TY - JOUR
T1 - NUT midline carcinoma
T2 - Morphoproteomic characterization with genomic and therapeutic correlates
AU - Sun, Hongxia
AU - McGuire, Mary F.
AU - Zhang, Songlin
AU - Brown, Robert E.
N1 - Publisher Copyright:
© 2015 by the Association of Clinical Scientists, Inc.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - NUT midline carcinoma is a rare entity arising primarily in the midline of teenagers and young adults. Genomically, it is associated with a translocation involving a nuclear protein in testis (NUT) gene with other genes, most commonly, the BRD4 gene. The resultant is a partial or near total block in differentiation of tumor cells into mature squamous elements. Such tumors are resistant to conventional therapy with a reported mean survival at less than 1 year. In this study, we investigated two cases with genomic confirmation as NUT midline carcinoma by morphoproteomic analysis using immunohistochemical antibodies. Our results showed overexpression, largely in the undifferentiated cells of the tumors of: 1) Stemness marker, SRY (sex determining region Y)-box 2 (Sox2); 2) Constitutive activation of the mTORC2 pathway with expression of total insulin-like growth factor-1 receptor (IGF-1R[Tyr1165/1166]), and nuclear p-mTOR (Ser 2448) and p-Akt (Ser 473); and 3) c-Myc, silent mating type information regulation 2 homolog 1 (Sirt1) and histone methyltransferase enhancer of Zeste, Drosophila, homolog 2 (EZH2) as molecular impediments to differentiation. These data were analyzed through the use of QIAGEN's Ingenuity® Pathway Analysis (IPA®, QIAGEN Redwood City, www.qiagen.com/ingenuity). The results established the interconnection of these pathways and molecules, and identified several pharmacogenomic agents - melatonin, metformin, vorinostat, curcumin, and sulforaphane - that have the potential to remove the block in differentiation and lead to the establishment of a more benign form of NUT midline carcinoma.
AB - NUT midline carcinoma is a rare entity arising primarily in the midline of teenagers and young adults. Genomically, it is associated with a translocation involving a nuclear protein in testis (NUT) gene with other genes, most commonly, the BRD4 gene. The resultant is a partial or near total block in differentiation of tumor cells into mature squamous elements. Such tumors are resistant to conventional therapy with a reported mean survival at less than 1 year. In this study, we investigated two cases with genomic confirmation as NUT midline carcinoma by morphoproteomic analysis using immunohistochemical antibodies. Our results showed overexpression, largely in the undifferentiated cells of the tumors of: 1) Stemness marker, SRY (sex determining region Y)-box 2 (Sox2); 2) Constitutive activation of the mTORC2 pathway with expression of total insulin-like growth factor-1 receptor (IGF-1R[Tyr1165/1166]), and nuclear p-mTOR (Ser 2448) and p-Akt (Ser 473); and 3) c-Myc, silent mating type information regulation 2 homolog 1 (Sirt1) and histone methyltransferase enhancer of Zeste, Drosophila, homolog 2 (EZH2) as molecular impediments to differentiation. These data were analyzed through the use of QIAGEN's Ingenuity® Pathway Analysis (IPA®, QIAGEN Redwood City, www.qiagen.com/ingenuity). The results established the interconnection of these pathways and molecules, and identified several pharmacogenomic agents - melatonin, metformin, vorinostat, curcumin, and sulforaphane - that have the potential to remove the block in differentiation and lead to the establishment of a more benign form of NUT midline carcinoma.
KW - Biomedical analytics
KW - C-Myc
KW - EZH2
KW - MTORC2 pathway
KW - Morphoproteomic
KW - NUT midline carcinoma
KW - Sirt1
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M3 - Article
C2 - 26663801
AN - SCOPUS:84950249972
SN - 0091-7370
VL - 45
SP - 692
EP - 701
JO - Annals of clinical and laboratory science
JF - Annals of clinical and laboratory science
IS - 6
ER -