Dysregulated cholinergic network as a novel biomarker of poor prognostic in patients with head and neck squamous cell carcinoma

Abstract

BackgroundIn airways, a proliferative effect is played directly by cholinergic agonists through nicotinic and muscarinic receptors activation. How tumors respond to aberrantly activated cholinergic signalling is a key question in smoking-related cancer. This research was addressed to explore a possible link of cholinergic signalling changes with cancer biology.MethodsFifty-seven paired pieces of head and neck squamous cell carcinoma (HNSCC) and adjacent non-cancerous tissue (ANCT) were compared for their mRNA levels for ACh-related proteins and ACh-hydrolyzing activity.ResultsThe measurement in ANCT of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities (5.416 ± 0.501 mU/mg protein and 6.350 ± 0.599 mU/mg protein, respectively) demonstrated that upper respiratory tract is capable of controlling the availability of ACh. In HNSCC, AChE and BChE activities dropped to 3.584 ± 0.599 mU/mg protein (p = 0.002) and 3.965 ± 0.423 mU/mg protein (p < 0.001). Moreover, tumours with low AChE activity and high BChE activity were associated with shorter patient overall survival. ANCT and HNSCC differed in mRNA levels for AChE-T, α3, α5, α9 and β2 for nAChR subunits. Tobacco exposure had a great impact on the expression of both AChE-H and AChE-T mRNAs. Unaffected and cancerous pieces contained principal AChE dimers and BChE tetramers. The lack of nerve-born PRiMA-linked AChE agreed with pathological findings on nerve terminal remodelling and loss in HNSCC.ConclusionsOur results suggest that the low AChE activity in HNSCC can be used to predict survival in patients with head and neck cancer. So, the ChE activity level can be used as a reliable prognostic marker.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1402-y) contains supplementary material, which is available to authorized users.

Review of emerging biomarkers in head and neck squamous cell carcinoma in the era of immunotherapy and targeted therapy

“…Among the key prognostic markers for survival, epidermal growth factor receptor (EGFR), cyclin D1(CCND1), ERCC1, p16, human papillomavirus (HPV), and B‐cell lymphoma‐extra large (Bcl‐xL)/Bcl‐2, as well as the amplification of genes including EMS1 , FGFR1 , and CCND1 have demonstrated some evidence in clinical trials. Others are slower to advance in clinical development because of unconvincing data and few published studies; for example, acetylcholinesterase(AchE), SNPs of specific genes, glutathione S‐transferase (GST), CD44, amplification of specific genes, hypoxic markers, KLK‐6, and MDA‐7/IL‐24; although, this does not preclude them from future investigations and clinical utility.…”

“…FGFR1,22 and CCND1 91-93 have demonstrated some evidence in clinical trials. Others are slower to advance in clinical development because of unconvincing data and few published studies; for example, acetylcholinesterase(AchE),64 SNPs of specific genes,19 glutathione S-transferase (GST),54 CD44,61 amplification of specific genes, 32 hypoxic markers, 35,94 KLK-6,60 and MDA-7/IL-24 72 ; although, this does not preclude them from future investigations and clinical utility.…”

Nicotinic Acetylcholine Receptors in Head and Neck Cancer and Their Correlation to Tumor Site and Progression

“…A proliferative effect is played directly by cholinergic agonists at nAChRs. Castillo-González et al [10] found that low expression of acetylcholine esterase, as a key protein in the non-neuronal cholinergic system, is associated with low prognosis and shorter survival by signaling downstream events that may favor tumor growth and aggressiveness. nAChRs of a different subunit composition lead to different signaling mechanisms [11].…”

Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation

“…Many studies recently have revealed that ACh also plays a non-neuronal role in some physiological and pathological process including inflammatory diseases89, functional bowel disorders1011, as well as several kinds of cancer1213. Several reports have indicated that ACh could act as a potential growth factor to stimulate cancer cell proliferation in lung cancer14, breast cancer15, colon cancer16 et al .…”