Lin-7C/VELI3/MALS-3: an essential component in metastasis of human squamous cell carcinoma.
Using proteomic selection, functional verification, and clinical validation, we identified specific down-regulation of Lin-7C/VELI3/MALS-3 (Lin-7C), which marks oral squamous cell carcinoma (OSCC) metastasis. Despite a rarity of sequence variations in the Lin-7C gene in both primary OSCC and OSCC-derived cells, a high prevalence of hypermethylation was detected in the CpG island region that strongly correlated with its down-regulation. Inducible Lin-7C mRNA by experimental demethylation was found in all OSCC cells tested. Overexpression of the Lin-7C gene in an OSCC cell clone does not contribute to underproliferation but results in a noninvasive phenotype with elevated beta-catenin expression. Experimental metastases in multiple organs of immunodeficient mice were inhibited in cells expressing Lin-7C. Finally, the Lin-7C expression status in primary tumors afforded significantly (P<0.001) high accuracy for predicting lymph node metastasis. These results establish Lin-7C as a novel target of early detection, prevention, and therapy for OSCC metastasis.
Onda
Takeshi
T
Department of Oral and Maxillofacial Surgery, Tokyo Dental College, and Division of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Japan.
Uzawa
Katsuhiro
K
Nakashima
Dai
D
Saito
Kengo
K
Iwadate
Yasuo
Y
Seki
Naohiko
N
Shibahara
Takahiko
T
Tanzawa
Hideki
H
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009368:Neoplasm Transplantation; D040901:Proteomics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C486531:LIN7C protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D051176:beta Catenin