Abstract
Breaking the balance between proliferation and differentiation in animal cells can lead to cancer, but the mechanisms maintaining this balance remain largely undefined. The calcium activated chloride channel A1 (CLCA1) is a member of the calcium sensitive chloride conductance family of proteins and is expressed mainly in the colon, small intestine and appendix. We show that CLCA1 plays a functional role in differentiation and proliferation of Caco-2 cells and of intestinal tissue. Caco-2 cells spontaneously differentiate either in confluent culture or when treated with butyrate, a molecule present naturally in the diet. Here, we compared CLCA1 expressional levels between patients with and without colorectal cancer (CRC) and determined the functional role of CLCA1 in differentiation and proliferation of Caco-2 cells. We showed that: 1) CLCA1 and CLCA4 expression were down-regulated significantly in CRC patients; 2) CLCA1 expression was up-regulated in Caco-2 cells induced to differentiate by confluent culture or by treatment with sodium butyrate (NaBT); 3) Knockdown of CLCA1 with siRNA significantly inhibited cell differentiation and promoted cell proliferation in Caco-2 confluent cultures, and 4) In Caco-2 3D culture, suppression of CLCA1 significantly increased cell proliferation and compromised NaBT-induced inhibition of proliferation. In conclusion, CLCA1 may contribute to promoting spontaneous differentiation and reducing proliferation of Caco-2 cells and may be a target of NaBT-induced inhibition of proliferation and therefore a potential diagnostic marker for CRC prognosis.
Highlights
In mammalian intestine the enterocytes are renewed continually every 4–8 days
We found that the calcium activated chloride channel CLCA1 plays a crucial role in regulation and maintenance of proliferation to differentiation transition (PDT) in colon enterocyte, since loss of CLCA1 led to reversion of cells to a low-differentiated status
CLCA1 Regulates the PDT in Intestinal Epithelial Cells The PDT of single progenitor cell is tightly regulated by morphogens, growth factors and hormones [29] and molecular alterations to specific components of the signaling pathways used by these different classes of molecule are important during the development of cancer [30]
Summary
In mammalian intestine the enterocytes are renewed continually every 4–8 days. This occurs through a coordinated series of events involving proliferation, differentiation, and migration from the intestinal crypts upwards toward the lumen [1]. Alterations of the tightly regulated balance between the highly proliferative/less differentiated enterocytes and the non-proliferative/highly differentiated state may lead to hyperplasia, benign (polyps) or malignant tumors [3]. Ion channels contribute to tumors by regulating the basic cellular processes of proliferation, differentiation, and apoptosis [5]. KCNK9 (potassium channel subfamily K member 9) is overexpressed and contributes to tumorigenesis by promoting cancer cell survival in breast cancer [6]. Studies describing the occurrence of individual ion channels in tumor cells and their functional consequences on growth, migration, or invasion are increasing [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
