Gene Expression Signature of the Gross Morphology in Hepatocellular Carcinoma

Murakata, Ayano; Tanaka, Shinji; Mogushi, Kaoru; Yasen, Mahmut; Noguchi, Norio; Irie, Tetsumi; Kudo, Atsushi; Nakamura, Noriaki; Tanaka, Hiroshi; Arii, Shigeki

doi:10.1097/sla.0b013e3181f9bc00

Cited by 47 publications

(43 citation statements)

References 35 publications

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“…Of the upregulated molecules in 2 cases with high Z-scores, SPP1 and RGS5 were selected. Integrins are a family of transmembrane receptors and SPP1 is a ligand of integrin α V β 3 , which is a combination of integrin subunit α V and β 3 . RGS5 has been reported to be a marker of cancer-associated endothelial cells (15) and is an endothelial cell marker that is highly expressed in HCC (16).…”

Section: Resultsmentioning

confidence: 99%

“…Portal vein invasion (PVI) is a major prognostic factor and is associated with intrahepatic metastasis and recurrence following curative resection. Des-γ-carboxyprothrombin (DCP) levels and/or macroscopic findings, including simple nodular type tumors with extranodular growth and confluent multinodular type tumors, have been reported to be associated with PVI (1)(2)(3)(4). Several molecules, including ubiquitin-conjugating enzyme E2C (5), importin-α1 (6), lysosomal-associated transmembrane protein 4β-35 (7), protein tyrosine phosphatase type IVA3 (8) and caveolin-1 (9), are reported to be associated with PVI.…”

Section: Introductionmentioning

confidence: 99%

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Regulator of G‑protein signaling 5 enhances portal vein invasion in hepatocellular carcinoma

et al. 2017

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Abstract. Portal vein invasion (PVI) is a major prognostic factor in hepatocellular carcinoma (HCC). The aim of the present study was to identify molecules that regulate PVI. Sections of cancerous tissue, paired noncancerous tissue and the PVI area were collected from 3 frozen HCC sections, using laser microdissection. The present study focused on 3 upregulated molecules, integrin β3 (ITGB3), secreted phosphoprotein 1 (SPP1) and regulator of G-protein signaling 5 (RGS5), and 2 molecules that were downregulated in PVI tissue compared with cancer tissue, metallothionein 1G (MT1G) and metallothionein 1H (MT1H), as determined by cDNA microarray analysis. Reverse transcription-quantitative polymerase chain reaction analysis of 32 HCC cases revealed that RGS5 mRNA levels were significantly increased and MT1 G and MT1H mRNA levels were significantly decreased in cancerous tissue compared with noncancerous tissue. However, there was no significant difference in ITGB3 and SPP1 expression. There were no significant differences between the expression of these molecules and any clinicopathologic factors, including PVI. Immunohistochemical staining for RGS5 in 60 HCC cases demonstrated that RGS5 protein levels were higher in cancerous tissue compared with paired noncancerous tissue in 63.3% of HCC cases. Furthermore, high expression of RGS5 in cancerous tissue was significantly associated with PVI and tended to be associated with intrahepatic metastasis. Confluent multinodular type was significantly more frequent in cases with high expression of RGS5 in the cancerous tissue.Therefore, RGS5 may be a useful prognostic biomarker as well as a potential target of molecular therapy to treat HCC.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulator of G‑protein signaling 5 enhances portal vein invasion in hepatocellular carcinoma

et al. 2017

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“…In particular, EpCAM might play a critical role in the aggressiveness of the confluent multinodular type of HCC. (35) The possibility that aberrant VIL1 expression may be related to the recurrence of HCC and to accelerated hepatocarcinogenesis may be mediated via epithelial-to-mesenchymal malignant transitions, the positive regulation of hepato-epithelial cell migration, and the epidermal growth factor receptor signaling pathway. Further study is required to verify these possibilities.…”

Section: Discussionmentioning

confidence: 99%

Villin 1 is a predictive factor for the recurrence of high serum alpha‐fetoprotein‐associated hepatocellular carcinoma after hepatectomy

