Muscarinic receptor M3 mediates cell proliferation induced by acetylcholine and contributes to apoptosis in gastric cancer

Wang, Linjun; Zhi, Xiaofei; Zhang, Qun; Wei, Song; Li, Zheng; Zhou, Jianping; Jiang, Jian-Guo; Zhu, Yaping; Yang, Li; Xu, Hao; Xu, Zekuan

doi:10.1007/s13277-015-4011-0

Cited by 39 publications

(40 citation statements)

References 37 publications

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“…Recent years, increasing evidences demonstrated that M3R may play a vital role in the carcinogenesis of many types of cancer, including colon cancer, lung cancer, and cholangiocarcinoma323334. Notably, in human gastric cancer tissue, M3R was over-expressed and correlated with the cancer stage and lymph node metastasis19. Those studies, combined with our preliminary data suggested that M3R plays a major role in ACh stimulated gastric cell proliferation.…”

Section: Discussionsupporting

confidence: 65%

“…9a). Our data was also consistent with Wang et al .’s study which indicated the proliferation-promoting role of ACh in gastric cancer cells19.…”

Section: Discussionmentioning

confidence: 99%

“…Very recently, Wang et al . reported that the M3 muscarinic receptor mediated ACh-induced proliferation in gastric cancer cells19. However, it’s still unclear about the concrete non-neuronal role of ACh in gastric carcinogenesis.…”

mentioning

confidence: 99%

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

Xiao

Tang

et al. 2017

Sci Rep

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Acetylcholine (ACh), known as a neurotransmitter, regulates the functions of numerous fundamental central and peripheral nervous system. Recently, emerging evidences indicate that ACh also plays an important role in tumorigenesis. However, little is known about the role of ACh in gastric cancer. Here, we reported that ACh could be auto-synthesized and released from MKN45 and BGC823 gastric cancer cells. Exogenous ACh promoted cell proliferation in a does-dependent manner. The M3R antagonist 4-DAMP, but not M1R antagonist trihexyphenidyl and M2/4 R antagonist AFDX-116, could reverse the ACh-induced cell proliferation. Moreover, ACh, via M3R, activated the EGFR signaling to induce the phosphorylation of ERK1/2 and AKT, and blocking EGFR pathway by specific inhibitor AG1478 suppressed the ACh induced cell proliferation. Furthermore, the M3R antagonist 4-DAMP and darifenacin could markedly inhibit gastric tumor formation in vivo. 4-DAMP could also significantly enhance the cytotoxic activity of 5-Fu against the MKN45 and BGC823 cells, and induce the expression of apoptosis-related proteins such as Bax and Caspase-3. Together, these findings indicated that the autocrine ACh could act through M3R and the EGFR signaling to promote gastric cancer cells proliferation, targeting M3R or EGFR may provide us a potential therapeutic strategy for gastric cancer treatment.

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Section: Discussionsupporting

confidence: 65%

“…9a). Our data was also consistent with Wang et al .’s study which indicated the proliferation-promoting role of ACh in gastric cancer cells19.…”

Section: Discussionmentioning

confidence: 99%

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

Xiao

Tang

et al. 2017

Sci Rep

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“…Our findings suggested that M3 in PDAC could play a significant role in the invasive process in vivo. Recent investigations into the functional role of M3 in carcinomas have demonstrated that the expression of M3 augmented cell motility on extracellular matrix components4–7 and promoted tumor growth in mice16,17 in addition to its effect on cancer cell proliferation 18. These findings support our hypothesis that M3 in PDAC could play a role in the invasive process and its expression could be a more malignant phenotype.…”

Section: Discussionsupporting

confidence: 88%

High expression of muscarinic acetylcholine receptor 3 predicts poor prognosis in patients with pancreatic ductal adenocarcinoma

Zhang¹,

Xiu²,

Zhan

et al. 2016

OTT

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AimsRecent studies showed that muscarinic acetylcholine receptor 3 (M3), as a muscarinic acetylcholine receptor family member that plays an important role in normal physiological function, is engaged in cancer progression. However, the role of M3 in pancreatic ductal adenocarcinoma (PDAC) is not known. The aim of this study is to investigate the expression and prognostic value of M3 in patients with PDAC.Materials and methodsThe localization and expression of M3 in PDAC were examined by immunohistochemistry. VAChT was employed to detect parasympathetic nerve fibers in the corresponding M3 PDAC tissues. The correlation between M3 expression and patients’ survival was assessed by Kaplan–Meier analysis.ResultsM3 was discovered predominantly localized in the cell cytoplasm and expressed in all specimens of PDAC patients. Significant correlation was noted between increased M3 intensity and high grade of PDAC (P<0.01), more lymph node metastasis (P<0.01) as well as shorter patient overall survival (P<0.01). Morphologically, cells with high M3 expression were more frequently located at the invasive tumor front/tumor budding cells, metastatic lymph nodes and parasympathetic nerve fibers.ConclusionHigh expression of M3 is a prognostic marker for PDAC.

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“…The immunohistochemistry method was performed as described preciously [28]. Smad3 (diluted 1:250, Abcam) was used as primary antibodies.…”

Section: Methodsmentioning

confidence: 99%

miR-424-5p promotes proliferation of gastric cancer by targeting Smad3 through TGF-β signaling pathway

Wei

et al. 2016

Oncotarget

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MiRNAs have been reported to regulate gene expression and be associated with cancer progression. Recently, miR-424-5p was reported to play important role in a variety of tumors. However, the role and molecular mechanisms of miR-424-5p in GC (gastric cancer) remains largely unknown. In this study, we aimed to explore the role of miR-424-5p in GC. QRT-PCR was used to determine the expression levels of miR-424-5p and Smad3. CCK8 assay, plate clone assay and cell cycle assay were used to measure the effects of miR-424-5p on GC cell proliferation. Luciferase reporter assay and western blotting were used to prove that Smad3 was one of the direct targets of miR-424-5p. Tumorigenesis assay was used to investigate the role of miR-424-5p in tumor growth of GC cells in vivo. We found that miR-424-5p was up-regulated in GC tissues and cells. Over-expression of miR-424-5p could promote the proliferation of GC cells. In addition, luciferase reporter assay and western blotting assay revealed that Smad3 was a direct target of miR-424-5p. Over-expression of Smad3 could partially reverse the effects of miR-424-5p on GC cell proliferation. Our study further revealed that miR-424-5p could inhibit TGF-β signaling pathway by Smad3.

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Muscarinic receptor M3 mediates cell proliferation induced by acetylcholine and contributes to apoptosis in gastric cancer

Cited by 39 publications

References 37 publications

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

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

High expression of muscarinic acetylcholine receptor 3 predicts poor prognosis in patients with pancreatic ductal adenocarcinoma

miR-424-5p promotes proliferation of gastric cancer by targeting Smad3 through TGF-β signaling pathway

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