title: Prox1 and FOXC2 act as regulators of lymphangiogenesis and angiogenesis in oral squamous cell carcinoma.
abstract: Prospero homeobox 1 (Prox1) and forkhead box (FOX) C2 regulate angiogenesis and/or lymphangiogenesis. However, the detailed role and function of Prox1 and FOXC2 in cancer remains controversial. In the present study, we examined the expression of Prox1 and FOXC2 proteins in specimens from 163 cases with oral squamous cell carcinoma (OSCC). Furthermore, the role of Prox1 and FOXC2 in cancer cell growth and invasion was evaluated in cultured OSCC cells. Prox1 expression was significantly associated with local progression of the tumor (P = 0.0023), clinical stage (P<0.0001), lymphovessel density (LVD) (P<0.0001), nodal metastasis (P<0.0001), and worse prognosis (P<0.0001). Immunoreactivity of FOXC2 was strongly correlated with microvessel density (MVD) (P<0.0001) and poor prognosis (P = 0.0076). In vitro analysis demonstrated that Prox1 regulates cell growth, proliferation, invasion, and lymphangiogenesis by activating vascular endothelial growth factor (VEGF)-C expression. Furthermore, FOXC2 enhanced the expression level of Prox1 and promoted angiogenesis by enhancement of VEGF-A expression. Our results suggested that Prox1 and FOXC2 play key roles in OSCC progression and that further studies focusing on these proteins may yield useful insights for diagnosis and therapy of OSCC.
authors.affiliation: Department of Molecular Pathology, Nara Medical University, Kashihara, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Sasahira
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nara Medical University, Kashihara, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ueda
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nara Medical University, Kashihara, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular Pathology, Nara Medical University, Kashihara, Japan; Department of Oral and Maxillofacial Surgery, Nara Medical University, Kashihara, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Kurihara
authors.affiliation: Department of Molecular Pathology, Nara Medical University, Kashihara, Japan.
authors.forename: Sayako
authors.initials: S
authors.lastname: Matsushima
authors.affiliation: Department of Molecular Pathology, Nara Medical University, Kashihara, Japan; Department of Biochemistry and Molecular Biology, Nihon University School of Dentistry at Matsudo, Matsudo, Japan.
authors.forename: Ujjal K
authors.initials: UK
authors.lastname: Bhawal
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nara Medical University, Kashihara, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Kirita
authors.affiliation: Department of Molecular Pathology, Nara Medical University, Kashihara, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kuniyasu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D042583:Lymphangiogenesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; C082078:mesenchyme fork head 1 protein; D000098551:Prospero-Related Homeobox 1 Protein