<i>RBSP3 (HYA22)</i>
            is a tumor suppressor gene implicated in major epithelial malignancies

Kashuba, Vladimir I.; Li, Jing‐Feng; Wang, Fuli; Senchenko, V. N.; Protopopov, Alexey; Malyukova, Alena; Kutsenko, Alexey S.; Kadyrova, E. L.; Zabarovska, Veronika I.; Muravenko, Olga V.; Zelenin, A. V.; Kisselev, Lev L.; Kuzmin, Igor; Minna, John D.; Winberg, Gösta; Ernberg, Ingemar; Брага, Э. А.; Lerman, Michael I.; Klein, George; Zabarovsky, Eugene R.

doi:10.1073/pnas.0401238101

Cited by 83 publications

(115 citation statements)

References 23 publications

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“…The whole short arm of chromosome 3 was consistently lost, as described previously (Zabarovsky et al 2002;Protopopov et al 2003;Kashuba et al 2004), with a peak recurrence at around 50 Mb, corresponding to 3p21.1 (29 of 79 samples, 36%). Segmentation did not identify obvious homozygous deletions that would point to a specific target in this recurrently deleted region of 3p; however, this region contains RASSF1, TUSC2, SEMA3B, HYAL2, and FHIT, genes that have shown LOH in NSCLC (Figs.…”

Section: Identification Of Known and Novel Cnas In The Nsclc Genomesupporting

confidence: 76%

Common and Contrasting Genomic Profiles among the Major Human Lung Cancer Subtypes

Tonon

Brennan

Protopopov

et al. 2005

Cold Spring Harbor Symposia on Quantitative Biology

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Lung cancer is the leading cause of cancer mortality worldwide. With the recent success of molecularly targeted therapies in this disease, a detailed knowledge of the spectrum of genetic lesions in lung cancer represents a critical step in the development of additional effective agents. An integrated high-resolution survey of regional amplifications and deletions and gene expression profiling of non-small-cell lung cancers (NSCLC) identified 93 focal high-confidence copy number alterations (CNAs), with 21 spanning less than 0.5 Mb with a median of five genes. Most CNAs were novel and included high-amplitude amplification and homozygous deletion events. Pathogenic relevance of these genomic alterations was further reinforced by their recurrence and overlap with focal alterations of other tumor types. Additionally, the comparison of the genomic profiles of the two major subtypes of NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SCC), showed an almost complete overlap with the exception of one amplified region on chromosome 3, specific for SCC. Among the few genes overexpressed within this amplicon was p63, a known regulator of squamous cell differentiation. These findings suggest that the AC and SCC subtypes may arise from a common cell of origin and they are driven to their distinct phenotypic end points by altered expression of a limited number of key genes such as p63.

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Section: Identification Of Known and Novel Cnas In The Nsclc Genomesupporting

confidence: 76%

Common and Contrasting Genomic Profiles among the Major Human Lung Cancer Subtypes

Tonon

Brennan

Protopopov

et al. 2005

Cold Spring Harbor Symposia on Quantitative Biology

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“…Identification of TSGs in the gene-rich 3p22 -21.3 region has been challenging, although several candidate TSGs within this region showed tumour suppressor functions, such as RASSF1A (Pfeifer et al, 2002), SEMA3B (Tomizawa et al, 2001), BLU/ZMYND10 (Qiu et al, 2004), FUS1 (Zabarovsky et al, 2002) and HYA22 (RBSP3) (Kashuba et al, 2004), with some of them (RASSF1A and BLU) frequently inactivated by promoter methylation-mediated silencing. DLEC1, also located at this region, contains 37 exons, spans B59 kb and encodes a 1755-amino-acid protein.…”

Section: Discussionmentioning

confidence: 99%

DLEC1 is a functional 3p22.3 tumour suppressor silenced by promoter CpG methylation in colon and gastric cancers

