Metabotropic Glutamate Receptor 4 Expression in Colorectal Carcinoma and Its Prognostic Significance

Abstract

Purpose: Metabotropic glutamate receptors (mGluR) play a variety of roles in both neuronal and nonneuronal cells. Recently, we reported that mGluR4 mediates 5-fluorouracil resistance in a human colon cancer cell line. In this study, we evaluated the nonneural expression of mGluR4 and clarified the existence of mGluR4 in normal colon epithelium and colorectal carcinomas. We also investigated the association of mGluR4 expression levels with various clinicopathologic parameters. Experimental Design: mGluR4 expression was investigated in 21 normal and 312 malignant tissues from various organs using immunohistochemistry. In addition, 241 cases of colorectal carcinomas were examined and correlations between mGluR4 expression and various clinicopathologic parameters were then statistically analyzed. Results: Expression of mGluR4 was identified in the normal epithelia of the upper respiratory tract, gastrointestinal tracts, breast, uterine cervix, urinary bladder, and skin, whereas it was not detected in the thyroid, lung alveoli, liver, testis, or prostate. In the corresponding malignant tissues, mGluR4 expression was frequently identified in colorectal carcinoma (68%), followed by malignant melanoma, laryngeal carcinoma, and breast carcinomas. Expression of mGluR4 was detected in131 (54%) of 241colorectal carcinomas and12 (5%) cases among them showed overexpression in their cytoplasms. Loss of mGluR4 expression was negatively associated with tumor differentiation (P = 0.028), whereas overexpression of mGluR4 was positively associated with recurrence (P = 0.034) and poor disease-free survival (P = 0.017) in multivariate analyses. Conclusions: Our results suggest that mGluR4 signaling may play a role in colorectal carcinomas and that overexpression of mGluR4 is associated with poor prognosis.

Metabotropic Glutamate Receptors in Peripheral Tissues: Implications for Toxicology

“…In addition, strong immunoreactivity for mGluR2/3 was observed in granular cells of the afferent arteriole (Gill & Pulido, 2001), indicating a possible role in the control of renin release, a hormone which belongs to the renin-angiotensin system involved in regulation of electrolyte, fluid balance and blood pressure (Jackson et al, 1985). In human kidney, focal expression of mGluR4 was detected in the collecting duct (Chang et al, 2005), whereas positivity of a normal mouse glomerulus for mGluR7 was found along the glomerular basement membrane (Rastaldi et al, 2006).…”

“…The presence of mGluR2/3 and mGluR1/5 has been demonstrated in neurons of jejunum and ileum, suggesting that they may play a role in the regulation of intestinal motility (Larzabal et al, 1999;Liu & Kirchgessner, 2000;Nasser et al, 2007). On the other hand, mGluR4 and mGluR7 are expressed in colon mucosa (Chang et al, 2005;Julio-Peper et al, 2010). Activation of mGluR7 in the colon could be a component of secretory disorders such as stress-induced diarrhea (Julio-Peper et al, 2010).…”

“…Likewise, in rat ovary, the oocyte showed intense staining for mGluR2/3, whereas the corpus luteum was moderately immunoreactive (Gill & Pulido, 2001). mGluR4 has been found in the human cervix and is weakly expressed in the endometrial glands (Chang et al, 2005). mGluR2/3 show positive immunoreactivity for the most superficial layer of the stratified squamous epithelium of the exocervix in rat uterus (Gill & Pulido, 2001).…”

Understanding Melanocyte Transformation – A Work in Progress

“…Aberrant glutamate signaling also plays roles in patho-physiological diseases such as chronic pain, depression and anxiety (Swanson, Bures et al 2005). Recently, glutamate signaling has been shown to be involved in various neoplasms including gliomas, colon cancer, breast carcinomas and melanoma (Albasanz, Ros et al 1997;Pollock, Cohen-Solal et al 2003;Chang, Yoo et al 2005). Metabotropic glutamate receptors transduce glutamate induced signaling through the activation of heterotrimeric G-proteins.…”

Metabotropic glutamate receptors regulate differentiation of embryonic stem cells into GABAergic neurons

“…9 Individual mGlu receptors have been detected in cancer cells both inside and outside the CNS. [10][11][12][13] In addition, mGlu receptor subtypes with a long C-terminal domain are endowed with 'constitutive activity', and are therefore active in the absence of extracellular glutamate. 14 These data suggest that mGlu receptors are involved in the regulation of general processes of cell biology that are common to developing cells, cells of peripheral organs, and cancer cells.…”