title: Identification of Akt1 as a potent therapeutic target for oral squamous cell carcinoma.
abstract: Oncogene addiction can provide therapeutic opportunities in human malignancies. In this study, we aimed to identify critical oncogenes for oral squamous cell carcinoma (OSCC) development and progression. We determined gene expression profiles in 10 primary OSCCs and 10 human OSCC cell lines using Applied Biosystems Human Genome Survey Arrays. Akt1 was the only gene identified that was expressed in all OSCC tissues and cultured cells, but not in non-neoplastic tissues and cells. Subsequently, western blot analysis showed that Akt1 protein was overexpressed in OSCC tissues and cell lines. Immunohistochemistry also showed Akt1 protein expression in 59 of 63 (94%) primary OSCCs. To clarify the oncogenic function of Akt1 in human OSCC cells, we used RNA interference. We designed and synthesized 5 small interfering RNAs specific for Akt1 (siAkt1). Transfecting human OSCC cells with siAkt1 in vitro markedly suppressed their expression of Akt1 protein and significantly reduced their growth rate. Furthermore, the growth of human OSCC tumors which had been subcutaneously xenografted in athymic nude mice lacking interferon responses was markedly inhibited by atelocollagen-mediated systemic siAkt1 administration. We also found that synthetic siAkt1 had an inhibitory effect on the growth of primary cultured OSCC cells. Finally, we investigated the molecular mechanisms involved in the growth inhibitory effect of Akt1 suppression using microarray analysis of human OSCC cells transfected with siAkt1. Knockdown of Akt1 induced the expression of CDKN2B, a tumor suppressor gene, and reduced the expression of TGFBR1, which supports malignant phenotypes. These results suggest that Akt1 functions as a critical oncogene in human OSCC cells and may therefore be an appropriate target for novel OSCC therapies.
authors: Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Koh-Ichi
authors: K
authors: Nakashiro
authors: Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Hiroshi
authors: H
authors: Tanaka
authors: Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Hiroyuki
authors: H
authors: Goda
authors: Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Kazuki
authors: K
authors: Iwamoto
authors: Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Norihiko
authors: N
authors: Tokuzen
authors: Department of Oral and Maxillofacial Surgery, Kochi Health Sciences Center, Kochi, Kochi, Japan.
authors: Shingo
authors: S
authors: Hara
authors: Koken Research Institute, Koken Co., Ltd., Tokyo, Japan.
authors: Jun
authors: J
authors: Onodera
authors: Koken Research Institute, Koken Co., Ltd., Tokyo, Japan.
authors: Ichiro
authors: I
authors: Fujimoto
authors: Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Satoshi
authors: S
authors: Hino
authors: Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors: Hiroyuki
authors: H
authors: Hamakawa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D005260:Female; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D034741:RNA, Small Interfering; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt