Biological indicators of prognosis in Ewing's sarcoma: an emerging role for lectin galactoside-binding soluble 3 binding protein (LGALS3BP).
Starting from an experimental model that accounts for the 2 most important adverse processes to successful therapy of Ewing's sarcoma (EWS), chemoresistance and the presence of metastasis at the time of diagnosis, we defined a molecular signature of potential prognostic value. Functional annotation of differentially regulated genes revealed 3 major networks related to cell cycle, cell-to-cell interactions and cellular development. The prognostic impact of 8 genes, representative of these 3 networks, was validated in 56 EWS patients. High mRNA expression levels of HINT1, IFITM2, LGALS3BP, STOML2 and c-MYC were associated with reduced risk to death and lower risk to develop metastasis. At multivariate analysis, LGALS3BP, a matricellular protein with a role in tumor progression and metastasis, was the most important predictor of event-free survival and overall survival. The association between LGALS3BP and prognosis was confirmed at protein level, when expression of the molecule was determined in tumor tissues but not in serum, indicating a role for the protein at local tumor microenvironment. Engineered enhancement of LGALS3BP expression in EWS cells resulted in inhibition of anchorage independent cell growth and reduction of cell migration and metastasis. Silencing of LGALS3BP expression reverted cell behavior with respect to in vitro parameters, thus providing further functional validation of genetic data obtained in clinical samples. Thus, we propose LGALS3BP as a novel reliable indicator of prognosis, and we offer genetic signatures to the scientific communities for cross-validation and meta-analysis, which are indispensable tools for a rare tumor such as EWS.
Zambelli
Diana
D
Laboratory of Oncologic Research, Istituti Ortopedici Rizzoli, Bologna, Italy.
Zuntini
Monia
M
Nardi
Filippo
F
Manara
Maria Cristina
MC
Serra
Massimo
M
Landuzzi
Lorena
L
Lollini
Pier-Luigi
PL
Ferrari
Stefano
S
Alberghini
Marco
M
Llombart-Bosch
Antonio
A
Piccolo
Enza
E
Iacobelli
Stefano
S
Picci
Piero
P
Scotlandi
Katia
K
D000818:Animals; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D020868:Gene Silencing; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D016326:Extracellular Matrix Proteins
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D006023:Glycoproteins; D012333:RNA, Messenger; C081856:LGALS3BP protein, human; D016326:Extracellular Matrix Proteins