Osteopontin Involves Cisplatin Resistance and Poor Prognosis in Oral Squamous Cell Carcinoma.
BACKGROUND
Osteopontin (OPN) is a multifunctional cytokine involved in cell survival, migration, and adhesion. However, its role in chemosensitivity in locally advanced oral squamous cell carcinoma (OSCC) in humans has not yet been investigated.


METHODS
We enrolled 121 patients with locally advanced stage IVA/B OSCC receiving cisplatin-based IC followed by CCRT from January 1, 2006, through January 1, 2012. Immunohistochemistry was used to assess OPN expression in OSCC patients' biopsy specimens from paraffin blocks before treatment. In addition, MTT/colony formation assay was used to estimate the influence of OPN in an oral cancer cell line treated with cisplatin.


RESULTS
Of the 121 patients, 94 had positive OPN findings and 52 responded to IC followed by CCRT. Positive osteopontin immunostaining also correlated significantly with positive N status/TNM stage/male gender and smoking. Univariate analyses showed that patients whose tumors had a low expression of OPN were more likely to respond to chemotherapy and have a significantly better OS than those whose tumors had a high expression of OPN. Multivariate analysis revealed that prolonged survival was independently predicted for patients with stage IVA disease, negative lymph nodes, and negative expressions of OPN and for those who received chemotherapy with Docetaxel/cisplatin/fluorouracil (TPF). An oral cancer line stimulated with OPN exhibited a dose-dependent resistance to cisplatin treatment. Conversely, endogenous OPN depletion by OPN-mediated shRNA increased sensitivity to cisplatin.


CONCLUSIONS
A positive expression of OPN predicts a poor response and survival in patients with locally advanced stage IVA/B OSCC treated with cisplatin-based IC followed by CCRT.
Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan ; Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan ; Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan ; Institute of Clinical Medical Sciences, Chang Gung University, Kaohsiung 83301, Taiwan.
Sheng-Dean
SD
Luo
Department of Anatomic Pathology, E-Da hospital, I-Shou University, Kaohsiung 83301, Taiwan.
Yi-Ju
YJ
Chen
Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan ; Institute of Clinical Medical Sciences, Chang Gung University, Kaohsiung 83301, Taiwan ; Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
Chien-Ting
CT
Liu
Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan ; Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
Kun-Ming
KM
Rau
Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan ; Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
Yi-Ching
YC
Chen
Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan ; Institute of Clinical Medical Sciences, Chang Gung University, Kaohsiung 83301, Taiwan.
Hsin-Ting
HT
Tsai
Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan ; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan ; Department of Applied Chemistry and Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Nantao 54561, Taiwan.
Chang-Han
CH
Chen
Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan ; Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan ; Institute of Clinical Medical Sciences, Chang Gung University, Kaohsiung 83301, Taiwan ; Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan ; Department of Applied Chemistry and Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Nantao 54561, Taiwan.
Tai-Jan
TJ
Chiu
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D053495:Osteopontin / Q000037:antagonists & inhibitors*; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage
D009363:Neoplasm Proteins; D043823:Taxoids; D053495:Osteopontin; D002945:Cisplatin; D005472:Fluorouracil