TY - JOUR
T1 - A unifying gene signature for adenoid cystic cancer identifies parallel MYB-dependent and MYB-independent therapeutic targets
AU - Gao, Ruli
AU - Cao, Chunxia
AU - Zhang, Min
AU - Lopez, Maria Cecilia
AU - Yan, Yuanqing
AU - Chen, Zirong
AU - Mitani, Yoshitsugu
AU - Zhang, Li
AU - Zajac-Kaye, Maria
AU - Liu, Bin
AU - Wu, Lizi
AU - Renne, Rolf
AU - Baker, Henry V.
AU - El-Naggar, Adel
AU - Kaye, Frederic J.
PY - 2014
Y1 - 2014
N2 - MYB activation is proposed to underlie development of adenoid cystic cancer (ACC), an aggressive salivary gland tumor with no effective systemic treatments. To discover druggable targets for ACC, we performed global mRNA/miRNA analyses of 12 ACC with matched normal tissues, and compared these data with 14 mucoepidermoid carcinomas (MEC) and 11 salivary adenocarcinomas (ADC). We detected a unique ACC gene signature of 1160 mRNAs and 22 miRNAs. MYB was the top-scoring gene (18-fold induction), however we observed the same signature in ACC without detectable MYB gene rearrangements. We also found 4 ACC tumors (1 among our 12 cases and 3 from public databases) with negligible MYB expression that retained the same ACC mRNA signature including over-expression of extracellular matrix (ECM) genes. Integration of this signature with somatic mutational analyses suggests that NOTCH1 and RUNX1 participate with MYB to activate ECM elements including the VCAN/HAPLN1 complex. We observed that forced MYB-NFIB expression in human salivary gland cells alters cell morphology and cell adhesion in vitro and depletion of VCAN blocked tumor cell growth of a short-term ACC tumor culture. In summary, we identified a unique ACC signature with parallel MYB-dependent and independent biomarkers and identified VCAN/HAPLN1 complexes as a potential target.
AB - MYB activation is proposed to underlie development of adenoid cystic cancer (ACC), an aggressive salivary gland tumor with no effective systemic treatments. To discover druggable targets for ACC, we performed global mRNA/miRNA analyses of 12 ACC with matched normal tissues, and compared these data with 14 mucoepidermoid carcinomas (MEC) and 11 salivary adenocarcinomas (ADC). We detected a unique ACC gene signature of 1160 mRNAs and 22 miRNAs. MYB was the top-scoring gene (18-fold induction), however we observed the same signature in ACC without detectable MYB gene rearrangements. We also found 4 ACC tumors (1 among our 12 cases and 3 from public databases) with negligible MYB expression that retained the same ACC mRNA signature including over-expression of extracellular matrix (ECM) genes. Integration of this signature with somatic mutational analyses suggests that NOTCH1 and RUNX1 participate with MYB to activate ECM elements including the VCAN/HAPLN1 complex. We observed that forced MYB-NFIB expression in human salivary gland cells alters cell morphology and cell adhesion in vitro and depletion of VCAN blocked tumor cell growth of a short-term ACC tumor culture. In summary, we identified a unique ACC signature with parallel MYB-dependent and independent biomarkers and identified VCAN/HAPLN1 complexes as a potential target.
KW - Adenoid cystic cancer
KW - Extracellular matrix
KW - MYB salivary gland cancer
UR - http://www.scopus.com/inward/record.url?scp=84921396345&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84921396345&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.2985
DO - 10.18632/oncotarget.2985
M3 - Article
C2 - 25587024
AN - SCOPUS:84921396345
SN - 1949-2553
VL - 5
SP - 12528
EP - 12542
JO - Oncotarget
JF - Oncotarget
IS - 24
ER -