Reduced Expression of Adherens Junctions Associated Protein 1 Predicts Recurrence of Hepatocellular Carcinoma After Curative Hepatectomy

Ezaka, Kazuhiro; Kanda, Mitsuro; Sugimoto, Hiroyuki; Shimizu, Dai; Oya, Hisaharu; Nomoto, Shuji; Sueoka, Satoshi; Tanaka, Yuri; Takami, Hideki; Hashimoto, R; Okamura, Yukiyasu; Yamada, Suguru; Fujii, Tsutomu; Nakayama, Goro; Koike, Masahiko; Fujiwara, Michitaka; Kodera, Yasuhiro

doi:10.1245/s10434-015-4695-9

Cited by 25 publications

(25 citation statements)

References 52 publications

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“…6 One study found that low AJAP1 mRNA levels in HCC tissues were associated with poor outcome after curative hepatectomy, particularly for disease-free survival (DFS). 14 In the present study, we showed that AJAP1 was highly expressed normal liver tissue, and was downregulated with HCC progression. In vitro experiments also indicated that AJAP1 expression was negatively correlated with metastasis.…”

Section: Discussionsupporting

confidence: 54%

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RETRACTED ARTICLE: Deregulated AJAP1/β-catenin/ZEB1 signaling promotes hepatocellular carcinoma carcinogenesis and metastasis

et al. 2017

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Adherens junctions-associated protein 1 (AJAP1) is an integral membrane protein that is thought to function as a tumor suppressor in various malignancies. Downregulation of AJAP1 mRNA levels may predict recurrence in hepatocellular carcinoma (HCC) patients, but the underlying molecular mechanism is unknown. This was addressed in the present study by examining the role of AJAP1 in HCC cell proliferation, migration, and invasion in vitro as well as in human specimens and mouse xenograft model. We found that AJAP1 expression was reduced in HCC cells and human HCC tissue, which was associated with metastasis. AJAP1 overexpression inhibited HCC progression and metastasis, while its silencing had the opposite effect both in vitro and in vivo. Furthermore, AJAP1 blocked epithelial–to–mesenchymal transition by interacting with β-catenin and inhibiting its nuclear translocation, which suppressed zinc finger E-box binding homeobox 1 (ZEB1) transcription. These results indicate that AJAP1 inhibits HCC metastasis, and is thus a potential therapeutic target for HCC treatment.

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Section: Discussionsupporting

confidence: 54%

“…It was recently reported that the AJAP1 promoter is highly methylated in HCC cell lines and tissues, suggesting that decreased levels of AJAP1 mRNA are linked to HCC recurrence. 14 …”

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confidence: 99%

RETRACTED ARTICLE: Deregulated AJAP1/β-catenin/ZEB1 signaling promotes hepatocellular carcinoma carcinogenesis and metastasis

et al. 2017

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“…HLE, HLF, HuH1 and HuH7 were obtained from the Japanese Collection of Research Bioresources Cell Bank (Osaka, Japan) (16). HuH2 cells were a gift from Aichi Cancer Center (Nagoya, Japan).…”

Section: Methodsmentioning

confidence: 99%

The protein arginine methyltransferase 5 promotes malignant phenotype of hepatocellular carcinoma cells and is associated with adverse patient outcomes after curative hepatectomy

