Epigenetic Inactivation of <i>Betaig-h3</i> Gene in Human Cancer Cells

Shao, Genze; Berenguer, J. Gallego; Borczuk, Alain C.; Powell, Charles A.; Hei, Tom K.; Zhao, Yongliang

doi:10.1158/0008-5472.can-05-2130

Cited by 44 publications

(39 citation statements)

References 29 publications

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“…Moreover, analysis by MSP showed clear ITIH5-promoter methylation in 41% of breast tumours, matching very well with a complete loss of the ITIH5-protein in 42% of breast tumours as analysed by immunohistochemistry. Since ITIHs represent the matrix-adhesive component of ITIs, these findings support the fundamental role of loss of adhesion molecules in tumorigenesis, like it has also been shown for hypermethylation of the E-cadherin gene (Graff et al, 1995), the tissue inhibitor of metalloproteinase 3 (Bachman et al, 1999) or the betaig-h3 gene (Shao et al, 2006).…”

Section: Discussionsupporting

confidence: 61%

“…They fall into several broad categories of fundamental cellular networks, such as cell cycle control or steroid receptor regulation (for a review, see Yang et al, 2001), thus representing critical genes exerting a tumour suppressive function. Few studies demonstrated that cell adhesion molecules and proteins involved in cell-matrix interactions are also target of epigenetic downregulation in breast cancer (Graff et al, 1995;Bachman et al, 1999;Shao et al, 2006). Decrease in cell adhesion and increase of proteolytic activity of extracellular matrix components are thought to contribute largely to a tumour's invasive phenotype.…”

Section: Discussionmentioning

confidence: 99%

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The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

et al. 2007

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Inter-a-trypsin inhibitors (ITIs) are protease inhibitors stabilizing the extracellular matrix. ITIs consist of one light (bikunin) and two heavy chains (ITIHs). We have recently characterized ITIH5, a novel member of the ITIH gene family, and showed that its messenger RNA is lost in a high proportion of breast tumours. In the present study, an ITIH5-specific polyclonal antibody was generated, validated with western blot and used for immunohistochemical analysis on a tissue microarray; ITIH5 was strongly expressed in epithelial cells of normal breast (n ¼ 11/15), while it was lost or strongly reduced in 42% (92/217) of invasive breast cancers. ITIH5 expression in invasive carcinomas was associated with positive expression of oestrogen receptor (P ¼ 0.008) and histological grade (P ¼ 0.024). Correlation of ITIH5 expression with clinical outcome revealed that patients with primary tumours retaining abundant ITIH5 expression had longer recurrence-free survival (RFS; P ¼ 0.037) and overall survival (OS; P ¼ 0.044), compared to those with reduced expression (mean RFS: 102 vs 78 months; mean OS: 120 vs 105 months). Methylation-specific PCR analysis frequently showed strong methylation of the ITIH5 promoter in primary breast tumours (41%, n ¼ 109) and breast cancer cell lines (n ¼ 6). Methylation was significantly associated with mRNA loss (Po0.001; n ¼ 39), and ITIH5 expression was induced after treatment of tumour cell lines with the demethylating agent 5-aza-2 0 -deoxycytidine. Moreover, ITIH5 promoter methylation was significantly associated with reduced OS (P ¼ 0.008). The cellular function of ITIH5 was evaluated by forced expression of a full-length ITIH5 complementary DNA in the breast cancer cell line MDA-MB-231, which does not endogenously express ITIH5. ITIH5-expressing clones showed a 40% reduced proliferation rate compared to mock-transfected cells. Overall, these data show that promoter methylation-mediated loss of ITIH5 expression is associated with unfavourable outcome in breast cancer patients, and thus ITIH5 could be used as a prognostic marker, although this marker is not multivariate independent due to its close association with ER expression. Our data indicate that ITIH5 is a candidate class II tumour suppressor gene and could be involved in tumour progression, invasion and metastasis, as its absence is associated with increased proliferation rates and a prognostic value indicating poor clinical outcome.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

et al. 2007

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“…To unravel the underlying molecular mechanism for this phenomenon, DNA methylation patterns of the BigH3 CpG island were examined in normal, immortalized, and cancer cell lines derived from lung, prostate, mammary, and kidney tumors. A good correlation was observed between promoter hypermethylation and lost expression of the BigH3 gene, which was supported by data that indicated demethylation of the promoter by 5-aza-2'-deoxycytidine reactivated BigH3 and restored its expression in BigH3-silenced tumor cell lines (54).…”

Section: Discussionsupporting

confidence: 59%

“…Such data strongly suggest that downregulation of BigH3 expression resulted from the defect in the TGF-ß1 signalling pathway and played a pivotal role in the tumorigenic process induced by 56 Fe heavy-ion radiation (53). Other studies (53,54) have indicated that the expression of the BigH3 gene was downregulated or lost in a variety of tumor cell lines derived from lung, prostate, mammary, and kidney tumors. The results showed that the BigH3 gene was expressed at a relatively high level in normal and immortalized cell lines, whereas it was downregulated in most of the tumor cell lines.…”

Section: Discussionmentioning

confidence: 94%

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BigH3 protein expression as a marker for breast cancer

