Disease relevance of CLCA2

• The breast cancer beta 4 integrin and endothelial human CLCA2 mediate lung metastasis [1].
• Our results suggest that CLCA1 could specify a new tumor suppressor and that, as in breast cancer, CLCA2 may function as a tumor suppressor in colorectal cancer [2].
• We have previously compared transcripts from squamous cell lung cancer and normal lung tissue using differential display analysis, and found a transcript that was overexpressed in malignant cells and was identical with the calcium-activated chloride channel 2 (CLCA2) gene [3].
• Recent studies have indicated the association of the second member of this gene family (CLCA2) with the development of breast cancer and metastasis [4].
• Expression in human trachea and lung suggests that hCLCA2 may play a role in the complex pathogenesis of cystic fibrosis [5].

High impact information on CLCA2

• Consistent with the electrophysiological data, RT-PCR showed that HaCaT keratinocytes express two types of Ca2+-activated Cl- channels, CaCC2 and CaCC3 (CLCA2), as well as the Ca2+-activated K+ channel hSK4 [6].
• Transfer of the hCLCA2 C-terminal hydrophobic segment to a secreted form of green fluorescent protein was sufficient to target that protein to the plasma membrane [7].
• Like hCLCA2, mCLCA5 was down-regulated in metastatic mammary tumor cell lines such as 4T1 and CSML-100 [8].
• A chimeric beta4 integrin in which the indicated SDL sequence had been replaced with the corresponding sequence from the beta1 integrin failed to bind hCLCA2 [9].
• CLCA2-specific CD8(+) T cells were absent from the peripheral blood of healthy donors [3].

Biological context of CLCA2

• The CLCA2 gene mapped to human chromosome 1p32 [10].
• CLCA2 tumour suppressor gene in 1p31 is epigenetically regulated in breast cancer [4].
• In contrast, in breast cancer cell lines, tumours, and control cell lines that express CLCA2, a much lower level, and often absence, of methylation of the promoter were demonstrated [4].
• Although we were able to identify CLCA2 mutations in breast cancers, somatic mutations are not the major cause of CLCA2 gene silencing [4].
• Tumor cell adhesion to endothelial hCLCA2 is mediated by the beta(4) integrin, establishing for the first time a cell-cell adhesion property for this integrin that involves an entirely new adhesion partner [1].

Anatomical context of CLCA2

• CONCLUSION: High and tissue specific expression of the CLCA2 gene in human corneal epithelium implies an important role in corneal transparency maintenance [10].
• Single-layered human epithelial cultures on amniotic membrane and early day embryonic chicken corneas expressed relatively little human CLCA2 or its chicken homologue [11].
• We have used suppression subtractive hybridization of mRNA from paired normal colon epithelium and tumor, followed by quantitative kinetic RT-PCR, to demonstrate that the transcription of two members of a novel Ca(2+)-dependent chloride channel family, CLCA1 and CLCA2, was significantly downregulated in approximately 80% of colorectal carcinomas [2].
• 5. Expression of hCLCA2 in normal mammary epithelium is consistently lost in human breast cancer and in all tumorigenic breast cancer cell lines [12].
• Epithelia of stomach and small intestine showed no hCLCA2 immunoreactivity [13].

Associations of CLCA2 with chemical compounds

• 4. The CLCA proteins expressed on the luminal surface of lung vascular endothelia (bCLCA2; mCLCA1; hCLCA2) serve as adhesion molecules for lung metastatic cancer cells, mediating vascular arrest and lung colonization [12].

Other interactions of CLCA2

• Here, we describe radiation hybrid mapping of the human CLCA2 and CLCA3 genes using the Genebridge 4 panel [14].
• RESULTS: We cloned a new Ca(2+)-activated chloride channel, CLCA2, from corneal epithelium [10].
• There was no association between CLCA2 and either CLCA1 or c-myc mRNA levels [2].
• Transmission disequilibrium and the significance of the association decreased within the locus from hCLCA2 towards hCLCA4 [15].
• Bisulphite-sequencing of the promoter-associated CpG island of the CLCA2 gene in breast tumours demonstrated that the absence of expression in these tumours was caused by hypermethylation of the promoter CpG island [4].

Analytical, diagnostic and therapeutic context of CLCA2

• These data indicate that an immune response can be induced against CLCA2, which thus may become an important Ag for anti-tumor vaccination approaches [3].
• Relative amounts of hCLCA2 were analysed using real-time PCR in several human epithelial tissues and tissues expressing high amounts were identified [16].
• Molecular cloning and transmembrane structure of hCLCA2 from human lung, trachea, and mammary gland [5].
• Subsequent immunohistochemistry clearly demonstrated colocalisation between hCLCA2 and integrin beta4 [16].

References