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Featured researches published by Shingo Hara.


American Journal of Pathology | 2004

Phenotypic Switch from Paracrine to Autocrine Role of Hepatocyte Growth Factor in an Androgen-Independent Human Prostatic Carcinoma Cell Line, CWR22R

Koh-ichi Nakashiro; Shingo Hara; Yuji Shinohara; Miho Oyasu; Hitoshi Kawamata; Satoru Shintani; Hiroyuki Hamakawa; Ryoichi Oyasu

Support mechanisms involved in growth of androgen-independent prostate cancer are primarily unknown. Hepatocyte growth factor (HGF)/Met has been suggested to be one of them based primarily on immunohistochemical studies. We conducted a series of experiments to assess the role of the HGF/Met system in an androgen-dependent human prostate carcinoma, CWR22 and its androgen-independent derivative, CWR22R. We found that action of HGF changed from paracrine to autocrine in progression to androgen-independent state. CWR22 tumors did not express HGF but expressed Met, whereas prostate stromal cells expressed HGF at a high level. Growth of CWR22 was stimulated either by addition of HGF to the culture or by the presence of prostate stromal cells. On the other hand, CWR22R cells expressed both HGF and Met. Knockdown of Met expression by RNA interference method suppressed the growth of CWR22R cells. Our data suggest that HGF is intimately involved in growth of human prostate cancer and that progression from the androgen-dependent to the androgen-independent state is associated with an adaptive switch in support mechanism from paracrine to autocrine. Our data offer one mechanism to account for androgen-independent human cancer growth.


Biochemical and Biophysical Research Communications | 2010

Knockdown of Akt isoforms by RNA silencing suppresses the growth of human prostate cancer cells in vitro and in vivo

Toyokazu Sasaki; Koh-ichi Nakashiro; Hiroshi Tanaka; Koji Azuma; Hiroyuki Goda; Shingo Hara; Jun Onodera; Ichiro Fujimoto; Nozomu Tanji; Masayoshi Yokoyama; Hiroyuki Hamakawa

The serine/threonine kinase Akt has three highly homologous isoforms in mammals: Akt1, Akt2, and Akt3. Recent studies indicate that Akt is often constitutively active in many types of human malignancy. Here we investigated the expression and function of Akt isoforms in human prostatic carcinoma cells. Initially, we used Western blotting to examine Akt expression in four human prostate cancer cell lines. Next, small-interfering RNAs (siRNAs) specific for Akt isoforms were used to elucidate their role on the in vitro and in vivo growth of prostate cancer cells. Expression of Akt1 and Akt2 was detected in all cells tested, but Akt3 was expressed only in cancer cells that did not express androgen receptors. All synthetic siRNAs against Akt isoforms suppressed their expression and inhibited the growth of cancer cells in vitro. Furthermore, atelocollagen-mediated systemic administration of siRNAs significantly reduced the growth of tumors that had been subcutaneously xenografted. These results suggest that targeting Akt isoforms could be an effective treatment for prostate cancers.


Biochemical and Biophysical Research Communications | 2008

Role of Akt isoforms in HGF-induced invasive growth of human salivary gland cancer cells

Shingo Hara; Koh-ichi Nakashiro; Hiroyuki Goda; Hiroyuki Hamakawa

The expression of hepatocyte growth factor (HGF) and c-Met is associated with tumor progression in many human malignancies. A recent study demonstrated HGF and c-Met expression in human salivary gland cancer tissues. Here, we investigated the role of the HGF/c-Met system in the invasive growth of two human salivary gland cancer cell lines: green fluorescent protein-adenoid cystic carcinoma 2 (GFP-ACC2) and GFP-ACCM. HGF enhanced the invasive growth of the two cell lines by activating PI3K/Akt signaling. All Akt isoforms (Akt1, Akt2, and Akt3) were detected in both cell types by Western blot analysis. Knockdown of any of the Akt isoforms using isoform-specific synthetic small-interfering RNAs largely abrogated the invasive growth induced by HGF. Our findings suggest that all of the Akt isoforms are required for the HGF-stimulated invasive growth of human salivary gland cancer cells, and that targeting a single Akt isoform could be effective in treating salivary gland cancers.


Biochemical and Biophysical Research Communications | 2009

CD151 regulates HGF-stimulated morphogenesis of human breast cancer cells

Sebastian K. Klosek; Koh-ichi Nakashiro; Shingo Hara; Hiroyuki Goda; Hitoshi Hasegawa; Hiroyuki Hamakawa

We previously demonstrated that CD151 forms a functional complex with c-Met and integrin alpha3/alpha6 in human salivary gland cancer cells. In the current study, we investigated the involvement of CD151, c-Met, and integrin alpha3/alpha6 in the cellular morphogenesis of human breast cancer cells. Knockdown of CD151, integrin alpha3, or integrin alpha6 expression abolished branching morphogenesis. Decreased c-Met expression in these cells led to the formation of rudimentary networks and prevented their conversion. Furthermore, hepatocyte growth factor (HGF) promoted cellular morphogenesis by accelerating network reorganization. Immunoprecipitation revealed a specific association between CD151 and c-Met. The involvement of CD151 and integrin alpha3/alpha6 in HGF-dependent signaling was confirmed by the decreased Akt phosphorylation in cells lacking CD151, integrin alpha3, or integrin alpha6. Hence, the regulation of CD151 expression might contribute to changes in HGF/c-Met signaling and thereby modulate the phenotypic characteristics of cancer cells.


International Journal of Oncology | 2015

Identification of Akt1 as a potent therapeutic target for oral squamous cell carcinoma

Koh-ichi Nakashiro; Hiroshi Tanaka; Hiroyuki Goda; Kazuki Iwamoto; Norihiko Tokuzen; Shingo Hara; Jun Onodera; Ichiro Fujimoto; Satoshi Hino; Hiroyuki Hamakawa

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.


Oncology Reports | 2009

Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma.

Tohru Ishikawa; Koh-ichi Nakashiro; Sebastian K. Klosek; Hiroyuki Goda; Shingo Hara; Daisuke Uchida; Hiroyuki Hamakawa


Oral Oncology | 2006

Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1α in human salivary gland cancer cells

Shingo Hara; Koh-ichi Nakashiro; Sebastian K. Klosek; Tohru Ishikawa; Satoru Shintani; Hiroyuki Hamakawa


International Journal of Oncology | 2006

CXCR4 expression is associated with lymph-node metastasis of oral squamous cell carcinoma

Tohru Ishikawa; Koh-ichi Nakashiro; Shingo Hara; Sebastian K. Klosek; Chunnan Li; Satoru Shintani; Hiroyuki Hamakawa


Biochemical and Biophysical Research Communications | 2005

CD151 forms a functional complex with c-Met in human salivary gland cancer cells

Sebastian K. Klosek; Koh-ichi Nakashiro; Shingo Hara; Satoru Shintani; Hitoshi Hasegawa; Hiroyuki Hamakawa


Biochemical and Biophysical Research Communications | 2006

Inactivation of AR activates HGF/c-Met system in human prostatic carcinoma cells ☆

Akinobu Maeda; Koh-ichi Nakashiro; Shingo Hara; Toyokazu Sasaki; Yoshihiro Miwa; Nozomu Tanji; Masayoshi Yokoyama; Hiroyuki Hamakawa; Ryoichi Oyasu

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