Calaf

Echiburú-Chau²,

Zhao³

et al. 2008

Int J Mol Med

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Abstract. The current hypothesis of tumorigenesis in humans suggests that cancer cells acquire their hallmarks of malignancy through the accumulation of advantageous gene activation and inactivation events over long periods of time. For breast cancer development, this multistep process may manifest itself as a sequence of pathologically defined stages. It is widely held that breast cancer originates at the premalignant stage of atypical ductal hyperplasia, progresses to the preinvasive stage of ductal carcinoma in situ, and culminates in the potentially lethal stage of invasive ductal carcinoma. Tumor grade has been a highly valuable prognostic factor for breast cancer, and high-grade ductal carcinoma in situ lesions are associated with poor clinical outcome. The aim of this work was to investigate the BigH3 protein expression changes associated with various stages of breast cancer progression in comparison to benign specimens using tissue microarray technology. Pathological characteristics of breast tissues ranged from benign lesions to breast cancers either of lobular or ductal carcinomas in origin, and included in situ ductal carcinomas, lobular carcinomas, infiltrating ductal carcinomas, carcinomas, scirrhous carcinomas, adenocarcinomas and infiltrating colloid carcinomas. BigH3 protein expression was analyzed by immunohistochemistry in 192 cases of breast tumors. Results indicated a decrease in BigH3 protein expression from benign tissues to in situ ductal carcinoma, lobular carcinoma, infiltrating ductal carcinomas, carcinomas, scirrhous carcinoma, adenocarcinomas to infiltrating colloid carcinomas. We observed that the benign tissue had a 23-fold increase in BigH3 protein expression compared to the infiltrating colloid carcinoma which was the most malignant tissue analyzed. In summary, these studies confirmed the suppressor effect of the BigH3 gene expressed as protein expression in those processes related to the progression of breast tumorigenesis. We conclude that this protein can be used as a marker for breast cancer progression.

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The aberrant methylation of TSP1 suppresses TGF‐β1 activation in colorectal cancer

Rojas¹,

Meherem²,

Kim³

et al. 2008

Intl Journal of Cancer

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Colorectal cancer arises from the progressive accumulation of mutations and epigenetic alterations in colon epithelial cells. Such alterations often deregulate signaling pathways that affect the formation of colon cancer, such as the Wnt, RAS-MAPK and TGF-b pathways. The tumor promoting effects of mutations in genes, such as APC, have been demonstrated in cancer cell lines and in mouse models of intestinal cancer; however, the biological effects of most epigenetic events identified in colorectal cancer remain unknown. Consequently, we assessed whether the aberrant methylation of TSP1, the gene for thrombospondin 1, a regulator of TGF-b ligand activation, is an epigenetic mechanism for inhibiting the TGF-b signaling pathway. We found methylated TSP1 occurs in colon cancer cell lines (33%), colon adenomas (14%) and colon adenocarcinomas (21%). In primary colorectal cancers, loss of TSP1 expression correlated with impaired TGF-b signaling as indicated by decreased Smad2 phosphorylation and nuclear localization. Furthermore, methylation-induced silencing of TSP1 expression reduced the concentration of secreted active TGF-b1 and attenuated TGF-b signaling. Reversal of TSP1 methylation resulted in increased TSP1 mediated activation of the latent LAP:TGF-b complex and subsequent TGF-b receptor activation. Our results demonstrate that the aberrant methylation of TSP1 has biological consequences and provide evidence that the aberrant methylation of TSP1 is a novel epigenetic mechanism for suppressing TGF-b signaling in colorectal cancer. ' 2008 Wiley-Liss, Inc.Key words: thrombospondin; transforming growth factor b; methylation; colorectal cancer; epigenetics Colorectal cancer is the third most common cancer in the United States. In 2008, 154,000 new cases of colorectal cancer will be diagnosed and more than 52,000 people are predicted to die from the disease. 1 Colon cancer arises from the accumulation of DNA alterations in colon epithelial cells, which mediate the initiation and progression of this cancer. Mutations in genes such as KRAS, TP53 and members of the transforming growth factor (TGF-b) signaling pathway play a pathogenic role in the polypcarcinoma sequence. [2][3][4] TGF-b is a pluripotent cytokine that has a multitude of effects on epithelial cells including the inhibition of proliferation, the induction of apoptosis and the stimulation of differentiation. Inactivating mutations in central members of the TGF-b signaling pathway, TGFBR2 and SMAD4, have been identified in approximately half of colon cancers. [5][6][7][8] The biological effects of TGF-b in the colon and the identification of inactivating mutations in TGFBR2 and SMAD4 in colon cancers have demonstrated that the TGF-b signaling pathway can act as a colon cancer tumor suppressor pathway.The TGF-b signaling pathway consists of the TGF-b ligand; the heteromeric TGF-b receptor composed of the type I and type II TGF-b receptors (TGFBR1 and TGFBR2); and the post-receptor signaling proteins, including SMAD2, 3, and 4. TGF-b1 is the most commonly expre...

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Epigenetic Inactivation of Betaig-h3 Gene in Human Cancer Cells

Cited by 44 publications

References 29 publications

The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

BigH3 protein expression as a marker for breast cancer

The aberrant methylation of TSP1 suppresses TGF‐β1 activation in colorectal cancer

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