Mucin 17 inhibits the progression of human gastric cancer by limiting inflammatory responses through a MYH9-p53-RhoA regulatory feedback loop

Abstract

Background Mucins are key components of the mucosal barrier in the stomach that protects epithelia from carcinogenic effects of chronic inflammation. Analysis of The Cancer Genome Atlas database indicated that mucin-17 (MUC17) was more highly expressed in gastric cancer (GC) specimens, with favourable prognosis for patients. To explore the underlying mechanisms, we investigated the potential role of MUC17 in controlling chronic gastric inflammation. Methods We initially quantified the expression of MUC17 and inflammatory factor, as well as the association of MUC17 with survive in GC using immunohistochemistry. To establish how the inflammatory factors affect MUC17 expression, we explored luciferase reporter, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift (EMSA) assays. The role and mechanism that MUC17 plays in inflammation-induced cell proliferation was examined in AGS cells with reduced MUC17 expression and MKN45 cells overexpressing a truncated MUC17 . Results We found MUC17 was induced by inflammatory cytokines in GC cells via CDX1upregulation. MUC17 thus inactivated NFκB to inhibit GC cell proliferation in response to pro-inflammatory cytokines. We also revealed that the function of MUC17 was dependent on its conserved epidermal growth factor domain and on downstream sequences to enable its interaction with myosin-9, resulting in a sustained regulatory feedback loop between myosin-9, p53, and RhoA, and then activation of p38 to negatively regulate the NFκB pathway in GC cells. This mechanism was also confirmed in vivo. Conclusions Our study demonstrates MUC17 as a GC suppressor protein which has the therapeutic potential for human GC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1279-8) contains supplementary material, which is available to authorized users.

Neuron-derived exosomes-transmitted miR-124-3p protect traumatically injured spinal cord by suppressing the activation of neurotoxic microglia and astrocytes

“…Western blot analysis found that the MYH9 protein level was downregulated when overexpressing miR-124-3p and upregulated with the knockdown of miR-124-3p in microglia, which further confirmed that MYH9 was the target downstream gene of miR-124-3p. MYH9 has been demonstrated to show a positive role in cell inflammation [38,47]. Additionally, MYH9 has been identified to participate in BBB dysfunction in ischemic stroke and to mediate oxidative stress-induced neuronal apoptosis [48,49].…”

“…It was found that myosin heavy chain 9 (MYH9) may be the potential target related to inflammation attenuation (Additional file 2: Figure S1). Moreover, MYH9 has been demonstrated to show a positive role in endothelial cell inflammation [38]. To verify that MYH9 3′UTR is a direct target for miR-124-3p, wild-type (WT) and mutated (MUT) 3′-UTR sequences of MYH9 were constructed (Fig.…”

Comprehensive Cohort Analysis of Mutational Spectrum in Early Onset Breast Cancer Patients

“…In their study, TTN was ranked as the single most prevalent gene among 518 protein kinase genes in 210 different human cancers associated with an extremely high density of cancer driver mutations [ 49 ]. On the other hand, although mucins are essential components of the mucous layer in extracellular space, mucins were also known to be involved in inflammation and cancer [ 50 ], while Mucin 17 was further found to inhibit the progression of human gastric cancer [ 51 ].…”

Identification of crucial genes in metastatic osteosarcoma and prognostic biomarker in osteosarcoma patients

“…None of the other three prognostic genes (MUC17, TAC4, OR8G5) have been reported in osteosarcoma, but MUC17 and TAC4 have been shown to play an important role in many cancers. MUC17 was more highly expressed in gastric cancer, and inhibited the progression of gastric cancer through a MYH9-p53-RhoA regulatory feedback loop to limited im ammatory responses [20]. TAC4 was a member of the tachykinin family of neurotransmitter-encoding genes.…”