Expression of the Ca²⁺-Activated Chloride Channel Genes CLCA1 and CLCA2 Is Downregulated in Human Colorectal Cancer

Abstract

The role of ion channels in carcinogenesis and tumor progression remains unclear. 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. This figure rose to >90% when expression was adjusted for tumor cell proliferation. In normal colon epithelium, CLCA1 mRNA levels were significantly associated with c-myc transcription but became decoupled in the tumor samples. There was no association between CLCA2 and either CLCA1 or c-myc mRNA levels. Transcription of both genes in three colorectal cancer cell lines, T84, HT29, and Caco2, was barely detectable. Illegitimate transcription of CLCA1 was detected in 12 of 15 blood samples taken from healthy volunteers, making its use as a marker for the detection of tumor spread unreliable. 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.

Gene trapping identifies chloride channel 4 as a novel inducer of colon cancer cell migration, invasion and metastases

“…These findings, and others (Soroceanu et al, 1999;Bustin et al, 2001;Chapman et al, 2002;Li et al, 2003;Ding et al, 2007), should direct attention to the importance of ion exchangers in tumour progression and could provide new avenues for managing patients at high risk for metastatic spread.…”

“…Although, to our knowledge, this is the first report of a causal role for CLCN4 in tumour progression, an earlier study (Soroceanu et al, 1999) is relevant for showing that pharmacological blockade of chloride channels was shown to reduce glioma cell migration and invasion into foetal rat brain aggregates. Unfortunately, the responsible chloride channel/exchanger driving migration/invasion was not identified in that investigation and, at present, at least 11 separate chloride exchangers/antiporters have been reported (Bustin et al, 2001;Jentsch, 2008). In contrast, the expression of two other chloride channels (the Ca 2 þ -dependent chloride channels CLCA1 and CLCA2) was downregulated in 80% of colorectal tumours, although the biological significance of this repression (Bustin et al, 2001) remains to be determined.…”

“…Unfortunately, the responsible chloride channel/exchanger driving migration/invasion was not identified in that investigation and, at present, at least 11 separate chloride exchangers/antiporters have been reported (Bustin et al, 2001;Jentsch, 2008). In contrast, the expression of two other chloride channels (the Ca 2 þ -dependent chloride channels CLCA1 and CLCA2) was downregulated in 80% of colorectal tumours, although the biological significance of this repression (Bustin et al, 2001) remains to be determined. Other ion transporters, in addition to the aforementioned chloride .…”

Re-expression of Detachment-inducible Chloride Channel mCLCA5 Suppresses Growth of Metastatic Breast Cancer Cells

“…In addition to the loss of hCLCA2 in human breast cancer and the data reported herein, we also detected down-regulation of other mouse CLCA family members, mCLCA1 and -2, in mammary tumor cell lines (21) and transformed endothelial cells. 2 Others have reported the near universal down-regulation of hCLCA1 and -4 in human colon cancer biopsies when compared with autologous normal tissues (54). Whether CLCAmediated chloride currents vary with the cell cycle has not been established.…”

Network-based analysis of calcium-binding protein genes identifies Grp94 as a target in human oral carcinogenesis

“…A number of Ca 2 þ -binding proteins are thought to be implicated in establishing the malignant and metastatic phenotypes of various tumours (Chen et al, 1997;Takenaga et al, 1997;Van Ginkel et al, 1998), and recent studies have reported altered expression of several Ca 2 þ -binding protein genes in a wide range of human malignancies (Bustin et al, 2001;Pietas et al, 2002;Lakshmikuttyamma et al, 2004;Imazawa et al, 2005). Regarding oral squamous cell carcinomas (OSCCs), aberrant expression of S100 Ca 2 þ -binding protein families seen in tumour sites has been correlated with cancer cell invasion or metastasis (Moriyama-Kita et al, 2004;Tsai et al, 2005).…”