Ng the time we drafted ?this manuscript. We all have to thank for her constructive contributions.Author ContributionsConceived and designed the experiments: MO HT PS. Performed the experiments: SJ SL ST. Analyzed the data: OJ SJS SL. Contributed reagents/materials/analysis tools: LP HS SH CvA MN HAK HK ML JW BF BH. Wrote the paper: SJ SL MO.
Elucidation of the role of CD44 and its alternative splice patterns in melanoma biology has been challenging. Beyond its standard (CD44S), constitutively expressed region it has ten variable exons (v1 10), forming the variable region (CD44v) [1], which potentially allows for the expression of thousands of different isoforms of different structure and function. At present, the expression of 42 CD44 isoforms has been confirmed at mRNA level, 29 of these have been shown to encode protein. Additionally, post-translational glycation adds a further layer of diversity to the possible protein structure and functions. These include Ornipressin binding to different components of the extracellular matrix, cytokine-binding and participation in signal pathways of cell ML-281 growth and migration. [2?]. Many of the variable exons’ individual functions have been examined individually demonstrating significant functional changes in signaling pathways. CD44 is the principal cell surface receptor for hyaluronate. When v3 is expressed [8] hyaluronate binding is weaker. Permitting further chondroitin and heparan sulphate glycosylation, results in the presentation of heparinbinding growth factors such as HB-EGF, b-FGF and amphiregulin. [9] For activating c-met by its ligand, HGF/SF, v6 is needed and important for the intracellular 24272870 signal pathway via MEK and Erk. [10] In Ras pathway-regulated CD44 alternative splicing, those isoforms containing v6 together with HGF form apositive feedback loop on Ras, causing the downregulation of nonv6 containing isoforms [11]. However, there is discrepancy around the data on the role of CD44 and its isoforms in tumour biology. Despite the fact that it has been known for a number of years now that healthy tissues have specific CD44 Alternative Splice Patterns (ASPs) [12], and a PCR based method has already been proposed to analyse the different CD44 splice variants [13], there has not been any follow up to this study. Conversely, most data on CD44 alternative splicing in neoplasia and tumour progression have focused on the associations of the expression of single CD44 variable exons. There are problematic discrepancies in the role of CD44v in tumour biology. For example, in colorectal carcinoma some studies indicate that v2 has a predictive role in progression [14], v3 and v6 play a role in cancer free survival [15] and v6 again in distant metastases [16,17]. Other studies have failed to demonstrate any such role [18,19,20]. Similar discrepancies emerge in the changing patterns of CD44v expression in human melanoma. Dome et al. demonstrated the up-regulation of v3 results in a higher visceral metastatic potential [21] while Pacifico et al. showed that CD44v3 expression is associated significantly with a better outcome [22]. Again v10 [23] and v6 [24] may be involved in metastasis formation, or not [25]. One study suggests that human melanomas do not expressCD44 Alternative Splicing Pattern of MelanomaCD44v isoforms at all and only express the CD44S form at a higher level, and does not correlate with the prognosis of this tumour type [26]. These varied findings may reflect the focus on the expression of sol.Ng the time we drafted ?this manuscript. We all have to thank for her constructive contributions.Author ContributionsConceived and designed the experiments: MO HT PS. Performed the experiments: SJ SL ST. Analyzed the data: OJ SJS SL. Contributed reagents/materials/analysis tools: LP HS SH CvA MN HAK HK ML JW BF BH. Wrote the paper: SJ SL MO.
Elucidation of the role of CD44 and its alternative splice patterns in melanoma biology has been challenging. Beyond its standard (CD44S), constitutively expressed region it has ten variable exons (v1 10), forming the variable region (CD44v) [1], which potentially allows for the expression of thousands of different isoforms of different structure and function. At present, the expression of 42 CD44 isoforms has been confirmed at mRNA level, 29 of these have been shown to encode protein. Additionally, post-translational glycation adds a further layer of diversity to the possible protein structure and functions. These include binding to different components of the extracellular matrix, cytokine-binding and participation in signal pathways of cell growth and migration. [2?]. Many of the variable exons’ individual functions have been examined individually demonstrating significant functional changes in signaling pathways. CD44 is the principal cell surface receptor for hyaluronate. When v3 is expressed [8] hyaluronate binding is weaker. Permitting further chondroitin and heparan sulphate glycosylation, results in the presentation of heparinbinding growth factors such as HB-EGF, b-FGF and amphiregulin. [9] For activating c-met by its ligand, HGF/SF, v6 is needed and important for the intracellular 24272870 signal pathway via MEK and Erk. [10] In Ras pathway-regulated CD44 alternative splicing, those isoforms containing v6 together with HGF form apositive feedback loop on Ras, causing the downregulation of nonv6 containing isoforms [11]. However, there is discrepancy around the data on the role of CD44 and its isoforms in tumour biology. Despite the fact that it has been known for a number of years now that healthy tissues have specific CD44 Alternative Splice Patterns (ASPs) [12], and a PCR based method has already been proposed to analyse the different CD44 splice variants [13], there has not been any follow up to this study. Conversely, most data on CD44 alternative splicing in neoplasia and tumour progression have focused on the associations of the expression of single CD44 variable exons. There are problematic discrepancies in the role of CD44v in tumour biology. For example, in colorectal carcinoma some studies indicate that v2 has a predictive role in progression [14], v3 and v6 play a role in cancer free survival [15] and v6 again in distant metastases [16,17]. Other studies have failed to demonstrate any such role [18,19,20]. Similar discrepancies emerge in the changing patterns of CD44v expression in human melanoma. Dome et al. demonstrated the up-regulation of v3 results in a higher visceral metastatic potential [21] while Pacifico et al. showed that CD44v3 expression is associated significantly with a better outcome [22]. Again v10 [23] and v6 [24] may be involved in metastasis formation, or not [25]. One study suggests that human melanomas do not expressCD44 Alternative Splicing Pattern of MelanomaCD44v isoforms at all and only express the CD44S form at a higher level, and does not correlate with the prognosis of this tumour type [26]. These varied findings may reflect the focus on the expression of sol.
