Promoter methylation of Wnt/β-Catenin signal inhibitor <i>TMEM88</i> is associated with unfavorable prognosis of non-small cell lung cancer

Ma, Rongna; Feng, Na; Yu, Xiao; Lin, Hongyan; Zhang, Xiaohong; Shi, Oumin; Zhang, Huan; Zhang, Shuo; Li, Lei; Zheng, Min; Gao, Ming; Yu, Herbert; Qian, Biyun

doi:10.20892/j.issn.2095-3941.2017.0061

Cited by 23 publications

(12 citation statements)

References 26 publications

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“…TMEM88 was first identified in silico as a PDZ-domain-binding protein (Lee et al., 2010), based on the presence of a VWV motif that was known to interact with DVL. This led naturally to the investigation of its ability to modulate Wnt signaling, which was confirmed in reporter assays (Lee et al., 2010), of potential significance given the association of TMEM88 expression patterns described in various human neoplasias (Ma et al., 2017, Yu et al., 2015, Zhang et al., 2015). However, whether the impact of TMEM88 on Wnt signaling is actually mediated through interaction with DVL had not been previously tested.…”

Section: Discussionmentioning

confidence: 94%

TMEM88 Inhibits Wnt Signaling by Promoting Wnt Signalosome Localization to Multivesicular Bodies

Lee

Evans

2019

iScience

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Summary Wnt/β-catenin signaling is regulated in a bimodal fashion during cardiogenesis. Signaling is initially required to promote generation of precardiac mesoderm, but subsequently must be repressed for cardiac progenitor specification. TMEM88 was discovered recently as a negative regulator during the later phase of cardiac progenitor specification, but how TMEM88 functions was unknown. Based on a C-terminal PDZ-binding motif, TMEM88 was proposed to act by targeting the PDZ domain of Dishevelled, the positive Wnt signaling mediator. However, we discovered that TMEM88 acts downstream of the β-catenin destruction complex and can inhibit Wnt signaling independent of Dishevelled. TMEM88 requires the PDZ-binding motif for trafficking from Golgi to the plasma membrane and is also found in the multivesicular body (MVB) associated with the endocytosed Wnt signalosome. Expression of Tmem88 promotes association of the Wnt signalosome including β-catenin to the MVB, leading to reduced accumulation of nuclear β-catenin and repression of Wnt signaling.

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Section: Discussionmentioning

confidence: 94%

TMEM88 Inhibits Wnt Signaling by Promoting Wnt Signalosome Localization to Multivesicular Bodies

Lee

Evans

2019

iScience

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“…The increase in membrane-associated TMEM88 expression also led to a decrease of proliferation, colony formation, migration and invasion and to a decrease in tumor growth in vivo highlighting the tumor suppressor role of TMEM88 when it is localized to the membrane of the cell. Furthermore, TMEM88 promoter methylation is associated with unfavorable prognosis in NSCLC (Ma et al, 2017). On the contrary, its cytosolic localization is correlated with a low level of differentiation of the tumor and poor prognosis of patients with NSCLC.…”

Section: Part 2: Tmems As Oncogenesmentioning

confidence: 99%

TMEM Proteins in Cancer: A Review

2018

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A transmembrane protein (TMEM) is a type of protein that spans biological membranes. Many of them extend through the lipid bilayer of the plasma membrane but others are located to the membrane of organelles. The TMEM family gathers proteins of mostly unknown functions. Many studies showed that TMEM expression can be down- or up-regulated in tumor tissues compared to adjacent healthy tissues. Indeed, some TMEMs such as TMEM48 or TMEM97 are defined as potential prognostic biomarkers for lung cancer. Furthermore, experimental evidence suggests that TMEM proteins can be described as tumor suppressors or oncogenes. TMEMs, such as TMEM45A and TMEM205, have also been implicated in tumor progression and invasion but also in chemoresistance. Thus, a better characterization of these proteins could help to better understand their implication in cancer and to allow the development of improved therapy strategies in the future. This review gives an overview of the implication of TMEM proteins in cancer.

