Wilms’ tumour 1 gene expression is increased in hepatocellular carcinoma and associated with poor prognosis

Sera, Toshiki; Hiasa, Yoichi; Mashiba, Toshie; Terada, Yoshio; Hirooka, Masashi; Konishi, Ichiro; Matsuura, Bunzo; Michitaka, Kojiro; Udaka, Keiko; Onji, Morikazu

doi:10.1016/j.ejca.2008.01.008

Cited by 44 publications

(38 citation statements)

References 26 publications

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“…To this end, we examined three HCC samples with high and three HCC samples with low WT1 mRNA levels. In agreement with a recent report (10) describing a close correlation between WT1 mRNA and protein expression in liver tumors, we found that those HCC samples with higher WT1 mRNA levels also showed enhanced WT1 immunostaining. These observations, together with our previous findings in chronic hepatitis and cirrhosis (9), indicate that WT1 expression in the liver is associated with chronic tissue injury and neoplastic transformation, situations in which liver parenchymal cells display enhanced proliferation.…”

Section: Resultssupporting

confidence: 82%

“…In this work, we show that WT1 is also expressed in tumor tissue in a high proportion of patients with hepatocellular carcinoma (HCC), a finding that is in agreement with a very recent report from Japan showing positive immunohistochemical staining in 95% of HCC specimens (10). Although in this report, the authors observed a correlation between WT1 expression and patient survival, there are no data showing the implication of WT1 in HCC biology.…”

Section: Introductionsupporting

confidence: 73%

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Wilms' Tumor 1 Gene Expression in Hepatocellular Carcinoma Promotes Cell Dedifferentiation and Resistance to Chemotherapy

et al. 2009

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The Wilms' tumor 1 gene (WT1) encodes a transcription factor involved in cell growth and development. As we previously reported, WT1 expression is hardly detectable in normal hepatic tissue but is induced in liver cirrhosis. Although WT1 has been found to be overexpressed in a number of malignancies, the role of WT1 in hepatocarcinogenesis has not been clarified. We found that WT1 is expressed in several human hepatocellular carcinoma (HCC) cell lines, including PLC/PRF/5 and HepG2, and in HCC tumor tissue in 42% of patients. WT1 small interfering RNAs did not affect proliferation rate of HCC cells but abrogated their resistance to anoikis. Transcriptome analysis of PLC/PRF/5 cells after WT1 knockdown showed up-regulation of 251 genes and downregulation of 321. Ninety percent of the former corresponded to metabolic genes, mostly those characterizing the mature hepatocyte phenotype. On the contrary, genes that decreased upon WT1 inhibition were mainly related to defense against apoptosis, cell cycle, and tumor progression. In agreement with these findings, WT1 expression increased the resistance of liver tumor cells to doxorubicin, a compound used to treat HCC. Interestingly, doxorubicin strongly enhanced WT1 expression in both HCC cells and normal human hepatocytes. Among different chemotherapeutics, induction of WT1 transcription was restricted to topoisomerase 2 inhibitors. When WT1 expression was prohibited, doxorubicin caused a marked increase in caspase-3 activation. In conclusion, WT1 is expressed in a substantial proportion of HCC contributing to tumor progression and resistance to chemotherapy, suggesting that WT1 may be an important target for HCC treatment.

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Section: Resultssupporting

confidence: 82%

Section: Introductionsupporting

confidence: 73%

Wilms' Tumor 1 Gene Expression in Hepatocellular Carcinoma Promotes Cell Dedifferentiation and Resistance to Chemotherapy

et al. 2009

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“…There is little controversy regarding the observation that solid cancers of non-mesodermal origin rarely show nuclear immunostaining but frequently exhibit cytoplasmic immunostaining, while mesodermal tissues provide the nuclear immunostaining (8)(9)(10)(11)(12)(13)(14)(15)(16)(18)(19)(20)(21)(22)(23)(24)28). Differences of the conclusions about WT1 expression in non-mesodermal solid cancers stem largely from a discrepancy in interpretations of the cytoplasmic immunostaining.…”

Section: Discussionmentioning

confidence: 99%

“…WT1 was prioritized as a promising target of immunotherapy against various malignancies (17) because dozens of studies have confirmed WT1 overexpression not only in mesodermally derived malignancies but also in a variety of non-mesodermal origin solid cancers such as esophageal (45-95%) (18,19), gastric (42%) (19), colon (69-89%) (19,20), hepatocellular (95%) (21), bile duct (68%) (19), pancreatic (65-75%) (19,22), thyroid (95%) (23), prostate (25%) (9), lung (30-83%) (19,24), breast (26-87%) (19,(25)(26)(27), Tissue samples. Cancer tissues and corresponding normal epithelial tissues were obtained from 552 patients with esophageal (101 patients), bile duct (96 patients), pancreatic (99 patients), and lung cancer (256 patients) who underwent resection in the Department of Gastroenterological surgery II, hokkaido University, Japan between 1994 and 2005.…”

