The Emerging Role of Calcium-activated Chloride Channel Regulator 1 in Cancer

Calcium-activated chloride channel regulator 1 (CLCA1) belongs to a group of secreted self-cleaving proteins, which activate calcium-dependent chloride channels. CLCA1 has been shown to participate in the pathogenesis of inflammatory airway diseases such as asthma. Recently, additional functions of CLCA1 have been unveiled, including its metalloprotease property and involvement in mucus homeostasis and immune modulation. Emerging evidence suggests that CLCA1 may also be involved in the pathophysiology of colorectal, pancreatic and ovarian cancer. There is growing interest in utilizing CLCA1 as a diagnostic, prognostic and predictive biomarker, as well as a potential therapeutic target. In this review, the functional role of CLCA1, with a particular focus on cancer, is described.

[1]  R. Andersson,et al.  Calcium-activated chloride channel regulator 1 as a prognostic biomarker in pancreatic ductal adenocarcinoma , 2018, BMC Cancer.

[2]  Y. Shiue,et al.  High chloride channel accessory 1 expression predicts poor prognoses in patients with rectal cancer receiving chemoradiotherapy , 2018, International journal of medical sciences.

[3]  A. Gruber,et al.  Calcium-activated Chloride Channel Regulator 1 (CLCA1) Controls Mucus Expansion in Colon by Proteolytic Activity , 2018, EBioMedicine.

[4]  V. Rajendran,et al.  Calcium-Activated Cl− Channel: Insights on the Molecular Identity in Epithelial Tissues , 2018, International journal of molecular sciences.

[5]  G. Marko‐Varga,et al.  Proteomic analyses identify prognostic biomarkers for pancreatic ductal adenocarcinoma , 2018, Oncotarget.

[6]  C. Verbeke,et al.  Highly Accurate Identification of Cystic Precursor Lesions of Pancreatic Cancer Through Targeted Mass Spectrometry: A Phase IIc Diagnostic Study. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  Jiekai Yu,et al.  CLCA1 suppresses colorectal cancer aggressiveness via inhibition of the Wnt/beta-catenin signaling pathway , 2017, Cell Communication and Signaling.

[8]  Yuan Yin,et al.  The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-Derived IL6 , 2017, Clinical Cancer Research.

[9]  Daniel J. Shiwarski,et al.  TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression , 2017, Clinical Cancer Research.

[10]  C. Nichols,et al.  Modulation of TMEM16A channel activity by the von Willebrand factor type A (VWA) domain of the calcium-activated chloride channel regulator 1 (CLCA1) , 2017, The Journal of Biological Chemistry.

[11]  R. Andersson,et al.  Pancreatic cancer stroma: controversies and current insights , 2017, Scandinavian journal of gastroenterology.

[12]  Jiekai Yu,et al.  High-throughput proteomics integrated with gene microarray for discovery of colorectal cancer potential biomarkers , 2016, Oncotarget.

[13]  Fei Wu,et al.  Identification of the Novel TMEM16A Inhibitor Dehydroandrographolide and Its Anticancer Activity on SW620 Cells , 2015, PloS one.

[14]  A. Schwab,et al.  Ion channels and transporters in metastasis. , 2015, Biochimica et biophysica acta.

[15]  Y. Shin,et al.  Anoctamin 1 (TMEM16A) is essential for testosterone-induced prostate hyperplasia , 2015, Proceedings of the National Academy of Sciences.

[16]  E. Diamandis,et al.  Comparative Proteomics of Ovarian Cancer Aggregate Formation Reveals an Increased Expression of Calcium-activated Chloride Channel Regulator 1 (CLCA1)* , 2015, The Journal of Biological Chemistry.

[17]  T. Gajewski,et al.  Innate immune recognition of cancer. , 2015, Annual review of immunology.

[18]  C. Nichols,et al.  Secreted CLCA1 modulates TMEM16A to activate Ca2+-dependent chloride currents in human cells , 2015, eLife.

[19]  C. McCaig,et al.  Low Expression of Chloride Channel Accessory 1 Predicts a Poor Prognosis in Colorectal Cancer , 2015, Cancer.

[20]  T. Ma,et al.  Inhibition of TMEM16A Expression Suppresses Growth and Invasion in Human Colorectal Cancer Cells , 2014, PloS one.

