Inhibition of NEDD4 inhibits cell growth and invasion and induces cell apoptosis in bladder cancer cells

Wen, Wu; Li, Jingying; Wang, Longwang; Xing, Yifei; Li, Xuechao; Ruan, Hailong; Xi, Xiaoqing; Xiong, Jie; Kuang, Renrui

doi:10.1080/15384101.2017.1338220

Cited by 30 publications

(25 citation statements)

References 34 publications

(44 reference statements)

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“…It was reported that NEDD4 is frequently overexpressed in many types of human cancers and always negatively regulate tumor suppressor PTEN [18,24,[39][40][41]. One study showed that depletion of NEDD4 inhibited cell proliferation in bladder cancer cells [42]. Our study here demonstrated that NEDD4 overexpression could favorite HCC cells proliferation, migration and invasion, and inhibited apoptosis.…”

Section: Discussionsupporting

confidence: 65%

NEDD4 promotes cell growth and motility in hepatocellular carcinoma

Zheng

et al. 2018

Cell Cycle

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Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. In China, the situation is even worse as cancer incidence and mortality continue to increase rapidly. Although tremendous progress has been made toward HCC treatments, the benefits for liver cancer patients are still limited. Therefore, it is necessary to identify and develop novel therapeutic methods. Neuronally expressed developmentally downregulated 4 (NEDD4), an E3 ubiquitin ligase, plays a critical role in the development and progression of various types of human cancers. In our study, NEDD4 acts as an oncoprotein in both QGY7703 and SMMC7721 liver cancer cell lines. We found that depletion of NEDD4 by siRNA transfection led to inhibition of cell growth, invasion and migration, and promotion of apoptosis. In contrast, overexpression of NEDD4 via plasmid transfection resulted in facilitated cell proliferation, invasion and migration, and decreased apoptosis. Importantly, we observed that tumor suppressor LATS1, also a core component of Hippo pathway, was negatively regulated by NEDD4 in liver cancer cells. Our findings suggested that NEDD4 may be involved in the HCC progression via regulating LATS1 associated signaling pathway. Therefore, targeting NEDD4-LATS1 signaling could be a potential therapeutic option for HCC treatment.

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Section: Discussionsupporting

confidence: 65%

NEDD4 promotes cell growth and motility in hepatocellular carcinoma

Zheng

et al. 2018

Cell Cycle

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“…Up-regulation of NEDD4 mediates cell migration in lung cancer cells. Down-regulation of NEDD4 inhibits cell growth and invasion, and induces cell apoptosis in bladder cancer cells [39][40][41]. These evidences supported the anticancer function of JAC1 as an indirect inhibitor on NEDD4.…”

Section: Discussionsupporting

confidence: 53%

The Agonist of JWA Gene JAC1 Suppresses Proliferation of Breast Cancer Through the JWA/p38/SMURF1/HER2 Signaling

Ren

Chen²,

Chen

et al. 2020

Preprint

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Background The overexpression of HER2 is associated with malignant proliferation and invasiveness in breast cancer. Although HER2-targeting drugs have been clinically applied for cancer treatment, none of them could reduce overexpressed HER2. In this study, we reported that JAC1 could suppress proliferation of breast cancer cells via degrading HER2. Methods JWA-HER2 association was analyzed by IHC in 90 paired cases of breast cancer and adjacent non-cancerous tissues. Regulatory effect of JAC1, the agonist of JWA gene, on HER2-positive breast cancer cells was studied using colony formation assay. The effect of JAC1 on the localization of HER2 was detected by immunofluorescence microscopy assay. Western blotting, RT-PCR and immunoprecipitation assay were utilized to investigate the mechanisms of JWA on regulating HER2. Finally, xenograft mouse models were established in nude mice using BT474 cells to confirm the effect of JAC1 in vivo. Results JAC1, a small molecule agonist of JWA gene, dose-dependently suppressed proliferation in HER2-positive breast cancer in vitro and in vivo through degrading HER2. The mechanistic evidences showed that JAC1 increased the ubiquitination of HER2 at the K716 through the E3 ubiquitin ligase SMURF1. Furthermore, SMURF1 was activated due to reduced expression of NEDD4, an E3 ubiquitin ligase for SMURF1 through the JWA-p38-GATA-1-NEDD4 axis. Conclusions JAC1 suppresses the proliferation in HER2-positive breast cancer through the JWA/p38/GATA-1/NEDD4/SMURF1/HER2 signaling. JAC1 may serve as a novel therapeutic agent to breast cancer.

