroRNA-155 expression is independently predictive of outcome in chordoma[J].Oncotarget,2015,6(11):9125-39.
[2]Zhou Z,Wang X,Wu Z,et al.Epidemiological characteristics of primary spinal osseous tumors in Eastern China[J].World J Surg Oncol,2017,15(1):73.
[3]Yakkioui Y,van Overbeeke JJ,Santegoeds R,et al.Chordoma:the entity[J].Biochim Biophys Acta,2014,1846(2):655-69.
[4]Otani R,Mukasa A,Shin M,et al.Brachyury gene copy number gain and activation of the PI3K/Akt pathway:association with upregulation of oncogenic Brachyury expression in skull base chordoma[J].J Neurosurg,2018,128(5):1428-37.
[5]Shah SR,David JM,Tippens ND,et al.Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer[J].Cell Rep,2017,21(2):495-507.
[6]Kelley MJ,Shi J,Ballew B,et al.Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma[J].Hum Genet,2014,133(10):1289-97.
[7]Wang K,Hu Q,Wang L,et al.T gene isoform expression pattern is significantly different between chordomas and notochords[J].Biochem Biophys Res Commun,2015,467(2):261-7.
[8]Yakkioui Y,Temel Y,Creytens D,et al.A comparison of cell-cycle markers in skull base and sacral chordomas[J].World Neurosurg,2014,82(1-2):e311-8.
[9]Mendoza M,Mandani G,Momand J.The MDM2 gene family[J].Biomol Concepts,2014,5(1):9-19.
[10]Naka T,Boltze C,Kuester D,et al.Alterations of G1-S checkpoint in chordoma:the prognostic impact of p53 overexpression[J].Cancer,2005,104(6):1255-63.
[11]Ma Y,Zhu B,Liu X,et al.iASPP overexpression is associated with clinical outcome in spinal chordoma and influences cellular proliferation,invasion,and sensitivity to cisplatin in vitro[J].Oncotarget,2017,8(40):68365-80.
[12]Liu JQ,Zhang QH,Wang ZL.Clinicopathological significance of p16,cyclin D1,Rb and MIB-1 levels in skull base chordoma and chondrosarcoma[J].World J Otorhinolaryngol Head Neck Surg,2015,1(1):50-6.
[13]Choy E,MacConaill LE,Cote GM,et al.Genotyping cancerassociated genes in chordoma identifies mutations in oncogenes and areas of chromosomal loss involving CDKN2A,PTEN,and SMARCB1[J].PLoS One,2014,9(7):e101283.
[14]Chen H,Garbutt CC,Spentzos D,et al.Expression and Therapeutic Potential of SOX9 in Chordoma[J].Clin Cancer Res,2017,23(17):5176-86.
[15]Li M,Zhai Y,Bai J,et al.SNF5 as a prognostic factor in skull base chordoma[J].J Neurooncol,2018,137(1):139-46.
[16]Antonelli M,Raso A,Mascelli S,et al.SMARCB1/INI1Involvement in Pediatric Chordoma:A Mutational and Immunohistochemical Analysis[J].Am J Surg Pathol,2017,41(1):56-61.
[17]Owosho AA,Zhang L,Rosenblum MK,et al.High sensitivity of FISH analysis in detecting homozygous SMARCB1 deletions in poorly differentiated chordoma:a clinicopathologic and molecular study of nine cases[J].Genes Chromosomes Cancer,2018,57(2):89-95.
[18]Cha YJ,Hong CK,Kim DS,et al.Poorly differentiated chordoma with loss of SMARCB1/INI1 expression in pediatric patients:A report of two cases and review of the literature[J].Neuropathology,2018,38(1):47-53.
[19]Scheipl S,Barnard M,Cottone L,et al.EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen[J].J Pathol,2016,239(3):320-34.
[20]Magnaghi P,Salom B,Cozzi L,et al.Afatinib is a new therapeutic approach in chordoma with a unique ability to target EGFR and Brachyury[J].Mol Cancer Ther,2018,17(3):603-13.
[21]Tosuner Z,Bozkurt SU,Kilic T,et al.The Role of EGFR,Hepatocyte Growth Factor Receptor(c-Met),c-ErbB2(HER2-neu)and Clinicopathological Parameters in the Pathogenesis and Prognosis of Chordoma[J].Turk Patoloji Derg,2017,33(2):112-20.
[22]Chen K,Mo J,Zhou M,et al.Expression of PTEN and mTORin sacral chordoma and association with poor prognosis[J].Med Oncol,2014,31(4):886.
[23]Wu Z,Wang L,Guo Z,et al.Experimental study on differences in clivus chordoma bone invasion:an iTRAQ-based quantitative proteomic analysis[J].PLoS One,2015,10(3):e119523.
[24]Hu Y,Mintz A,Shah SR,et al.The FGFR/MEK/ERK/brachyury pathway is critical for chordoma cell growth and survival[J].Carcinogenesis,2014,35(7):1491-9.
[25]Choudhry Z,Rikani AA,Choudhry AM,et al.Sonic hedgehog signalling pathway:a complex network[J].Ann Neurosci,2014,21(1):28-31.
[26]Cates JM,Itani DM,Coffin CM,et al.The sonic hedgehog pathway in chordoid tumours[J].Histopathology,2010,56(7):978-9.
[27]Chen K,Chen H,Zhang K,et al.MicroRNA profiling and bioinformatics analyses reveal the potential roles of microRNAs in chordoma[J].Oncol Lett,2017,14(5):5533-9.
[28]Marucci G,Morandi L,Mazzatenta D,et al.MGMT promoter methylation status in clival chordoma[J].J Neurooncol,2014,118(2):271-6.
[29]Alholle A,Brini AT,Bauer J,et al.Genome-wide DNAmethylation profiling of recurrent and non-recurrent chordomas[J].Epigenetics,2015,10(3):213-20.
[30]Osaka E,Yang X,Shen JK,et al.MicroRNA-1(miR-1)inhibits chordoma cell migration and invasion by targeting slug[J].JOrthop Res,2014,32(8):1075-82.
[31]Zhang Y,Schiff D,Park D,et al.MicroRNA-608 and microRNA-34a regulate chordoma malignancy by targeting EGFR,Bcl-xLand MET[J].PLoS One,2014,9(3):e91546.
[32]Wei W,Zhang Q,Wang Z,et al.miR-219-5p inhibits proliferation and clonogenicity in chordoma cells and is associated with tumor recurrence[J].Oncol Lett,2016,12(6):4568-76.
[33]Zou MX,Huang W,Wang XB,et al.Reduced expression of mi RNA-1237-3p associated with poor survival of spinal chordoma patients[J].Eur Spine J,2015,24(8):1738-46.
[34]Osaka E,Kelly AD,Spentzos D,et al.MicroRNA-155 expression is independently predictive of outcome in chordoma[J].Oncotarget,2015,6(11):9125-39.