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Expression of polarity genes in human cancer.

Lin WH, Asmann YW, Anastasiadis PZ - Cancer Inform (2015)

Bottom Line: Polarity protein complexes are crucial for epithelial apical-basal polarity and directed cell migration.Since alterations of these processes are common in cancer, polarity proteins have been proposed to function as tumor suppressors or oncogenic promoters.Additionally, polarity expression profiles correlated with disease progression and aggressiveness, as well as with identified cancer types, where specific polarity genes were commonly altered.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.

ABSTRACT
Polarity protein complexes are crucial for epithelial apical-basal polarity and directed cell migration. Since alterations of these processes are common in cancer, polarity proteins have been proposed to function as tumor suppressors or oncogenic promoters. Here, we review the current understanding of polarity protein functions in epithelial homeostasis, as well as tumor formation and progression. As most previous studies focused on the function of single polarity proteins in simplified model systems, we used a genomics approach to systematically examine and identify the expression profiles of polarity genes in human cancer. The expression profiles of polarity genes were distinct in different human tissues and classified cancer types. Additionally, polarity expression profiles correlated with disease progression and aggressiveness, as well as with identified cancer types, where specific polarity genes were commonly altered. In the case of Scribble, gene expression analysis indicated its common amplification and upregulation in human cancer, suggesting a tumor promoting function.

No MeSH data available.


Related in: MedlinePlus

Expression of polarity complex genes in breast (A) and brain (B) cancers. Integrative clustering of the expression of polarity genes in breast (A, normal = green; primary solid tumor = blue, metastatic = red) and brain cancer (B, blue = glioblastoma, brown = low grade glioma) is shown. Relative mRNA level is depicted by the blue-red intensities (red = 3.0 high; white = 0.0, average; blue = –3.0, low).
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f4-cin-suppl.3-2015-015: Expression of polarity complex genes in breast (A) and brain (B) cancers. Integrative clustering of the expression of polarity genes in breast (A, normal = green; primary solid tumor = blue, metastatic = red) and brain cancer (B, blue = glioblastoma, brown = low grade glioma) is shown. Relative mRNA level is depicted by the blue-red intensities (red = 3.0 high; white = 0.0, average; blue = –3.0, low).

Mentions: Using the same unsupervised clustering method to analyze both the normal and breast cancer data as above, we have clustered polarity genes according to their overall expression pattern (Fig. 4A, Supplementary Table 2). Interestingly, the expression profiles of the 20 polarity genes automatically segregated normal from tumor breast tissue samples. Similar results were obtained when analyzing other cancer types, showing the power of this analysis for differentiating normal from tumor samples and highlighting the significance of polarity genes in tumor formation (Supplementary Fig. 1). In breast cancer, normal tissue samples and a very small number of tumors clustered closely together, whereas breast cancer samples were classified into two major clusters. This finding is consistent with the presence of genomic heterogeneity in breast cancer, and further analysis will be required to assess whether this segregation is dependent on the subtype (luminal vs basal) or aggressiveness of each tumor sample. Our analysis revealed significant expression changes in polarity genes in breast cancer. Although SCRIB (Scribble) was initially thought to be downregulated in breast cancer,138,139 a recent study argued its upregulation,140 which is consistent with our data. As mentioned earlier, several members of polarity complex proteins are expressed as multiple paralogs, often referred to as isoforms. In most cases, we know very little about the differences in the expression and function of different isoforms. Our bioinformatics analysis suggests that polarity protein isoforms exhibit differential expression patterns in breast cancer, likely reflecting isoform-specific functions. For example, while Dlg3 is upregulated in breast cancer samples, Dlg2 is downregulated (Fig. 4A). Similarly, there is an upregulation of PARD6A (Par6α) and PARD6B (Par6β), but a decrease in the levels of PARD6G (Par6γ). Crb3 is upregulated in our breast cancer samples, while its paralogs Crb1 and Crb2 are downregulated (Fig. 4A, supplementary Table 2). Crb1 and Crb2 are large proteins with extended extracellular regions like Drosophila Crumbs, while Crb3 is a relatively small molecule (13 kDa) with a very short extracellular domain.3 Despite the discrepancy, Crb isoforms possess similar cytoplasmic domains that mediate their interaction with Pals1, Patj, and Mupp1.18,205,206 Moreover, in polarized epithelial cells, both Crb1 and Crb3 localize at tight junctions,18,205 although little is known about the role of Crb1 in epithelial polarity as early studies suggested lack of expression in epithelial tissues.207,208 Similar to Crb isoforms, differential expression patterns were also found for aPKC isoforms and Patj/Mupp1 paralogs (Fig. 4A, Supplementary Table 2).