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“…Metastasis is the major cause of the poor prognosis of NSCLC ( 48 ). Accumulating evidence has revealed that multiple TMEM proteins, such as TMEM209A ( 19 ), TMEM88 ( 20 , 21 ), TMEM106A ( 22 ), TMEM17 ( 23 ), TMEM98 ( 49 ) and TMEM48 ( 50 ), can serve as prognostic markers for NSCLC. In the present study, survival analysis using the Kaplan-Meier Plotter online bioinformatics datasets revealed that patients with low TMEM229A expression had a poorer prognosis compared with those with high TMEM229A expression, suggesting that TMEM229A could be considered as a prognostic marker for patients with NSCLC.…”

Section: Discussionmentioning

confidence: 99%

“…For example, TMEM209, localized to the nuclear envelope and in the cytoplasm of lung cancer cells, is upregulated in lung cancer and promotes cell proliferation and tumor progression by interacting with nucleoporin 205 kDa ( 19 ). TMEM88 is a Wnt regulatory protein, and its cytosolic form and the methylation of TMEM88 are highly expressed in lung cancer, which accelerates the tumorigenesis and progression of lung cancer ( 20 , 21 ). Moreover, Liu and Zhu ( 22 ) reported that TMEM106A was lowly expressed in NSCLC and suppressed cell proliferation, migration and invasion, as well as induced cell apoptosis via the PI3K/AKT/NF-κB signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

TMEM229A suppresses non‑small cell lung cancer progression via inactivating the ERK pathway

Zhang

Jiang

et al. 2021

Oncol Rep

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Transmembrane protein 229A (TMEM229A) is a member of the TMEM family that plays an important role in tooth differentiation and development. However, the expression level and biological role of TMEM229A in cancer remains unknown. The present study aimed to investigate the expression level of TMEM229A in non-small cell lung cancer (NSCLC), as well as its effect and mechanism on NSCLC progression. Clinical specimens from patients with NSCLC were enrolled from the First People's Hospital of Huzhou (Huzhou, China). TMEM229A expression was detected using reverse transcription-quantitative PCR (RT-qPCR), western blotting and immunohistochemical analysis. The relationship between TMEM229A expression and the survival rate of patients with NSCLC was analyzed using Kaplan-Meier Plotter datasets. The effects of TMEM229A on cell proliferation, migration and invasion were detected using Cell Counting Kit-8, colony formation, soft agar, real-time cellular analysis and Transwell assays. The expression levels of epithelial-mesenchymal transition (EMT)-related proteins, as well as ERK and AKT phosphorylation were determined via RT-qPCR and western blot analysis. The results demonstrated that TMEM229A expression was significantly downregulated in human NSCLC tissues and in several cell lines compared with adjacent normal lung tissues and BEAS-2B cells, respectively. Survival analysis of lung adenocarcinoma and squamous cell lung carcinoma cases identified that low TMEM229A expression was associated with a poor prognosis. The in vitro assays indicated that overexpressing TMEM229A significantly inhibited cell proliferation, migration and invasion, while TMEM229A knockdown had the opposite effect. Mechanistically, TMEM229A overexpression effectively increased E-cadherin expression and reduced N-cadherin, snail family transcriptional repressor 1 and MMP2 expression, indicating that EMT was suppressed. In addition, overexpression of TMEM229A reduced the expression levels of phosphorylated (p)-ERK and p-AKT, and this effect was partially suppressed by the incorporation of specific ERK inhibitor PD98059. Collectively, the results of the present study demonstrated that the effects of TMEM229A on inhibiting cell proliferation, migration and invasion were partially mediated by inactivating the ERK signaling pathway, thereby providing a potential therapeutic target for the treatment of NSCLC.

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Promoter methylation of Wnt/β-Catenin signal inhibitor TMEM88 is associated with unfavorable prognosis of non-small cell lung cancer

Cited by 23 publications

References 26 publications

TMEM88 Inhibits Wnt Signaling by Promoting Wnt Signalosome Localization to Multivesicular Bodies

TMEM88 Inhibits Wnt Signaling by Promoting Wnt Signalosome Localization to Multivesicular Bodies

TMEM Proteins in Cancer: A Review

TMEM229A suppresses non‑small cell lung cancer progression via inactivating the ERK pathway

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