Protumorigenic role of HAPLN1 and its IgV domain in malignant pleural mesothelioma.
OBJECTIVE
Tumor extracellular matrix (ECM) plays a crucial role in cancer progression mediating and transforming host-tumor interactions. Targeting the ECM is becoming an increasingly promising therapeutic approach in cancer treatment. We find that one of the ECM proteins, HAPLN1, is overexpressed in the majority of mesotheliomas. This study was designed to characterize the protumorigenic role of HAPLN1 in mesothelioma.


METHODS
Overexpression of HAPLN1 was assessed and validated on a large set of normal/mesothelioma specimens on the RNA and protein levels. We also analyzed DNA copy number alterations in the HAPLN1 genomic locus using the array-based comparative genomic hybridization representational oligonucleotide microarray analysis tool. Tumorigenic activities of the HAPLN1 domains were evaluated in vitro on mesothelioma cells transfected with HAPLN1-expressing constructs.


RESULTS
We found that HAPLN1 is 23-fold overexpressed in stage I mesothelioma and confirmed it for 76% samples (n = 53) on RNA and 97% (n = 40) on protein levels. The majority of lung cancers showed no differential expression of HAPLN1. Analysis of DNA copy number alterations identified recurrent gain in the 5q14.3 HAPLN1 locus in approximately 27% of tumors. Noteworthy, high expression of HAPLN1 negatively correlated with time to progression (P = 0.05, log-rank test) and overall survival (P = 0.006). Proliferation, motility, invasion, and soft-agar colony formation assays on mesothelioma cells overexpressing full-length HAPLN1 or its functional domains strongly supported the protumorigenic role of HAPLN1 and its SP-IgV domain.


CONCLUSIONS
Overexpression of HAPLN1 and its SP-IgV domain increases tumorigenic properties of mesothelioma. Thus, targeting the SP-IgV domain may be one of the therapeutic approaches in cancer treatment.
Ivanova
Alla V
AV
Department of Cardiothoracic Surgery, Langone School of Medicine, New York University, New York, New York, USA. alla.ivanova@vanderbilt.edu
Goparaju
Chandra M V
CM
Ivanov
Sergey V
SV
Nonaka
Daisuke
D
Cruz
Christina
C
Beck
Amanda
A
Lonardo
Fulvio
F
Wali
Anil
A
Pass
Harvey I
HI
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism*; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010997:Pleural Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D000099249:Proteoglycan Link Protein
D016326:Extracellular Matrix Proteins; D006820:Hyaluronic Acid; D011509:Proteoglycans; D000099249:Proteoglycan Link Protein