Reduced expression of cell cycle regulator p18INK4C in human hepatocellular carcinoma

Morishita, Asahiro; Masaki, Tsutomu; Yoshiji, Hitoshi; Nakai, S.; Ogi, Tomohiro; Miyauchi, Y.; Yoshida, Shuhei; Funaki, Toshiharu; Uchida, Naoshige; Kita, Yuko; Funakoshi, Fumi; Usuki, Hisashi; Okada, Setsuo; Izuishi, Kunihiko; Watanabe, Seishiro; Kurokohchi, Kazutaka; Kuriyama, Shigeki

doi:10.1002/hep.20337

Cited by 46 publications

(34 citation statements)

References 45 publications

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“…Briefly, the membranes were incubated with primary antibodies after blocking and then with HRP-conjugated secondary antibodies. Immunoreactive proteins were visualized with an enhanced chemiluminescence detection system (Perkin Elmer Co.) on X-ray film, as described in our previous studies (16)(17)(18).…”

Section: Methodsmentioning

confidence: 99%

Mechanism of gemcitabine-induced suppression of human cholangiocellular carcinoma cell growth

Toyota

Iwama

Kato

et al. 2015

International Journal of Oncology

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Abstract. Although gemcitabine (2',2'-difluorocytidine monohydrochloride) is a common anticancer agent of cholangiocellular carcinoma (CCC), its growth inhibitory effects and gemcitabine resistance in CCC cells are poorly understood. Our aims were to uncover the mechanism underlying the antitumor effect of gemcitabine and to analyze the mechanism regulating in vitro CCC cell gemcitabine resistance. In addition, we sought to identify miRNAs associated with the antitumor effects of gemcitabine in CCCs. Using a cell proliferation assay and flow cytometry, we examined the ability of gemcitabine to inhibit cell proliferation in three types of human CCC cell lines (HuCCT-1, Huh28, TKKK). We also employed western blotting to investigate the effects of gemcitabine on cell cycle-related molecules in CCC cells. In addition, we used array chips to assess gemcitabine-mediated changes in angiogenic molecules and activated tyrosine kinase receptors in CCC cells. We used miRNA array chips to comprehensively analyze gemcitabine-induced miRNAs and examined clusters of differentially expressed miRNAs in cells with and without gemcitabine treatment. Gemcitabine inhibited cell proliferation in a dose-and time-dependent manner in HuCCT-1 cells, whereas cell proliferation was unchanged in Huh28 and TKKK cells. Gemcitabine inhibited cell cycle progression in HuCCT-1 cells from G0/G1 to S phase, resulting in G1 cell cycle arrest due to the reduction of cyclin D1 expression. In addition, gemcitabine upregulated the angiogenic molecules IL-6, IL-8, ENA-78 and MCP-1. In TKKK cells, by contrast, gemcitabine did not arrest the cell cycle or modify angiogenic molecules. Furthermore, in gemcitabine-sensitive HuCCT-1 cells, gemcitabine markedly altered miRNA expression. The miRNAs and angiogenic molecules altered by gemcitabine contribute to the inhibition of tumor growth in vitro.

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Section: Methodsmentioning

confidence: 99%

Mechanism of gemcitabine-induced suppression of human cholangiocellular carcinoma cell growth

Toyota

Iwama

Kato

et al. 2015

International Journal of Oncology

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“…In the current study, we found the expression of four INK4 family members all increased to a different extent, in both the protein and the mRNA levels, after the RhoA pathways were blocked. In fact, loss of p15 INK4b , p16 INK4a , and p18 INK4c by gene mutation, deletion, and/or methylation has been reported in a variety of human cancers (39,40).…”

Section: Kip1mentioning

confidence: 99%

RhoA Regulates G1-S Progression of Gastric Cancer Cells by Modulation of Multiple INK4 Family Tumor Suppressors

Zhang

Tang

et al. 2009

Molecular Cancer Research

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“…3, only p18 mRNA was significantly suppressed by DAPK knockdown. Although p18, a member of cyclindependent kinase inhibitor, is reported to be a tumor suppressor gene (19)(20)(21), further investigations are needed to clarify whether suppressed p18 expression can affect anticancer drug sensitivity of the cells. …”