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“…NEDD4 has a role in promoting the growth of hepatocellular [32] and bladder cancer cell lines [33]. To determine the role of NEDD4 in BC growth, we first examined how NEDD4 expression affects cell growth using BC cell lines from different BC subtypes.…”

Section: Resultsmentioning

confidence: 99%

NEDD4 expression is associated with breast cancer progression and is predictive of a poor prognosis

et al. 2019

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BackgroundA role for neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4) in tumorigenesis has been suggested. However, information is lacking on its role in breast tumor biology. The purpose of this study was to determine the role of NEDD4 in the promotion of the growth and progression of breast cancer (BC) and to evaluate the clinicopathologic and prognostic significance of NEDD4.MethodsThe impact of NEDD4 expression in BC cell growth was determined by Cell Counting Kit-8 and colony formation assays. Formalin-fixed paraffin-embedded specimens were collected from 133 adjacent normal tissues (ANTs), 445 BC cases composed of pre-invasive ductal carcinoma in situ (DCIS, n = 37), invasive ductal carcinomas (IDC, n = 408, 226 without and 182 with lymph node metastasis), and 116 invaded lymph nodes. The expression of NEDD4 was analyzed by immunohistochemistry. The association between NEDD4 expression and clinicopathological characteristics was analyzed by chi-square test. Survival was evaluated using the Kaplan–Meier method, and curves were compared using a log-rank test. Univariate and multivariate analyses were performed using the Cox regression method.ResultsNEDD4 promoted BC growth in vitro. In clinical retrospective studies, 16.5% of ANTs (22/133) demonstrated positive NEDD4 staining. Strikingly, the proportion of cases showing NEDD4-positive staining increased to 51.4% (19/37) in DCIS, 58.4% (132/226) in IDC without lymph node metastasis, and 73.1% (133/182) in BC with lymph node metastasis (BCLNM). In addition, NEDD4-positive staining was associated with clinical parameters, including tumor size (P = 0.030), nodal status (P = 0.001), estrogen receptor status (P = 0.035), and progesterone receptor status (P = 0.023). Moreover, subset analysis in BCLNM revealed that high NEDD4 expression correlated with an elevated risk of relapse (P = 0.0276). Further, NEDD4 expression was an independent prognostic predictor. Lastly, the rates for 10-year overall survival and disease-free survival were significantly lower in patients with positive NEDD4 staining than those in BC patients with negative NEDD4 staining BC (P = 0.0024 and P = 0.0011, respectively).ConclusionsNEDD4 expression is elevated in BC and is associated with BC growth. NEDD4 correlated with clinicopathological parameters and predicts a poor prognosis. Thus, NEDD4 is a potential biomarker of poor prognosis and a potential therapeutic target for BC treatment.

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Inhibition of NEDD4 inhibits cell growth and invasion and induces cell apoptosis in bladder cancer cells

Cited by 30 publications

References 34 publications

NEDD4 promotes cell growth and motility in hepatocellular carcinoma

NEDD4 promotes cell growth and motility in hepatocellular carcinoma

The Agonist of JWA Gene JAC1 Suppresses Proliferation of Breast Cancer Through the JWA/p38/SMURF1/HER2 Signaling

NEDD4 expression is associated with breast cancer progression and is predictive of a poor prognosis

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