The Expression of NMDA Receptor 1 Correlates with Clinicopathological Parameters in Cutaneous Squamous Cell Carcinoma

Abstract

Background: Ionotropic glutamate receptors of the N-methyl-D-aspartate receptor (NMDAR) type are expressed on keratinocytes and play a role in the proliferation, differentiation, and cornification of keratinocytes. However, the expression profile of NMDAR and its role in cutaneous malignancy is unclear. Objective: We analyzed the expression of NMDAR-1 in cutaneous squamous cell carcinoma (SCC) and investigated the relationship between NMDAR-1 expression and clinicopathological parameters. Methods: Thirty-two patients with biopsy-proven cutaneous SCC were enrolled in this study. Each patient was analyzed for tumor diameter, location, local recurrence, and metastasis by conducting a chart review. The SCC specimens were histologically divided into differentiated and undifferentiated groups based on Broders' system. NMDAR-1 expression was examined by performing immunohistochemistry, and the relative staining intensity in the SCCs was graded into 5 levels. According to the staining intensity of NMDAR-1, the specimens were categorized into two groups: the higher group and the lower group. Results: Fifteen (88%) of 17 tumors in the higher group were differentiated SCC, whereas 14 (93%) of 15 tumors in the lower group were undifferentiated SCC. In addition, NMDAR-1 expression was inversely correlated with metastasis (p=0.049). Local recurrence was associated with a lower staining intensity, but the results were not statistically significant. Conclusion: Our results demonstrate that NMDAR-1 expression in cutaneous SCC is significantly correlated with its differentiation and metastasis. Therefore, it may be a prognostic indicator for cutaneous SCC. INTRODUCTIONGlutamate is an essential amino acid and neurotransmitter in the central nervous system (CNS). It plays a major role in excitotoxicity as well as in learning and memory. In addition, it functions as a trophic factor for cancer cells in vitro 1 , suggesting an involvement of glutamate and its receptors in tumor cell proliferation and migration. Glutamate activates various glutamate receptors, including N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, kainite, and metabotropic receptors 2,3 . NMDAR has two distinct subunits: the main subunit, NMDAR-1, and the modulatory subunit, NMDAR 2A-2D. NMDAR-1 is essential and sufficient to form an active NMDA receptor channel, in contrast to the NMDAR-2 subunits 4 . The NMDAR is a ligand-gated ion-channel that is permeable to the cations Na ＋ , K ＋ , and most importantly, Ca 2＋ .Although the expression of the glutamate receptor was initially restricted to the CNS, glutamate signaling occurs in non-neuronal tissues such as bone, pancreas, and skin, raising the possibility of a more widespread glutamate receptor activity 5 . Moreover, NMDAR-1 is expressed on keratinocytes 6 . NMDAR-1 expression increased with keratinocytic differentiation in the epidermis of normal human These results suggest that NMDAR could play a role in the proliferation and differentiation of normal keratinocytes. In ad...

Glutamate receptor, ionotropic, N‑methyl D‑aspartate‑associated protein 1 promotes colorectal cancer cell proliferation and metastasis, and is negatively regulated by miR‑296‑3p

“…Survival analysis demonstrated that upregulated GRINA expression was associated with worse OS in patients with CRC. These results were consistent with previous studies ( 7 , 18 , 19 ). Collectively, these results highlighted the potential role of GRINA in the development and progression of CRC.…”

“…Aberrant NMDAR expression has been detected in several types of cancer, including oral squamous cell carcinoma (OSCC), cutaneous squamous cell carcinoma, prostate cancer and GC ( 17 ). NMDAR1 (a glutamate receptor) expression in cutaneous squamous cell carcinoma is significantly associated with cancer metastasis and differentiation ( 18 ). In OSCC, NMDAR1 upregulation is significantly associated with cancer stage, lymph node metastasis and tumor size ( 19 ).…”

Physiological Roles of Non-Neuronal NMDA Receptors

“…GluN1 expression in oral squamous cell carcinoma significantly correlated with tumor size, incidence of lymph node metastasis. and cancer stage [140,141], while GluN1 silencing reduced cancer cell proliferation [142]. This suggests that GluN1 expression may predict poor patient outcome.…”

“…GRIN2A and GRIN2B hypermethylation inversely correlated with GluN2A and GluN2B expression levels, and was associated with increased cancer cell proliferation and colony formation in vitro [143,144]. In [129,198] Small-cell GluN1; GluN2A-C [134] Connective tissue (muscle, bone) Sarcoma GluN1; GluN2A-D; GluN3A,B [198] Thyroid Carcinoma GluN1; GluN2B-D; GluN3A,B [198] Plasma cell Multiple myeloma GluN1; GluN2A-D [198] Colon/rectum Adenocarcinoma GluN1; GluN2A-D; GluN3A [129,138,198,199] T cell Leukemia GluN2A-D; GluN3A [198] Breast Adenocarcinoma GluN1; GluN2A-D; GluN3A [126,129,198] Ovaries Cystadenocarcinoma GluN1; GluN2B [202] Endometrioid adenocarcinoma GluN1; GluN2B [202] Clear-cell carcinoma GluN1; GluN2B [202] Megakaryoblasts Leukemic megarkaryoblasts GluN1; GluN2A-D; GluN3A,B [132] Oral cavity Squamous cell carcinoma GluN1 [140,141] Larynx Squamous cell carcinoma GluN1; GluN2A-D; GluN3A [136] Bone Osteosarcoma GluN1; GluN2A,B,D; GluN3A [203] accordance, ectopic GluN2B overexpression induced NMDAR-mediated apoptosis in gastric [144] and esophageal squamous cell carcinoma cells [143], and GluN2A overexpression stimulated colorectal cancer cell death [146]. In addition, whole-exome sequencing in malignant melanoma tumor samples revealed a significant prevalence of clustered mutations within GRIN2A functional domains, leading to truncated GluN2A [147], reduced NMDAR complex formation, and increased cancer cell growth, migration [148], and disease progression [149].…”