Expression of polarity genes in human cancer.

Lin WH, Asmann YW, Anastasiadis PZ - Cancer Inform (2015)

Expression of polarity complex genes in breast (A) and brain (B) cancers. Integrative clustering of the expression of polarity genes in breast (A, normal = green; primary solid tumor = blue, metastatic = red) and brain cancer (B, blue = glioblastoma, brown = low grade glioma) is shown. Relative mRNA level is depicted by the blue-red intensities (red = 3.0 high; white = 0.0, average; blue = –3.0, low).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4390136&req=5

f4-cin-suppl.3-2015-015: Expression of polarity complex genes in breast (A) and brain (B) cancers. Integrative clustering of the expression of polarity genes in breast (A, normal = green; primary solid tumor = blue, metastatic = red) and brain cancer (B, blue = glioblastoma, brown = low grade glioma) is shown. Relative mRNA level is depicted by the blue-red intensities (red = 3.0 high; white = 0.0, average; blue = –3.0, low).
Mentions: Using the same unsupervised clustering method to analyze both the normal and breast cancer data as above, we have clustered polarity genes according to their overall expression pattern (Fig. 4A, Supplementary Table 2). Interestingly, the expression profiles of the 20 polarity genes automatically segregated normal from tumor breast tissue samples. Similar results were obtained when analyzing other cancer types, showing the power of this analysis for differentiating normal from tumor samples and highlighting the significance of polarity genes in tumor formation (Supplementary Fig. 1). In breast cancer, normal tissue samples and a very small number of tumors clustered closely together, whereas breast cancer samples were classified into two major clusters. This finding is consistent with the presence of genomic heterogeneity in breast cancer, and further analysis will be required to assess whether this segregation is dependent on the subtype (luminal vs basal) or aggressiveness of each tumor sample. Our analysis revealed significant expression changes in polarity genes in breast cancer. Although SCRIB (Scribble) was initially thought to be downregulated in breast cancer,138,139 a recent study argued its upregulation,140 which is consistent with our data. As mentioned earlier, several members of polarity complex proteins are expressed as multiple paralogs, often referred to as isoforms. In most cases, we know very little about the differences in the expression and function of different isoforms. Our bioinformatics analysis suggests that polarity protein isoforms exhibit differential expression patterns in breast cancer, likely reflecting isoform-specific functions. For example, while Dlg3 is upregulated in breast cancer samples, Dlg2 is downregulated (Fig. 4A). Similarly, there is an upregulation of PARD6A (Par6α) and PARD6B (Par6β), but a decrease in the levels of PARD6G (Par6γ). Crb3 is upregulated in our breast cancer samples, while its paralogs Crb1 and Crb2 are downregulated (Fig. 4A, supplementary Table 2). Crb1 and Crb2 are large proteins with extended extracellular regions like Drosophila Crumbs, while Crb3 is a relatively small molecule (13 kDa) with a very short extracellular domain.3 Despite the discrepancy, Crb isoforms possess similar cytoplasmic domains that mediate their interaction with Pals1, Patj, and Mupp1.18,205,206 Moreover, in polarized epithelial cells, both Crb1 and Crb3 localize at tight junctions,18,205 although little is known about the role of Crb1 in epithelial polarity as early studies suggested lack of expression in epithelial tissues.207,208 Similar to Crb isoforms, differential expression patterns were also found for aPKC isoforms and Patj/Mupp1 paralogs (Fig. 4A, Supplementary Table 2).

Bottom Line: Polarity protein complexes are crucial for epithelial apical-basal polarity and directed cell migration.Since alterations of these processes are common in cancer, polarity proteins have been proposed to function as tumor suppressors or oncogenic promoters.Additionally, polarity expression profiles correlated with disease progression and aggressiveness, as well as with identified cancer types, where specific polarity genes were commonly altered.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.

ABSTRACT
Polarity protein complexes are crucial for epithelial apical-basal polarity and directed cell migration. Since alterations of these processes are common in cancer, polarity proteins have been proposed to function as tumor suppressors or oncogenic promoters. Here, we review the current understanding of polarity protein functions in epithelial homeostasis, as well as tumor formation and progression. As most previous studies focused on the function of single polarity proteins in simplified model systems, we used a genomics approach to systematically examine and identify the expression profiles of polarity genes in human cancer. The expression profiles of polarity genes were distinct in different human tissues and classified cancer types. Additionally, polarity expression profiles correlated with disease progression and aggressiveness, as well as with identified cancer types, where specific polarity genes were commonly altered. In the case of Scribble, gene expression analysis indicated its common amplification and upregulation in human cancer, suggesting a tumor promoting function.

No MeSH data available.


Related in: MedlinePlus