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Regulation of motility, invasion, and metastatic potential of squamous cell carcinoma by 1α,25‐dihydroxycholecalciferol
Author(s) -
Ma Yingyu,
Yu WeiDong,
Su Bing,
Seshadri Mukund,
Luo Wei,
Trump Donald L.,
Johnson Candace S.
Publication year - 2012
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.27531
Subject(s) - pathology , motility , flow cytometry , cell migration , medicine , metastasis , cancer research , matrigel , cell , biology , cancer , angiogenesis , immunology , microbiology and biotechnology , genetics
BACKGROUND: The active metabolite of vitamin D 1α,25‐dihydroxycholecalciferol (1,25D 3 ) has exhibited broad‐spectrum antitumor activity in xenograft animal models. However, its activity against metastatic disease has not been extensively investigated. METHODS: Squamous cell carcinoma (SCC) or 1,25D 3 ‐resistant variant SCC‐DR cells were treated with 1,25D 3 . Actin organization was examined by immunofluorescence assay. Cell migration was assessed by “wound” healing and chemotactic migration assays. Cell invasion was assessed by a Matrigel‐based invasion assay and in situ zymography. Matrix metalloproteinase 2 (MMP‐2) and MMP‐9 expression and secretion were examined by immunoblot analysis and an enzyme‐linked immunosorbent assay, respectively. E‐cadherin expression was assessed by flow cytometry, immunoblot analysis, and immunohistochemistry. Knockdown of E‐cadherin was achieved by small interfering RNA. An experimental metastasis mouse model was created by intravenous injection of tumor cells; and lung tumor development in the mice was assessed by magnetic resonance imaging, gross observation, and histology. RESULTS: SCC cellular morphology and actin organization were altered by 10 nM 1,25D 3 . 1,25D 3 inhibited SCC cell motility and invasion, which were associated with reduced expression and secretion of MMP‐2 and MMP‐9, and 1,25D 3 promoted the expression of E‐cadherin. These findings were not observed in SCC‐DR cells. Knock down of E‐cadherin rescued 1,25D 3 ‐inhibited cell migration. Intravenous injection of SCC or SCC‐DR cells resulted in the establishment of extensive pulmonary lesions in saline‐treated C3H mice. Treatment with 1,25D 3 resulted in a marked reduction in the formation of lung tumor colonies in mice that were injected with SCC cells, but not in mice that were injected with SCC‐DR cells. CONCLUSIONS: 1,25D 3 suppressed SCC cell motility, invasion, and metastasis, partially through the promotion of E‐cadherin‐mediated cell‐cell adhesion. Cancer 2013. © 2012 American Cancer Society.