Src plays a key role in ADAM28 expression in v-src-transformed epithelial cells and human carcinoma cells

Hitoshi Abe, Satsuki Mochizuki, Kentaro Ohara, Mari Ueno, Hiroki Ochiai, Yuukou Kitagawa, Okio Hino, Hiroshi Sato, Yasunori Okada

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

ADAM28, a disintegrin and metalloproteinase 28, is overexpressed by carcinoma cells with direct correlations with carcinoma cell proliferation and progression in human lung and breast carcinomas. However, the molecular mechanisms of ADAM28 gene expression in carcinoma cells remain elusive. Herein, we investigated the expression of ADAM28 in Madin-Darby canine kidney epithelial cells transformed by oncogenes, including v-src, LMP1, ErbB2, Ha-Ras, and c-Fos, and found that v-src transformants selectively induce ADAM28. Implantation of the v-src transformants showed a progressively growing tumor, which was significantly suppressed by local injections of anti-ADAM28 antibody. ADAM28 expression in v-src transformants was partially inhibited by treatment with inhibitors to Src kinase, mitogen-activated protein kinase kinase (MEK), phosphatidylinositol 3-kinase (PI3K), or mammalian target of rapamycin, and abrogated by v-Src kinase inhibitor, radicicol, or a mixture of MEK and PI3K inhibitors. Human carcinoma cell lines of the lung, breast, ovary, kidney, and colon showed ADAM28 expression, which was correlated with phosphorylation of c-Src and suppressed by the inhibitors in a similar way to v-src transformants. IHC of the human tumor tissues demonstrated co-expression of ADAM28 and phosphorylated Src in neoplastic cells of the breast, lung, and colon carcinomas and some adenomas of the colon, but not in nonneoplastic colon mucosa. Our data provide, to the best of our knowledge, the first evidence that Src is an inducer of ADAM28 gene expression through the MEK/extracellular signal-regulated kinase and PI3K/mammalian target of rapamycin pathways.

Original languageEnglish
Pages (from-to)1667-1678
Number of pages12
JournalAmerican Journal of Pathology
Volume183
Issue number5
DOIs
Publication statusPublished - 2013 Nov

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Phosphatidylinositol 3-Kinase
Epithelial Cells
Carcinoma
Mitogen-Activated Protein Kinase Kinases
Colon
src-Family Kinases
Sirolimus
Lung
Breast
src Genes
MAP Kinase Kinase Kinases
Disintegrins
Gene Expression
Madin Darby Canine Kidney Cells
Extracellular Signal-Regulated MAP Kinases
Metalloproteases
Adenoma
Anti-Idiotypic Antibodies
Ovary
Neoplasms

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Src plays a key role in ADAM28 expression in v-src-transformed epithelial cells and human carcinoma cells. / Abe, Hitoshi; Mochizuki, Satsuki; Ohara, Kentaro; Ueno, Mari; Ochiai, Hiroki; Kitagawa, Yuukou; Hino, Okio; Sato, Hiroshi; Okada, Yasunori.

In: American Journal of Pathology, Vol. 183, No. 5, 11.2013, p. 1667-1678.

Research output: Contribution to journalArticle

Abe, Hitoshi ; Mochizuki, Satsuki ; Ohara, Kentaro ; Ueno, Mari ; Ochiai, Hiroki ; Kitagawa, Yuukou ; Hino, Okio ; Sato, Hiroshi ; Okada, Yasunori. / Src plays a key role in ADAM28 expression in v-src-transformed epithelial cells and human carcinoma cells. In: American Journal of Pathology. 2013 ; Vol. 183, No. 5. pp. 1667-1678.
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