et al. 2012

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The prognostic assessment of patients with hepatocellular carcinoma (HCC) after resection is an important clinical issue. The present study investigated those genes associated with high serum alpha-fetoprotein (AFP), and their clinical significance, including prognosis and recurrence after hepatectomy. Based on gene expression analysis of 110 training HCC cases, 20 genes whose mRNA expression levels were significantly upregulated and 50 genes that were downregulated correlated with high serum AFP-associated HCC patients. Gene expression profiles of Villin1 (Vil1) were obtained in high serum AFP-associated HCC tumor tissues. In the present analysis, only VIL1 was significantly correlated with the recurrence of HCC. The results were validated independently using Taqman gene expression assays and immunostaining analysis. Results showed that the upregulation of VIL1 mRNA was also correlated with high serum PIVKAII, vascular invasion (P < 0.05), poor differentiation, an advanced cancer stage (P < 0.01) and recurrence-free survival (P = 0.017). The upregulation of VIL1 mRNA was observed more frequently in the early recurrence patients as compared to the late recurrence patients. Cox regression univariate and multivariate analyses indicated that high serum AFP levels (overall survival, HR 1.675, P = 0.002; FRS, HR 1.359, P = 0.039) and Vil1 protein expression (overall survival, HR 0.253, P = 0.009; FRS, HR 0.401, P = 0.041) were independent, unfavorable prognostic factors for overall and recurrence-free survival of patients. We demonstrated that the VIL1 gene is a potential candidate molecular marker for high serum AFP-associated HCC and a predictive candidate for the postoperative recurrence and poorer prognosis of HCC. (Cancer Sci 2012; 103: 1493-1501 H epatocellular carcinoma (HCC) is the sixth most common cancer in the world, and the 5-year survival rate of individuals with HCC is lower than 10%.(1,2) The prognosis of HCC patients remains dismal, and novel diagnostic modalities as well as improvements in therapeutic strategies currently in use are crucial to improve the clinical outcome for HCC patients. Surgical resection is not the only curative treatment for HCC. Liver transplant is another option for selected patients; however, the rapid recurrence of these tumors is observed frequently, even after apparently curative resections. (3,4) In ten years, various molecules have been proposed as predictive markers for the recurrence of HCC, but none have proved useful clinically, because different patterns of recurrence have not been considered. (5,6) In Tanaka et al.,we report that aberrant Aurora B expression in primary HCC might be a predictive factor of HCC recurrence exceeding the Milan criteria after a curative hepatectomy.The risk factors of recurrence after a curative resection for macroscopic vascular invasion negative hepatocellular carcinoma are closely related to serum alpha-fetoprotein (AFP) levels, multiple tumor formation and non-anatomic hepatic resection. Network expression analysis revealed that dist...

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“…Frequent mutations of beta-catenin at the GSK3 recognition site, as well as truncated mutations of Axin, have been observed in HCC [40,41]. The accumulated beta-catenin is translocated to the nucleus, where it binds to Tcf transcription factor and thereby stimulates the expression of various genes, including the EMT regulator WISP [42] and the stemness marker EpCAM [43]. Currently, some smallmolecule compounds (XAV939 and pyrvinium) are under intense study for the development of agents targeting the Wnt/beta-catenin pathway [44,45].…”

Section: Cancer Stemness As the Next Potential Targetmentioning

confidence: 99%

Molecular targeted therapy for hepatocellular carcinoma in the current and potential next strategies

Tanaka

Arii

2011

J Gastroenterol

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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and its incidence is still increasing. While the primary curative treatment for HCC is surgical resection, a major obstacle for the treatment of HCC is the high frequency of tumor recurrence even after curative resection. Effective palliative treatment is hindered by the evidence that HCC is frequently resistant to conventional chemotherapy and radiotherapy. Targeted therapy which specifically inhibits molecular abnormalities has emerged as a novel approach for the innovative and effective medical treatment of malignancies. In order to fulfill this promise there is an urgent need to identify the optimal targets for the treatment of HCC. A multi-kinase angiogenesis inhibitor, sorafenib, has been revealed as the first agent to show favorable overall survival in patients with advanced HCC. A new era of HCC treatment has arrived, but there has been limited improvement in survival benefits with the status quo. This review summarizes molecular targeted therapy for HCC, with a focus on angiogenesis, growth signaling, and mitosis, as well as a promising concept, "cancer stemness" for the current and potential next strategies of HCC treatment.

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Gene Expression Signature of the Gross Morphology in Hepatocellular Carcinoma

Abstract: Our studies suggest that the distinct signature of gene expression is closely related to morphological progression in HCC. Especially, EpCAM might play a critical role in the aggressiveness of CM-type HCC.

Cited by 47 publications

References 35 publications

Regulator of G‑protein signaling 5 enhances portal vein invasion in hepatocellular carcinoma

Regulator of G‑protein signaling 5 enhances portal vein invasion in hepatocellular carcinoma

Villin 1 is a predictive factor for the recurrence of high serum alpha‐fetoprotein‐associated hepatocellular carcinoma after hepatectomy

Molecular targeted therapy for hepatocellular carcinoma in the current and potential next strategies

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