HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA

Frost, Gregory I.; Mohapatra, Gayatry; Wong, Tim; Csóka, Antonei B.; Gray, Joe W.; Stern, Robert

doi:10.1038/sj.onc.1203317

Cited by 65 publications

(45 citation statements)

References 27 publications

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“…However, because HYAL1 (and also HYAL2 and HYAL3) is present on chromosome 3p 21.3 locus, and this region is a critical tumor homozygous deletion region in lung and breast cancers, it has been suggested that HYAL1 may be a tumor suppressor (7,49). A recent study clearly demonstrates that the RASSF1 gene and not HYAL1 is the tumor suppressor gene present in that locus (50).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Hyaluronidase Activity by Alternative mRNA Splicing

Lokeshwar

Schroeder

Carey

et al. 2002

Journal of Biological Chemistry

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Hyaluronidase is a hyaluronic acid-degrading endoglycosidase that is present in many toxins and the levels of which are elevated in cancer. Hyaluronidases (HAases)1 are a family of enzymes that are crucial for the spread of bacterial infections, toxins present in various venoms, and possibly, cancer progression (1-6). In humans, six HAase genes have been identified. These genes occur in clusters of three at two chromosomal locations (Ref. 7 and human genome blast search). HYAL1, HYAL2, and HYAL3 occur on chromosome 3p21.3, and PH20, HYAL4, and HYALP1 occur on chromosome 7q31.3. With the possible exception of HYAL4 and HYALP1, all other HAases degrade hyaluronic acid (HA) (7).HA is a nonsulfated glycosaminoglycan made up of repeating disaccharide units, D-glucuronic acid, and N-acetyl-D-glucosamine. HA is present in body fluids, tissues, and the extracellular matrix (8 -10). It keeps tissues hydrated and maintains osmotic balance and cartilage integrity (8, 10). HA also actively regulates cell adhesion, migration, and proliferation by interacting with specific cell surface receptors such as CD44 and RHAMM (11). The concentrations of HA are elevated in several inflammatory diseases and various carcinomas (e.g. bladder, prostate, breast, lung, colon, and so forth; Refs. 9 and 12-19). For example, we have shown that urinary HA concentration is a highly sensitive and specific marker for detecting bladder cancer, regardless of its grade (18,19). In tumor tissues, HA may promote tumor growth and metastasis probably by actively supporting tumor cell migration and offering protection against immune surveillance (20 -22). Small fragments of HA, generated by HAases, stimulate angiogenesis (23-25). We recently showed that HA fragments of ϳ10 -15 disaccharide units stimulate endothelial cell proliferation by acting through cell surface HA receptor, RHAMM, and activating the mitogenactivated protein kinase pathway (26). We have also shown that elevated levels of HYAL1-type HAase coincide with the presence of angiogenic HA fragments in prostate tumor tissues and in the urine of bladder cancer patients (17,27).Among the six HAases, HYAL1, HYAL2, and PH20 are well characterized. HYAL1 type HAase was originally purified from human plasma and urine (28, 29). However, we have shown that HYAL1 is the major tumor-derived HAase expressed in bladder and prostate cancer tissues (17,30). It has a optimum pH range of 4.0 -4.3, and the enzyme is 50 -80% active at pH 4.5 (17). have shown that a lack of functional HYAL1 results in a disorder called mucopolysaccharidosis IX. In this study the authors identified that aa Glu 268 is crucial for HYAL1 activity. HYAL2 was originally designated as the lysosomal HAase, and it cleaves high molecular mass HA into ϳ20-kDa HA fragments (32). It has a pH optimum of ϳ4.0 and is possibly less active than other HAases. HYAL-2 may also be exposed to the cell surface through a GPI anchor (32). The third HAase gene in the 3p21.3 locus is HYAL3. Although

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Section: Discussionmentioning

confidence: 99%

Regulation of Hyaluronidase Activity by Alternative mRNA Splicing

Lokeshwar

Schroeder

Carey

et al. 2002

Journal of Biological Chemistry

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“…Hyaluronidases would then qualify as candidate tumor suppressor gene products but no frequent inactivating mutations were identified so far. However, another inactivating mechanism was suggested and demonstrated in some oral cancers (Frost et al, 2000). The unusually large 5' UTR, found by PCR, indicated the presence of a retained intron.…”

Section: Hyal1mentioning

confidence: 99%

Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers

Zabarovsky¹,

2002

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Loss of heterozygosity (LOH) involving several chromosome 3p regions accompanied by chromosome 3p deletions are detected in almost 100% of small (SCLCs) and more than 90% of non-small (NSCLCs) cell lung cancers. In addition, these changes appear early in the pathogenesis of lung cancer and are found as clonal lesions in the smoking damaged respiratory epithelium including histologically normal epithelium as well as in epithelium showing histologic changes of preneoplasia. These 3p genetic alterations lead to the conclusion that the short arm of human chromosome 3 contains several tumor suppressor gene(s) (TSG(s)). Although the first data suggesting that 3p alterations were involved in lung carcinogenesis were published more than 10 years ago, only recently has significant progress been achieved in identifying the candidate TSGs and beginning to demonstrate their functional role in tumor pathogenesis. Some of the striking results of these findings has been the discovery of multiple 3p TSGs and the importance of tumor acquired promoter DNA methylation as an epigenetic mechanism for inactivating the expression of these genes in lung cancer. This progress, combined with the well known role of smoking as an environmental causative risk factor in lung cancer pathogenesis, is leading to the development of new diagnostic and therapeutic strategies which can be translated into the clinic to combat and prevent the lung cancer epidemic. It is clear now that genetic and epigenetic abnormalities of several genes residing in chromosome region 3p are important for the development of lung cancers but it is still obscure how many of them exist and which of the numerous candidate TSGs are the key players in lung cancer pathogenesis. We review herein our current knowledge and describe the most credible candidate genes.

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“…We showed recently that HYAL1 expression in radical prostatectomy specimens is an independent predictor of biochemical recurrence in prostate cancer patients (27,34). In tumor cells, the expression of enzymatically active HYAL1 seems to be regulated by alternative mRNA splicing (35)(36)(37).…”

Section: Introductionmentioning

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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HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA

Cited by 65 publications

References 27 publications

Regulation of Hyaluronidase Activity by Alternative mRNA Splicing

Regulation of Hyaluronidase Activity by Alternative mRNA Splicing

Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers

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

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