Shimizu

Kanda

Sugimoto

et al. 2017

International Journal of Oncology

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The prognosis of advanced hepatocellular carcinoma (HCC) is dismal. Novel molecular targets for diagnosis and therapy is urgently required. This study evaluated expression and functions of the protein arginine methyltransferase 5 (PRMT5) in HCC. Using HCC cell lines, the expression levels of PRMT5 mRNA were determined using the quantitative real-time reverse-transcription polymerase chain reaction, and the effect of a small interfering PRMT5-siRNA on cell phenotype was evaluated. Further, PRMT5 expression was determined in 144 pairs of resected liver tissues to evaluate its clinical significance. Regardless of their differentiated phenotypes, nine HCC cell lines expressed different levels of PRMT5 mRNA. Inhibition of PRMT5 expression significantly decreased the proliferation, invasion, and migration of HCC cell lines. Although the level of PRMT5 mRNA was not influenced by patient's background liver status, it was significantly higher in HCC tissues than in the corresponding noncancerous tissues. High levels of PRMT5 mRNA in HCC tissues were significantly associated with advanced disease stage and adverse prognosis. In conclusion, our results indicate that PRMT5 may act as a putative oncogene in HCC and that the levels of PRMT5 mRNA represent a promising prognostic marker and a potential target of molecular therapy for HCC.

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“…According to these analyses, shrew-1 (also called AJAP1) is a tumor suppressor whose gene becomes hypermethylated and thus epigenetically silenced in the course of tumor development (Chen et al, 2014; Cogdell et al, 2011; Ezaka et al, 2015; Lai et al, 2014). In some cases described for glioblastoma, loss of function of shrew-1 occurs through deletions of the respective genomic region chr1p36 harboring its gene (Ernst et al, 2009; Lin et al, 2012; McDonald et al, 2006; Milde et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…The function of shrew-1 in epithelial tissues remains elusive, however, it is known from progressive promoter silencing or gene deletion in brain tumors that shrew-1 can act as a tumor suppressor protein (Cogdell et al, 2011; Ernst et al, 2009; McDonald et al, 2006; Milde et al, 2009). More recent evidence indicates that the SHREW-1/AJAP1 gene is also silenced in other tumor types such as gastric (Matsusaka et al, 2011), cervical (Chen et al, 2014) and endometrial cancer (Lai et al, 2014), or hepatocellular carcinoma (Ezaka et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Alternative exon usage creates novel transcript variants of tumor suppressor SHREW-1 gene with differential tissue expression profile

et al. 2016

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Shrew-1, also called AJAP1, is a transmembrane protein associated with E-cadherin-mediated adherence junctions and a putative tumor suppressor. Apart from its interaction with β-catenin and involvement in E-cadherin internalization, little structure or function information exists. Here we explored shrew-1 expression during postnatal differentiation of mammary gland as a model system. Immunohistological analyses with antibodies against either the extracellular or the cytoplasmic domains of shrew-1 consistently revealed the expression of full-length shrew-1 in myoepithelial cells, but only part of it in luminal cells. While shrew-1 localization remained unaltered in myoepithelial cells, nuclear localization occurred in luminal cells during lactation. Based on these observations, we identified two unknown shrew-1 transcript variants encoding N-terminally truncated proteins. The smallest shrew-1 protein lacks the extracellular domain and is most likely the only variant present in luminal cells. RNA analyses of human tissues confirmed that the novel transcript variants of shrew-1 exist in vivo and exhibit a differential tissue expression profile. We conclude that our findings are essential for the understanding and interpretation of future functional and interactome analyses of shrew-1 variants.

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Reduced Expression of Adherens Junctions Associated Protein 1 Predicts Recurrence of Hepatocellular Carcinoma After Curative Hepatectomy

Abstract: AJAP1 may function as a key regulatory molecule associated with the recurrence of HCC. Hypermethylation of the AJAP1 promoter is a key regulatory mechanism controlling AJAP1 expression.

Cited by 25 publications

References 52 publications

RETRACTED ARTICLE: Deregulated AJAP1/β-catenin/ZEB1 signaling promotes hepatocellular carcinoma carcinogenesis and metastasis

RETRACTED ARTICLE: Deregulated AJAP1/β-catenin/ZEB1 signaling promotes hepatocellular carcinoma carcinogenesis and metastasis

The protein arginine methyltransferase 5 promotes malignant phenotype of hepatocellular carcinoma cells and is associated with adverse patient outcomes after curative hepatectomy

Alternative exon usage creates novel transcript variants of tumor suppressor SHREW-1 gene with differential tissue expression profile

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