title: Decorin in human oral cancer: a promising predictive biomarker of S-1 neoadjuvant chemosensitivity.
abstract: We reported previously that decorin (DCN) is significantly up-regulated in chemoresistant cancer cell lines. DCN is a small leucine-rich proteoglycan that exists and functions in stromal and epithelial cells. Accumulating evidence suggests that DCN affects the biology of several types of cancer by directly/indirectly targeting the signaling molecules involved in cell growth, survival, metastasis, and angiogenesis, however, the molecular mechanisms of DCN in chemoresistance and its clinical relevance are still unknown. Here we assumed that DCN silencing cells increase chemosusceptibility to S-1, consisted of tegafur, prodrug of 5-fluorouracil. We first established DCN knockdown transfectants derived from oral cancer cells for following experiments including chemosusceptibility assay to S-1. In addition to the in vitro data, DCN knockdown zenografting tumors in nude mice demonstrate decreasing cell proliferation and increasing apoptosis with dephosphorylation of AKT after S-1 chemotherapy. We also investigated whether DCN expression predicts the clinical responses of neoadjuvant chemotherapy (NAC) using S-1 (S-1 NAC) for oral cancer patients. Immunohistochemistry data in the preoperative biopsy samples was analyzed to determine the cut-off point for status of DCN expression by receiver operating curve analysis. Interestingly, low DCN expression was observed in five (83%) of six cases with complete responses to S-1 NAC, and in one (10%) case of 10 cases with stable/progressive disease, indicating that S-1 chemosensitivity is dramatically effective in oral cancer patients with low DCN expression compared with high DCN expression. Our findings suggest that DCN is a key regulator for chemoresistant mechanisms, and is a predictive immunomarker of the response to S-1 NAC and patient prognosis.
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba 260-8670, Japan. Electronic address: kasamatsua@faculty.chiba-u.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasamatsu
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba 260-8670, Japan. Electronic address: uzawak@faculty.chiba-u.jp.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Uzawa
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Minakawa
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Ishige
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kasama
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba 260-8670, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Endo-Sakamoto
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba 260-8670, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ogawara
authors.affiliation: Medical Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiiba
authors.affiliation: Medical Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takiguchi
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba 260-8670, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tanzawa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001706:Biopsy; D045744:Cell Line, Tumor; D058575:Decorin / Q000378:metabolism*; D004338:Drug Combinations; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020360:Neoadjuvant Therapy; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010094:Oxonic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D005641:Tegafur / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C546878:DCN protein, human; D058575:Decorin; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid
keywords: AKT pathway; Chemoresistant; Decorin; Neoadjuvant chemotherapy; Oral squamous cell carcinoma; S-1