Section: Introductionmentioning

confidence: 99%

Differential detection of cytoplasmic Wilms tumor 1 expression by immunohistochemistry, western blotting and mRNA quantification

Maki

Ikeda

Kuroda

et al. 2016

International Journal of Oncology

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Abstract. Wilms tumor 1 (WT1) is considered to be a promising target of cancer treatment because it has been reported to be frequently expressed at high levels in various malignancies. Although WT1-targeted cancer treatment has been initiated, conclusive detection methods for WT1 are not established. The present study aimed to consolidate immunohistochemistry for WT1 with statistical basis. Transfected cells with forced WT1 expression yielded specific western blot bands and nuclear immunostaining; cytoplasmic immunostaining was not specifically recognized. Immunohistochemistry, western blotting, and quantitative reverse transcriptase-polymerase chain reaction were performed in 35 human cell lines using multiple WT1 antibodies and their results were quantified. Relationships among the quantified results were statistically analyzed; the nuclear immunostaining positively correlated with western blot bands and mRNA expression levels, whereas cytoplasmic immunostaining did not. These results indicate that nuclear immunostaining reflects WT1 expression but cytoplasmic immunostaining does not. The nuclear immunostaining was barely (3/541) observed in primary cancer of esophagus, bile duct, pancreas and lung. Although the present study has some limitations, the results indicate that the cytoplasmic immunostaining does not correlate with actual WT1 expression and prompts researchers to carefully evaluate target molecule expression in treatment of cancer.

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“…Several works investigated antigen specific immunotherapy against potential tumor-associated antigens (TAAs) in HCC, including alpha-fetoprotein (AFP) (10)(11), carcinoembryonic antigen (CEA) (12), glypican-3 (GPC3) (13), Wilm's tumor 1 gene (WTl) (14), cancer testis antigen NY-ESO-l (15) and melanoma-associated antigens (MAGE) (16). In particular, AFP is an oncofetal protein whose expression level is increased in many primary liver tumors; as a result, elevated serum levels of AFP may serve as a liver tumor marker (11).…”

mentioning

confidence: 99%

Strategies for Successful Vaccination against Hepatocellular Carcinoma

Rinaldi

Iurescia

Fioretti

et al. 2009

Int J Immunopathol Pharmacol

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Current therapies against hepatocellular carcinoma (HCC) are not curative in the majority of patients. In the past, immunotherapy approaches aimed to non-specifically stimulate immune response were quite ineffective. New treatments based on stimulation of specific anti-tumor immune response are currently proposed and appear more promising. Tumor-specific antigens identified in HCC demonstrated immunogenicity both in preclinical and clinical trials. Effectiveness in animal studies raised interest in the clinical applicability of non-specific adoptive immunotherapy that prevented disease recurrence after tumor resection. Dendritic cell (DC)-based tumor vaccines achieved encouraging results, and cellular vaccines based on DCs have already entered clinical trials. Preventive and therapeutic DNA vaccination have been proposed, all based on tumor-associated antigens (TAAs), either modified or not, an example being alpha-fetoprotein (AFP). The concomitant expression of co-stimulatory molecules and cytokines was used to increase tumor immunogenicity. Syngeneic or nude mice models indicated that immunotherapy for HCC could stimulate an anti-tumor T-cell response leading to clinical benefit devoid of significant toxicity. The use of DNA-based vaccination raises exciting possibilities in preventing HCC in high-risk individuals such as those with cirrhosis. Novel immunotherapy strategies may contribute in the future to prevention and treatment of HCC.

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Wilms’ tumour 1 gene expression is increased in hepatocellular carcinoma and associated with poor prognosis

Cited by 44 publications

References 26 publications

Wilms' Tumor 1 Gene Expression in Hepatocellular Carcinoma Promotes Cell Dedifferentiation and Resistance to Chemotherapy

Wilms' Tumor 1 Gene Expression in Hepatocellular Carcinoma Promotes Cell Dedifferentiation and Resistance to Chemotherapy

Differential detection of cytoplasmic Wilms tumor 1 expression by immunohistochemistry, western blotting and mRNA quantification

Strategies for Successful Vaccination against Hepatocellular Carcinoma

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