Ying

Poon

et al. 2009

Br J Cancer

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Promoter CpG methylation of tumour suppressor genes (TSGs) is an epigenetic biomarker for TSG identification and molecular diagnosis. We screened genome wide for novel methylated genes through methylation subtraction of a genetic demethylation model of colon cancer (double knockout of DNMT1 and DNMT3B in HCT116) and identified DLEC1 (Deleted in lung and oesophageal cancer 1), a major 3p22.3 TSG, as one of the methylated targets. We further found that DLEC1 was downregulated or silenced in most colorectal and gastric cell lines due to promoter methylation, whereas broadly expressed in normal tissues including colon and stomach, and unmethylated in expressing cell lines and immortalised normal colon epithelial cells. DLEC1 expression was reactivated through pharmacologic or genetic demethylation, indicating a DNMT1/DNMT3B-mediated methylation silencing. Aberrant methylation was further detected in primary colorectal (10 out of 34, 29%) and gastric tumours (30 out of 89, 34%), but seldom in paired normal colon (0 out of 17) and gastric (1 out of 20, 5%) samples. No correlation between DLEC1 methylation and clinical parameters of gastric cancers was found. Ectopic expression of DLEC1 in silenced HCT116 and MKN45 cells strongly inhibited their clonogenicity. Thus, DLEC1 is a functional tumour suppressor, being frequently silenced by epigenetic mechanism in gastrointestinal tumours.

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“…HYAL1 levels in various cancers are associated with high-grade invasive tumors (7,8,26,27,34). However, chromosome region 3p21.3 that contains HYAL1, HYAL2, and HYAL3 genes is deleted in some cancer lines (50)(51)(52)(53). Although the tumor suppressor gene in 3p21.3 is not HYAL1, HYAL2, or HYAL3, it originally gave rise to the idea that hyaluronidase is a tumor suppressor (54).…”

Section: Discussionmentioning

confidence: 99%

HYAL1 Hyaluronidase: A Molecular Determinant of Bladder Tumor Growth and Invasion

Cerwinka²,

2005

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Hyaluronic acid and HYAL1-type hyaluronidase show high accuracy in detecting bladder cancer and evaluating its grade, respectively. Hyaluronic acid promotes tumor progression; however, the functions of hyaluronidase in cancer are largely unknown. In this study, we stably transfected HT1376 bladder cancer cells with HYAL1-sense (HYAL1-S), HYAL1-antisense (HYAL1-AS), or vector cDNA constructs. Whereas HYAL1-S transfectants produced 3-fold more HYAL1 than vector transfectants, HYAL1-AS transfectants showed f f 90% reduction in HYAL1 production. HYAL1-AS transfectants grew four times slower than vector and HYAL1-S transfectants and were blocked in the G 2 -M phase of the cell cycle. The expression of cdc25c and cyclin B1 and cdc2/p34-associated H1 histone kinase activity also decreased in HYAL1-AS transfectants. HYAL1-S transfectants were 30% to 44% more invasive, and HYAL1-AS transfectants were f f 50% less invasive than the vector transfectants in vitro. In xenografts, there was a 4-to 5-fold delay in the generation of palpable HYAL1-AS tumors, and the weight of HYAL1-AS tumors was 9-to 17-fold less than vector and HYAL1-S tumors, respectively (P < 0.001). Whereas HYAL1-S and vector tumors infiltrated skeletal muscle and blood vessels, HYAL1-AS tumors resembled benign neoplasia. HYAL1-S and vector tumors expressed significantly higher amounts of HYAL1 (in tumor cells) and hyaluronic acid (in tumor-associated stroma) than HYAL1-AS tumors. Microvessel density in HYAL1-S tumors was 3.8-and 9.5-fold higher than that in vector and HYAL1-AS tumors, respectively. These results show that HYAL1 expression in bladder cancer cells regulates tumor growth and progression and therefore serves as a marker for high-grade bladder cancer. (Cancer Res 2005; 65(6): 2243-50)

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RBSP3 (HYA22) is a tumor suppressor gene implicated in major epithelial malignancies

Cited by 83 publications

References 23 publications

Common and Contrasting Genomic Profiles among the Major Human Lung Cancer Subtypes

Common and Contrasting Genomic Profiles among the Major Human Lung Cancer Subtypes

DLEC1 is a functional 3p22.3 tumour suppressor silenced by promoter CpG methylation in colon and gastric cancers

HYAL1 Hyaluronidase: A Molecular Determinant of Bladder Tumor Growth and Invasion

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