Correlation of NEDD4-1 and PTEN expression with the invasive capacity of pituitary adenomas

Zhang, Jing; Li, Xin; Zhang, Yanyan

doi:10.3892/mco.2016.1092

Cited by 4 publications

(2 citation statements)

References 24 publications

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“…12 The PTEN-PI3K/AKT signaling pathway plays important roles in mediating cancer cell migration or invasion. 13–15 However, the relationship between the invasiveness of PitNET and the LAMA2/PTEN-PI3K/AKT signaling pathway requires further investigation.…”

Section: Introductionmentioning

confidence: 99%

Expression and methylation status of LAMA2 are associated with the invasiveness of nonfunctioning PitNET

Wang

Lan

Lou

et al. 2019

Therapeutic Advances in Endocrinology

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The laminin subunit alpha 2 (LAMA2) gene encodes an alpha 2 chain, which constitutes one of the subunits of laminin 2 (merosin) and laminin 4 (s-merosin). In the current study, we investigated the relationship between LAMA2 promoter methylation status and the invasiveness of clinically nonfunctioning pituitary adenomas (PitNETs). Specimens from patients with nonfunctioning PitNET were classified into three groups according to preoperative computed tomography (CT)/magnetic resonance imaging findings: a normal group (n = 6), non-invasive group (n = 11) and invasive group (n = 6). LAMA2 expression was assessed using quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting, and the methylation status of the LAMA2 promoter region was observed using sodium bisulfite sequencing. Furthermore, 5-aza-2-deoxycytidine was used to explore the relationship between decreased LAMA expression and methylation in PitNET cells. According to the RT-qPCR and western blotting results, LAMA2 expression was downregulated in invasive PitNET, while the methylation of the LAMA2 promoter was increased. Methylation of the LAMA2 promoter decreased the expression of LAMA2. Thus, changes in LAMA2 expression due to promoter methylation were inversely correlated with the invasiveness of PitNET and the protein functions as a tumor suppressor. In addition, overexpression and demethylation of LAMA2 suppressed the invasion of PitNET cells, partially by exerting effects on the PTEN-PI3K/AKT signaling pathway and matrix metalloproteinase-9 (MMP-9). Furthermore, a xenograft model was also generated, and LAMA2 overexpression significantly suppressed tumor growth in vivo. Thus, LAMA2 expression and methylation patterns might be used as biomarkers to predict the prognosis of patients with PitNET.

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Section: Introductionmentioning

confidence: 99%

Expression and methylation status of LAMA2 are associated with the invasiveness of nonfunctioning PitNET

Wang

Lan

Lou

et al. 2019

Therapeutic Advances in Endocrinology

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“…Among these cues, the PI3K/AKT/mTOR signaling pathway is one of the main perpetrators that maintains and enhances the population of CSCs in various cancers [ 12 , 13 , 14 ]. Thus, through this study, we investigated the role of neuronal precursor cell-expressed developmentally downregulated 4-1 (NEDD4-1), a founding member of the NEDD4 family of E3 ubiquitin ligase, known for its ubiquitination activity on molecule phosphatase and tensin homolog (PTEN), one of the main regulators of the PI3K/AKT/mTOR signaling axis [ 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

The E3 Ubiquitin Ligase NEDD4-1 Mediates Temozolomide-Resistant Glioblastoma through PTEN Attenuation and Redox Imbalance in Nrf2–HO-1 Axis

