CLCA4 Membrane Protein Introduction

Introduction of CLCA4

Chloride channel accessory 4, also known as CLCA4, is a protein which is encoded by humans CLCA4 gene. The protein is one of the chloride channels. Result of protein structure prediction suggests that the N-terminal region of CLCA4 protein is a zinc metalloprotease, and the protein is not a metal ion channel. CLCA4 is widely expressed in colon, along with another member of the CLCA family, such as CLCA1. Both of them are precipitously downregulated with tumor development. Reports have shown that this tumor suppressor contributes to the progression of several human cancers. But its role in bladder carcinoma is still unknown.

Function of CLCA4 Membrane Protein

CLCA4 has been regarded as a mark of tumor for a long time. Reports show that as a member of the CLCA gene family, CLCA4 is expressed in mammary epithelial cells and is similarly downregulated in breast tumors and in breast cancer cell lines. CLCA4 and CLCA2 together are markers for mammary epithelial differentiation, both of which play complementary but distinct roles in epithelial differentiation. Low expression of CLCA4 signals lower relapse-free survival in basal and luminal B breast cancers. Recently research suggests that its expression is down-regulated in bladder carcinoma tissues and cells. Low CLCA4 expression has a relationship with larger tumor size, advanced tumor stage, and poor prognosis, while it profoundly attenuates the proliferation, growth, migratory and invasive capabilities of bladder cancer cells. This process is mechanistically related to its function in PI3K/AKT signaling pathway.

Fig1. CLCA4 expression inhibits breast cancer cell proliferation. A, western blot showing expression of Flag-tagged CLCA4 and CLCA2 transfected into 293 T cells. B, clonogenicity assays. C, microimages of the surviving colonies. (Yu, 2013)

Application of CLCA4 Membrane Protein in Literature

1. Pawłowski K., et al. Novel conserved hydrolase domain in the CLCA family of alleged calcium-activated chloride channels. Proteins. 2006, 63(3):424-39. PubMed ID: 16470849
   
   

   Advanced protein structure prediction methods combined with structure modeling show that the mammalian proteins appear to be membrane anchored metal-dependent hydrolases, possibly proteases, which have heretofore been described as calcium-activated chloride channels (CLCAs). The hydrolase prediction combined with the presented experimental data give a doubtful influence on the function of CLCAs acting as chloride channels and strengthening the hypothesis of channel-activating and/or channel-accessory roles.

2. Liu Z., et al. CLCA4 inhibits cell proliferation and invasion of hepatocellular carcinoma by suppressing epithelial-mesenchymal transition via PI3K/AKT signaling. Aging (Albany NY). 2018, 10(10):2570-2584. PubMed ID: 30312171
   
   

   This article indicates that CLCA4 is responsible for migration and invasion by inhibiting EMT via PI3K/ATK signaling, thus providing a novel sight for prognosis of HCC. Besides, CLCA4/AFP expression may help to distinguish different risks of HCC patients after hepatectomy.

3. Yu Y., et al. Loss of CLCA4 promotes epithelial-to-mesenchymal transition in breast cancer cells. PLoS One. 2013, 8(12): e83943. PubMed ID: 24386311
   
   

   The epithelial to mesenchymal transition (EMT) is a developmental program in which epithelial cells downregulate their cell-cell junctions, acquire spindle cell morphology and exhibit cellular motility. This article suggests that CLCA4 and CLCA2 play complementary but distinct roles in epithelial differentiation. Clinically, low expression of CLCA4 signaled lower relapse-free survival in basal and luminal B breast cancers.

4. Kolbe E.W. et al. CLCA4 variants determine the manifestation of the cystic fibrosis basic defect in the intestine. Eur J Hum Genet. 2013, 21(6):691-4. PubMed ID: 23073314
   
   

   The manifestation of the monogenic disease cystic fibrosis results from the cystic fibrosis transmembrane conductance regulator (CFTR)-mediated basic defect is defined as an altered chloride transport. The results of their studies strongly argue that CLCA4 regulates the capability to express residual chloride secretion in colonic tissue.

5. Hou T., et al. CLCA4 inhibits bladder cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT pathway. Oncotarget. 2017, 8(54):93001-93013. PubMed ID: 29190973
   
   

   In this study, the authors show that CLCA4 expression is down-regulated in bladder carcinoma tissues and cells compared to adjacent non-tumor tissues and normal urothelial cells. CLCA4 expression is negatively correlated with larger tumor size, advanced tumor stage, and poor prognosis. They suggest that CLCA4 may represent a promising prognostic biomarker for bladder cancer and provide a possible mechanism for bladder cancer growth and invasion.

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Reference

1. Yu Y, et al. (2013). Loss of CLCA4 promotes epithelial-to-mesenchymal transition in breast cancer cells. PLoS One. 8(12), e83943.

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