[21]  D. Sauter,et al.  ANO1 (TMEM16A) in pancreatic ductal adenocarcinoma (PDAC) , 2014, Pflügers Archiv - European Journal of Physiology.

[22]  Florian Lang,et al.  Ion channels in cancer: future perspectives and clinical potential , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[23]  O. Crociani,et al.  Interaction of tumour cells with their microenvironment: ion channels and cell adhesion molecules. A focus on pancreatic cancer , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[24]  M. Loewen,et al.  Secreted hCLCA1 Is a Signaling Molecule That Activates Airway Macrophages , 2013, PloS one.

[25]  H. Gabra,et al.  Ovarian cancer: Ion channel and aquaporin expression as novel targets of clinical potential. , 2013, European journal of cancer.

[26]  B. Liu,et al.  The Transition from Proliferation to Differentiation in Colorectal Cancer Is Regulated by the Calcium Activated Chloride Channel A1 , 2013, PloS one.

[27]  M. Holtzman,et al.  IL-13-induced airway mucus production is attenuated by MAPK13 inhibition. , 2012, The Journal of clinical investigation.

[28]  C. Nichols,et al.  Self-cleavage of Human CLCA1 Protein by a Novel Internal Metalloprotease Domain Controls Calcium-activated Chloride Channel Activation*♦ , 2012, The Journal of Biological Chemistry.

[29]  Alyssa D Gregory,et al.  Tumor-associated neutrophils: new targets for cancer therapy. , 2011, Cancer research.

[30]  E. Lundberg,et al.  Towards a knowledge-based Human Protein Atlas , 2010, Nature Biotechnology.

[31]  N. Prevarskaya,et al.  Ion channels and the hallmarks of cancer. , 2010, Trends in molecular medicine.

[32]  M. Holtzman,et al.  The role of CLCA proteins in inflammatory airway disease. , 2009, Annual review of physiology.

[33]  Yuan Luo,et al.  Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4 , 2008, Molecular and Cellular Biology.

[34]  N. Meinander,et al.  Novel conserved hydrolase domain in the CLCA family of alleged calcium‐activated chloride channels , 2006, Proteins.

[35]  N. Thompson,et al.  hCLCA1 and mCLCA3 Are Secreted Non-integral Membrane Proteins and Therefore Are Not Ion Channels* , 2005, Journal of Biological Chemistry.

[36]  J. Neoptolemos,et al.  Comprehensive Analysis of Matrix Metalloproteinase and Tissue Inhibitor Expression in Pancreatic Cancer , 2004, Clinical Cancer Research.

[37]  Haiqun Lin,et al.  The Interacting Binding Domains of the β4 Integrin and Calcium-activated Chloride Channels (CLCAs) in Metastasis* , 2003, Journal of Biological Chemistry.

[38]  R. Elble,et al.  Focal Adhesion Kinase Activated by β4 Integrin Ligation to mCLCA1 Mediates Early Metastatic Growth* , 2002, The Journal of Biological Chemistry.

[39]  O. Nishimura,et al.  Increased expression of the human Ca2+-activated Cl- channel 1 (CaCC1) gene in the asthmatic airway. , 2002, American journal of respiratory and critical care medicine.

[40]  Q. Hamid,et al.  A calcium-activated chloride channel (HCLCA1) is strongly related to IL-9 expression and mucus production in bronchial epithelium of patients with asthma. , 2002, The Journal of allergy and clinical immunology.

[41]  Yukio Fujisawa,et al.  Role of gob-5 in mucus overproduction and airway hyperresponsiveness in asthma , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[42]  A. Gruber,et al.  Molecular cloning and biochemical characterization of a truncated, secreted member of the human family of Ca2+-activated Cl- channels. , 1999, Biochimica et biophysica acta.

[43]  A. Gruber,et al.  Genomic cloning, molecular characterization, and functional analysis of human CLCA1, the first human member of the family of Ca2+-activated Cl- channel proteins. , 1998, Genomics.

[44]  T. Vermat,et al.  Identification of three novel members of the calcium-dependent chloride channel (CaCC) family predominantly expressed in the digestive tract and trachea. , 1999, FEBS letters.