Downregulation of Betaig-h3 gene is causally linked to tumorigenic phenotype in asbestos treated immortalized human bronchial epithelial cells

Zhao, Yong; Piao, Chang Q.; Hei, Tom K.

doi:10.1038/sj.onc.1205891

Cited by 57 publications

(74 citation statements)

References 41 publications

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“…Such results strongly suggested that loss of BigH3 expression is a frequent event in human cancer and causally related to acquisition of the tumorigenic phenotype in asbestos-treated BEP2D cells (52). Furthermore, ectopic expression of the BigH3 gene in asbestos-induced tumorigenic cells inhibited cell growth in vitro, the anchorage-independent phenotype, as well as tumorigenicity in nude mice.…”

Section: Discussionmentioning

confidence: 74%

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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Section: Discussionmentioning

confidence: 74%

BigH3 protein expression as a marker for breast cancer

Calaf

Echiburú-Chau²,

Zhao³

et al. 2008

Int J Mol Med

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“…In addition, a novel class of TSGs has been identified where epigenetic inactivation plays the predominant role, whereas somatic mutations are a relatively rare event (16,17). We have shown previously that Betaig-h3 gene is ubiquitously expressed in normal human tissues, whereas its expression was either down-regulated or lost in a variety of human tumor cell lines (11)(12)(13). Downregulation of this gene has been shown to correlate with the tumorigenic phenotype in human bronchial epithelial cells, suggesting an antitumor function of this gene (12,13).…”

Section: Introductionmentioning

confidence: 99%

“…This gene product is composed of 683 amino acids containing four homologous internal repeat domains (Fas-1) and has been reported to function as an extracellular matrix protein to mediate cell adhesion and migration through interacting with integrin (a 3 h 1 , a v h 3 , and a v h 5 ), collagen (I, IV, and VI), laminin, and fibronectin (8,9). In addition, Betaig-h3 is involved in cell growth, cell differentiation, wound healing, apoptosis, and tumorigenesis (10)(11)(12)(13). Betaig-h3 gene mutations were identified in families affected with human autosomal dominant corneal dystrophies (14).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Inactivation of Betaig-h3 Gene in Human Cancer Cells

Shao¹,

Berenguer²,

Borczuk

et al. 2006

Cancer Research

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Gene silencing by CpG island methylation in the promoter region is one of the mechanisms by which tumor suppressor genes are inactivated in human cancers. It has been shown previously that Betaig-h3 gene, which encodes an extracellular matrix protein involved in cell adhesion and tumorigenesis, is down-regulated or silenced in a variety of human cancer cell lines. To unravel the underlying molecular mechanism(s) for this phenomenon, DNA methylation patterns of Betaig-h3 CpG island were examined in normal, immortalized, and cancer cell lines derived from lung, prostate, mammary, and kidney. A good correlation was observed between promoter hypermethylation and lost expression of Betaig-h3 gene, which was supported by the data that demethylation of promoter by 5-aza-2V -deoxycytidine reactivated Betaig-h3 and restored its expression in Betaig-h3-silenced tumor cell lines. This result was further substantiated by a luciferase reporter assay, showing the restoration of promoter activities and increased response to transforming growth factor-B treatment in Betaig-h3-negative 293T cells when transfected with unmethylated Betaig-h3 promoter. In contrast, activity of Betaig-h3 promoter was completely inactivated by in vitro methylation. Furthermore, CpG methylation of Betaig-h3 promoter was also shown in primary lung tumors that expressed decreased level of Betaig-h3 protein. These results suggest that promoter methylation plays a critical role in promoter silencing of the Betaig-h3 gene in human tumor cells.

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“…TGFBI mediates integrin binding to extracellular matrix proteins such as collagen, laminin and fibronectin (14). Loss of TGFBI expression has been reported in several types of cancers including lung cancer (15), and it has been suggested to act as a tumor-suppressor gene (16). Additionally, overexpression of TGFBI in lung cancer cells increased the sensitivity to gemcitabine (17), and overexpression of TGFBI has also been reported to be associated with a better response to gemcitabine chemotherapy in lung cancer cells and patients.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of Cul4A increases chemosensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells

Hung

Chen

et al. 2015

Oncology Reports

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Abstract. Cullin 4A (Cul4A) promotes oncogenesis through overexpression and then ubiquitination-mediated proteolysis of tumor suppressors in various types of cancers. Transforming growth factor β-induced (TGFBI) has been implicated as a tumor suppressor, which enhances gemcitabine chemosensitivity in lung cancer cells. The present study aimed to investigate the association of TGFBI and Cul4A and the mechanism by which Cul4A regulates TGFBI. In addition, we also evaluated the therapeutic value of Cul4A RNAi using adenoviral transfection of Cul4A RNAi in nude mouse xenograft models. We observed that knockdown of Cul4A was associated with increased sensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells. Cul4A regulated TGFBI through direct interaction and then ubiquitin-mediated protein degradation. In the nude mouse xenograft models, adenoviral transfection of Cul4A RNAi in combination with gemcitabine chemotherapy inhibited lung cancer tumor growth. As the result, combination of Cul4A RNAi with chemotherapy may provide a new approach to lung cancer treatment.

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Downregulation of Betaig-h3 gene is causally linked to tumorigenic phenotype in asbestos treated immortalized human bronchial epithelial cells

Cited by 57 publications

References 41 publications

BigH3 protein expression as a marker for breast cancer

BigH3 protein expression as a marker for breast cancer

Epigenetic Inactivation of Betaig-h3 Gene in Human Cancer Cells

Knockdown of Cul4A increases chemosensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells

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