CD44 variant isoforms in head and neck squamous cell carcinoma progression.
OBJECTIVE
The CD44 family of receptors includes multiple variant isoforms, several of which have been linked to malignant properties including migration, invasion, and metastasis. The objective of this study was to investigate the role of the CD44 v3, v6, and v10 variant isoforms in head and neck squamous cell carcinoma (HNSCC) tumor progression behaviors.


METHODS
Laboratory study involving cell cultures and clinical tissue specimens.


METHODS
Analysis of the expression of standard CD44s and the CD44 variant isoforms v3, v6, and v10 was carried out in the HNSCC cell line, HSC-3. The role of CD44 isoforms in migration, proliferation, and cisplatin resistance was determined. Immunohistochemical analysis was performed on clinical tissue specimens obtained from a series of 82 HNSCC patients. The expression of standard CD44s and the CD44 v3, v6, and v10 variants in primary tumor specimens (n = 82) and metastatic cervical lymph nodes (n = 24) were analyzed with respect to various clinicopathologic variables.


RESULTS
HSC-3 cells express at least four CD44 isoforms, and these CD44 isoforms mediate migration, proliferation, and cisplatin sensitivity. Compared with primary tumors, a greater proportion of metastatic lymph nodes demonstrated strong expression of CD44 v3 (lymph node 14/24 vs. primary tumor 38/82), CD44 v6 (lymph node 18/24 vs. primary tumor 26/82), and CD44 v10 (lymph node 14/24 vs. primary tumor 16/82), while expression of standard CD44 was not significantly different in metastatic lymph nodes and primary tumors (lymph node 10/24 vs. primary tumor 60/82). Expression of CD44 variant isoforms were associated with advanced T stage (v3 and v6), regional (v3) and distant (v10) metastasis, perineural invasion (v6), and radiation failure (v10). CD44 v6 and CD44 v10 were also significantly associated with shorter disease-free survival.


CONCLUSIONS
CD44 isoforms mediate migration, proliferation, and cisplatin sensitivity in HNSCC. Furthermore, expression of certain CD44 variants may be important molecular markers for HNSCC progression and should be investigated as potential therapeutic targets for therapy.
Wang
Steven J
SJ
Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, Veterans Affairs Medical Center, USA. swang@ohns.ucsf.edu
Wong
Gabriel
G
de Heer
Anne-Martine
AM
Xia
Weiliang
W
Bourguignon
Lilly Y W
LY
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000737:chemistry*; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000556:secondary / Q000628:therapy; D045744:Cell Line, Tumor / Q000187:drug effects / Q000473:pathology; D002465:Cell Movement / Q000502:physiology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry* / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020033:Protein Isoforms / Q000737:chemistry* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D018960:Hyaluronan Receptors; D020033:Protein Isoforms