Transmembrane protein 88 (TMEM88), a newly discovered protein localized on the cell membrane.Recent studies showed that TMEM88 was involved in the regulation of several types of cancer.TMEM88 was expressed at significantly higher levels in breast cancer (BC) cell line than in normal breast cell line with co-localized with Dishevelled (DVL) in the cytoplasm of BC cell line. TMEM88 silencing in the ovarian cancer cell line CP70 resulted in significant upregulation of Wnt downstream genes (c-Myc, cyclin-D1) and other Wnt target genes including JUN, PTIX2, CTNNB1 (β-catenin), further supporting that TMEM88 inhibits canonical Wnt signaling pathway. Wnt signaling pathway has been known to play important roles in many diseases, especially in cancer. For instance, hepatocellular carcinoma (HCC) has become one of the most common tumors harboring mutations in the Wnt signaling pathway. As the inhibitor of Wnt signaling, TMEM88 has been considered to act as an oncogene or a tumor suppressor. Up-regulated TMEM88 or gene therapy approaches could be an effective therapeutic approach against tumor as TMEM88 inhibits Wnt signaling through direct interaction with DVL. Here, we review the current knowledge on the functional role and potential clinical application of TMEM88 in the control of various cancers. HighlightsWnt signaling displays an important role in several pathogenesis of cancer.Wnt signaling pathway is activated during cancer development.TMEM88 has an impact on cancer by inhibiting canonical Wnt signaling.We discuss the importance and new applications of TMEM88 in cancer therapy. K E Y W O R D Sβ-catenin, cancer, cancer therapy, TMEM88, Wnt signalling pathway Abbreviations: 1,25(OH)2D3, 1,25-Dihydroxyvitamin D3; AKT/mTOR, protein kinase B/the mammalian target of rapamycin; ATF2, Activating transcription factor 2; BC, breast cancer; CBE, clinical breast exam; CIZ1b, b-variant form of CIZ1; CK1, casein kinase 1; CRD, cystein-rich domain; CTNNB1, catenin β1; Dnmt3a, DNA (cytosine-5)-methyltransferase 3A; DVL, dishevelled; EMT, epithelial-mesenchymal transition; FAK, focal adhesion kinase; FZD, frizzled; GSK3β, glycogen synthase kinase 3β; HCC, hepatocellular carcinoma; HSCs, hematopoietic stem cells; IDCs, invasive ductal carcinomas; LC, lung cancer; LRP5, low density lipoprotein receptor-related protein-5; METTL13, methyltransferase like 13; MMP-7, matrix metalloproteinase-7; MRI, magnetic resonance imaging; NSCLC, nonsmall cell lung cancer; OC, ovarian cancer; P38, protein 38; PFS, progression-free survival; TCF/LEF, T cell factor/lymphoid enhancer factor; TCGA, the cancer genome atlas; TMEM88, transmembrane protein 88; TNBC, triple-negative breast cancer; VWV, Val-Trp-Val; Zo-1, tight junction protein 1.Yun-xuan Ge, Chang-hui Wang, and Fu-yong Hu have contribute equally to this work.
Background and Purpose Neointimal hyperplasia (NIH) is the fundamental cause for vascular diseases and vascular smooth muscle cell (VSMC) dysregulation has been widely implicated in NIH. Neutrophil elastase is a potential therapeutic target for multiple diseases. We investigated the role of neutrophil elastase in VSMC functions and injury‐induced NIH and explored the therapeutic potential of targeting neutrophil elastase in NIH. Experimental Approach VSMCs were used to analyse the effects of neutrophil elastase. Proteomic analysis was used to identify potential neutrophil elastase targets. Artery injury model and neutrophil elastase inhibitor GW311616A were used to investigate the role of neutrophil elastase in NIH. Key Results TNF‐α up‐regulated neutrophil elastase in VSMCs through modulating GAPBα/Runx1/CEBPα/c‐Myb signalling. Up‐regulated neutrophil elastase promoted VSMC migration, proliferation and inflammation. Toll‐like receptor 4 (TLR4) was identified as a target protein for neutrophil elastase in VSMCs and the TLR4/MyD88/IRAK1/TRAF6/NF‐κB regulatory axis was shown to be the signalling pathway for neutrophil elastase in VSMC pathology. Importantly, TLR4 inhibition abolished neutrophil elastase‐mediated VSMC dysregulation. Injury‐induced NIH was significantly reduced in both neutrophil elastase‐deficient mice and mice treated with GW311616A. The formation of neutrophil extracellular traps was impaired in injured arteries from neutrophil elastase‐deficient mice. Finally, a similar role for neutrophil elastase in human VSMC pathology was confirmed and we observed higher expression levels of neutrophil elastase but lower expression levels of TLR4 in human atherosclerotic lesions. Conclusion and Implications We provide new insight into the molecular mechanisms underlying NIH and identify neutrophil elastase as a potential therapeutic target for vascular disease.
Aim Pathological arterial remodelling including neointimal hyperplasia and atherosclerosis is the main underlying cause for occluding arterial diseases. Cezanne is a novel deubiquitinating enzyme, functioning as a NF-кB negative regulator, and plays a key role in renal inflammatory response and kidney injury induced by ischemia. Here we attempted to examine its pathological role in vascular smooth muscle cell (VSMC) pathology and arterial remodelling. Methods and Results Cezanne expression levels were consistently induced by various atherogenic stimuli in VSMCs, and in remodelled arteries upon injury. Functionally, VSMCs over-expressing wild-type Cezanne, but not the mutated catalytically-inactive Cezanne (C209S), had an increased proliferative ability and mobility, while the opposite was observed in VSMCs with Cezanne knockdown. Surprisingly, we observed no significant effects of Cezanne on VSMC apoptosis, NF-κB signalling, or inflammation. RNA-sequencing and biochemical studies showed that Cezanne drives VSMC proliferation by regulating CCN family member 1 (CCN1) by targeting β-catenin for deubiquitination. Importantly, local correction of Cezanne expression in the injured arteries greatly decreased VSMC proliferation, and prevented arterial inward remodelling. Interestingly, global Cezanne gene deletion in mice led to smaller atherosclerotic plaques, but with a lower level of plaque stability. Translating, we observed a similar role for Cezanne in human VSMCs, and higher expression levels of Cezanne in human atherosclerotic lesions. Conclusion Cezanne is a key regulator of VSMC proliferation and migration in pathological arterial remodelling. Our findings have important implications for therapeutic targeting Cezanne signalling and VSMC pathology in vascular diseases. Translational Perspective In this study, we have identified the deubiquitinating enzyme Cezanne as a novel regulator in governing VSMC phenotype, injury-induced neointimal hyperplasia, and hyperlipidaemia-induced atherosclerosis. Since accumulating evidence highlights an important role for VSMC dysfunctions in many cardiovascular pathological conditions including atherosclerosis, arterial remodelling, hypertension, and stroke, local modulation of this newly identified signal axis (Cezanne/β-catenin/CCN1) could represent as a novel therapy for post-angioplasty restenosis and aforementioned diseases.
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