| |  |
| |
| | The HYAL2 protein contains a N-terminal signal peptide (1-20) and a epidermal growth factor (EGF)-like domain (365-469). |
| |
| Description | The 473 amino-acid peptide encodes the HYAL2 protein with a predicted molecular weight of 53.9 KDa. The protein is comprised of a N-terminal signal peptide (amino acids 1-20) and a epidermal growth factor ( EGF )-like domain at amino acids 365-469 (by SMART prediction). |
| Expression | High level of HYAL2 expression was detected in most tissues, including liver, kidney, lung and heart. Expression was low or absent in brain. |
| Localisation | Originally shown to be lysosomal but subsequently proved to be a glycosylphosphatidylinositol (GPI)-anchored cell surface protein. |
| Function | Hyaluronidases degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix (ECM). The level of hyaluronan is regulated by a balance between hyaluronan synthase and HYAL enzyme activities. Hyaluronan is suggested to be involved in embryonic development, cell proliferation, migration and wound healing. Although originally supposed to be active at pH 4.0, HYAL2 actually displayed minimal to undetectable hyaluronidase activity in subsequent studies. The hyaluronidase activity of HYAL2 remains controversial. |
| Homology | HYAL2 belongs to a family of hyaluronoglucosaminidases. Other members include HYAL1, HYAL3, HYAL4 and Spam1. |
| Entity | Possible in lung cancer and breast cancer. |
| Note | HYAL2 is located within a 120-kb minimal deletion region at 3p21.3. a chromosomal segment known to harbor multiple candidate tumor suppressor genes in breast and lung cancers. Nevertheless, HYAL2 does not possess tumor suppressor function, as evident by in vitro and in vivo studies in lung cancer models.
HYAL2 serves as the cellular receptor that mediates entry of the Jaagsiekte sheep retrovirus (JSRV), and its receptor function is independent on its catalytic activity. The JSRV envelope (Env) protein is believed to be the active oncogene. The viral Env transforms epithelial cells through activation of RON receptor tyrosine kinase, also called macrophage stimulating-1 receptor ( MST1R ), and followed by activating PI3K/Akt signaling cascade and MAPK signaling cascade. HYAL2 physically interacts and negatively regulates RON.
JSRV infects the epithelial cells of the lower airway of sheep and goats, resulting in ovine pulmonary adenocarinoma, sharing features with human bronchioloalveolar carcinoma. Danilkovitch-Miagkova et al. (2003) demonstrated activated RON in a subset of human bronchioloalveolar carcinoma tumors, suggesting RON involvement in this type of human lung cancer. |
| Disease | Lung cancer; bronchioloalveolar carcinoma; non-Hodgkin lymphoma ; breast cancer. |
| Prognosis | Increased level of HYAL2 deletions in sputum of Stage I non-small-cell lung cancer patients was associated with pack-years of smoking, but independent on patients' age, gender, histologic tumor type and tumor size and location. HYAL2 mRNA expression was inversely correlated with lymphoma aggressiveness. |
| Oncogenesis | HYAL2 mRNA expression was lost in lung cancer cell lines. However, expression of HYAL2 was retained in esophageal squamous carcinoma and nasopharyngeal carcinoma cell lines. Highly invasive breast cancer cell lines preferentially express HYAL2.
Systemic administration of protamine-complexed vectors expressing HYAL2 inhibited lung metastatic foci in nu/nu mice. Intratumoral injection of same construct failed to suppress primary tumor growth or induce apoptosis, suggesting HYAL2 may function at the level of metastasis. |
| | |
| HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity. |
| Lepperdinger G, Strobl B, Kreil G |
| The Journal of biological chemistry. 1998 ; 273 (35) : 22466-22470. |
| PMID 9712871 |
| |
| Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene. |
| Sekido Y, Ahmadian M, Wistuba II, Latif F, Bader S, Wei MH, Duh FM, Gazdar AF, Lerman MI, Minna JD |
| Oncogene. 1998 ; 16 (24) : 3151-3157. |
| PMID 9671394 |
| |
| Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation. |
| Rai SK, Duh FM, Vigdorovich V, Danilkovitch-Miagkova A, Lerman MI, Miller AD |
| Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (8) : 4443-4448. |
| PMID 11296287 |
| |
| Expression of several genes in the human chromosome 3p21.3 homozygous deletion region by an adenovirus vector results in tumor suppressor activities in vitro and in vivo. |
| Ji L, Nishizaki M, Gao B, Burbee D, Kondo M, Kamibayashi C, Xu K, Yen N, Atkinson EN, Fang B, Lerman MI, Roth JA, Minna JD |
| Cancer research. 2002 ; 62 (9) : 2715-2720. |
| PMID 11980673 |
| |
| Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus. |
| Danilkovitch-Miagkova A, Duh FM, Kuzmin I, Angeloni D, Liu SL, Miller AD, Lerman MI |
| Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (8) : 4580-4585. |
| PMID 12676986 |
| |
| RASSF1A is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma. |
| Chow LS, Lo KW, Kwong J, To KF, Tsang KS, Lam CW, Dammann R, Huang DP |
| International journal of cancer. Journal international du cancer. 2004 ; 109 (6) : 839-847. |
| PMID 15027117 |
| |
| Expression of HYAL2 mRNA, hyaluronan and hyaluronidase in B-cell non-Hodgkin lymphoma: relationship with tumor aggressiveness. |
| Bertrand P, Courel MN, Maingonnat C, Jardin F, Tilly H, Bastard C |
| International journal of cancer. Journal international du cancer. 2005 ; 113 (2) : 207-212. |
| PMID 15386412 |
| |
| The over-expression of HAS2, Hyal-2 and CD44 is implicated in the invasiveness of breast cancer. |
| Udabage L, Brownlee GR, Nilsson SK, Brown TJ |
| Experimental cell research. 2005 ; 310 (1) : 205-217. |
| PMID 16125700 |
| |
| Genetic deletions in sputum as diagnostic markers for early detection of stage I non-small cell lung cancer. |
| Li R, Todd NW, Qiu Q, Fan T, Zhao RY, Rodgers WH, Fang HB, Katz RL, Stass SA, Jiang F |
| Clinical cancer research : an official journal of the American Association for Cancer Research. 2007 ; 13 (2 Pt 1) : 482-487. |
| PMID 17255269 |
| |
| Ability of hyaluronidase 2 to degrade extracellular hyaluronan is not required for its function as a receptor for jaagsiekte sheep retrovirus. |
| Vigdorovich V, Miller AD, Strong RK |
| Journal of virology. 2007 ; 81 (7) : 3124-3129. |
| PMID 17229709 |
| |