Chuang

Hsu

Pan

et al. 2021

IJMS

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Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is highly resistant to chemotherapy, and tumor recurrence is common. Neuronal precursor cell-expressed developmentally downregulated 4-1 (NEDD4-1) is an E3 ligase that controls embryonic development and animal growth. NEDD4-1 regulates the tumor suppressor phosphatase and tensin homolog (PTEN), one of the major regulators of the PI3K/AKT/mTOR signaling axis, as well as the response to oxidative stress. Methods: The expression levels of NEDD4-1 in GBM tissues and different cell lines were determined by quantitative real-time polymerase chain reaction and immunohistochemistry. In vitro and in vivo assays were performed to explore the biological effects of NEDD4-1 on GBM cells. Temozolomide (TMZ)-resistant U87MG and U251 cell lines were specifically established to determine NEDD4-1 upregulation and its effects on the tumorigenicity of GBM cells. Subsequently, miRNA expression in TMZ-resistant cell lines was investigated to determine the dysregulated miRNA underlying the overexpression of NEDD4-1. Indole-3-carbinol (I3C) was used to inhibit NEDD4-1 activity, and its effect on chemoresistance to TMZ was verified. Results: NEDD4-1 was significantly overexpressed in the GBM and TMZ-resistant cells and clinical samples. NEDD4-1 was demonstrated to be a key oncoprotein associated with TMZ resistance, inducing oncogenicity and tumorigenesis of TMZ-resistant GBM cells compared with TMZ-responsive cells. Mechanistically, TMZ-resistant cells exhibited dysregulated expression of miR-3129-5p and miR-199b-3p, resulting in the induced NEDD4-1 mRNA-expression level. The upregulation of NEDD4-1 attenuated PTEN expression and promoted the AKT/NRF2/HO-1 oxidative stress signaling axis, which in turn conferred amplified defense against reactive oxygen species (ROS) and eventually higher resistance against TMZ treatment. The combination treatment of I3C, a known inhibitor of NEDD4-1, with TMZ resulted in a synergistic effect and re-sensitized TMZ-resistant tumor cells both in vitro and in vivo. Conclusions: These findings demonstrate the critical role of NEDD4-1 in regulating the redox imbalance in TMZ-resistant GBM cells via the degradation of PTEN and the upregulation of the AKT/NRF2/HO-1 signaling pathway. Targeting this regulatory axis may help eliminate TMZ-resistant glioblastoma.

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Advancements in Molecular Diagnosis and Pharmacotherapeutic Strategies for Invasive Pituitary Adenomas

Xu,

Wang,

Zheng

2024

Immunity Inflam & Disease

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BackgroundThe overwhelming majority of pituitary tumors consist of pituitary adenomas (PAs), which have recently also been termed pituitary neuroendocrine tumors (PitNETs). Clinically significant PAs occur in approximately one in every 1000 individuals, while other types of pituitary tumors, such as craniopharyngiomas and pituicytomas, are significantly less common. Although PAs are generally benign, a subset of them exhibits malignant‐like biological traits. They tend to infiltrate and grow aggressively into adjacent tissues and organs, including the dura mater, cavernous sinus, and sphenoid sinus. This invasive behavior often results in the destruction of the normal anatomical architecture of the sella turcica and skull base. Clinically, such tumors are classified as invasive PAs (IPAs), emphasizing their aggressive and destructive nature.Objective and SignificanceCurrently, the diagnostic indicators for IPAs frequently suffer from suboptimal sensitivity and specificity. The invasiveness assessment of PAs lacks a definitive gold standard and instead serves as a predictive tool, with a greater number of indicators met suggesting a higher likelihood of invasiveness. Consequently, a comprehensive approach that integrates imaging, pathological, molecular biological, and other disciplinary metrics is crucial for accurate evaluation. Despite surgery being the primary treatment modality for IPAs, their malignant‐like behavior complicates complete resection, resulting in lower resection rates and heightened postoperative recurrence, necessitating multiple surgeries. Therefore, adjunctive drug therapy is often necessary for IPA patients. Preoperative drug therapy can shrink tumor size, facilitating resection and postoperative recovery, mitigating hormone imbalances, delaying recurrence, and enhancing patients' quality of life.ConclusionsThis article comprehensively reviews the diagnostic criteria for assessing the invasiveness of PAs in the domains of imaging, pathology, and molecular biology, provides an overview of the current research status of drug therapy for these conditions, and deepens our insight into the biological and therapeutic aspects of the tumor microenvironment in PAs.

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Correlation of NEDD4-1 and PTEN expression with the invasive capacity of pituitary adenomas

Cited by 4 publications

References 24 publications

Expression and methylation status of LAMA2 are associated with the invasiveness of nonfunctioning PitNET

Expression and methylation status of LAMA2 are associated with the invasiveness of nonfunctioning PitNET

The E3 Ubiquitin Ligase NEDD4-1 Mediates Temozolomide-Resistant Glioblastoma through PTEN Attenuation and Redox Imbalance in Nrf2–HO-1 Axis

Advancements in Molecular Diagnosis and Pharmacotherapeutic Strategies for Invasive Pituitary Adenomas

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