Section: Discussionmentioning

confidence: 99%

Suppressed protein expression of the death-associated protein kinase enhances 5-fluorouracil-sensitivity but not etoposide-sensitivity in human endometrial adenocarcinoma cells

Tanaka

Bai²,

Yukawa³

2010

Oncol Rep

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Abstract. Targeted knockdown of the death-associated protein kinase (DAPK) expression in the endometrial adenocarcinoma HHUA cells reportedly induces cell death by enhancing the tumor necrosis factor-related apoptosisinducing ligand (TRAIL)-mediated apoptosis in an autocrine/ paracrine manner. This suggests that endogenous DAPK is a potential candidate for a molecularly targeted anticancer therapy for patients with endometrial adenocarcinoma. To investigate the role of endogenous DAPK in anticancer drug sensitivity, we examined effects on cellular anticancer drug sensitivities of transfections with 5 different specific DAPK small-interfering RNAs (siRNAs) into HHUA cells. DAPK siRNA transfections strongly enhanced 5-fluorouracil (5FU)-sensitivity, but not etoposide-sensitivity, of HHUA cells compared with control siRNA-transfected cells. These results indicate that etoposide-stimulated cell death signals may share or include TRAIL-mediated apoptotic signals, and that 5FU-stimulated cell death signals may be independent from TRAIL-mediated apoptotic signals induced by DAPK siRNA transfections. Moreover, 5FU-combined chemotherapy with DAPK siRNA transfection may show stronger anticancer effects on patients with endometrial adenocarcinoma than does chemotherapy alone. IntroductionThe death-associated protein kinase (DAPK) cDNA was isolated as a positive mediator of apoptosis triggered by IFN-Á from human cervical carcinoma cells (1). Investigations have revealed that DAPK functions as a Ca 2+ /calmodulindependent serine/threonine kinase to regulate cell death or cell survival (1-14). However, DAPK's physiological functions have not been fully clarified. Loss of DAPK expression has been implicated in tumorigenesis and metastasis (3,4,13), thereby suggesting a crucial role for DAPK in the apoptotic process under pathological conditions. On the other hand, inhibition of DAPK expression in HeLa cells, 3T3 fibroblasts and primary human vascular smooth muscle cells with an antisense DAPK was found to increase apoptosis (6,12).In a human cervical squamous cell carcinoma cell line ME180, DAPK protein expression is constitutively suppressed but can be strongly induced by treatment with a demethylation agent, 5-aza-2'-deoxycitidine (5-aza-CdR), and a histone deacetylation inhibitor, trichostatin (15). However, in ME180-derived cisplatin (CDDP)-resistant cell lines, DAPK protein expression can not be induced by treatment with 5-azaCdR and trichostatin. Although DAPK mRNA is expressed in the CDDP-resistant cells as in ME180 parent cells, DAPK mRNA translation is strongly suppressed in CDDP-resistant cells (15). These facts suggest that strong suppression of DAPK protein induction is involved in acquisition of CDDP resistance, and that DAPK protein regulates anticancer drug sensitivity and/or acquired anticancer drug resistance in cancer cells.We recently reported that targeted knockdown of DAPK protein expression in the HHUA cell line (16), a highly differentiated endometrial adenocarcinoma cell line, induced cell death by enh...

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Reduced expression of cell cycle regulator p18INK4C in human hepatocellular carcinoma

Cited by 46 publications

References 45 publications

Mechanism of gemcitabine-induced suppression of human cholangiocellular carcinoma cell growth

Mechanism of gemcitabine-induced suppression of human cholangiocellular carcinoma cell growth

RhoA Regulates G1-S Progression of Gastric Cancer Cells by Modulation of Multiple INK4 Family Tumor Suppressors

Suppressed protein expression of the death-associated protein kinase enhances 5-fluorouracil-sensitivity but not etoposide-sensitivity in human endometrial adenocarcinoma cells

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