<i>MTNR1B</i> loss promotes chordoma recurrence by abrogating melatonin‐mediated β‐catenin signaling repression

Liu, Lei; Wang, Tingting; Xiaoming, Yang; Xu, Caixia; Liao, Zhiheng; Wang, Xudong; Su, Deying; Li, Yongyong; Zhou, Hang; Qiu, Xianjian; Chen, Yuyu; Huang, Dongsheng; Lian, Chengjie; Su, Peiqiang

doi:10.1111/jpi.12588

Cited by 21 publications

(13 citation statements)

References 51 publications

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“…Drp1-related mitochondrial fission is regulated by multiple mechanisms [110][111][112][113]. In NAFLD, p53 induces Drp1-related mitochondrial fission and mitophagy arrest, which results in mitochondrial dysfunction through mPTP opening, reduced mitochondrial potential, oxidative stress, calcium overload, and ATP depletion [109].…”

Section: Agingmentioning

confidence: 99%

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Toan

Zhou

2020

Aging

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Nutrient oversupply and mitochondrial dysfunction play central roles in nonalcoholic fatty liver disease (NAFLD). The mitochondria are the major sites of β-oxidation, a catabolic process by which fatty acids are broken down. The mitochondrial quality control (MQC) system includes mitochondrial fission, fusion, mitophagy and mitochondrial redox regulation, and is essential for the maintenance of the functionality and structural integrity of the mitochondria. Excessive and uncontrolled production of reactive oxygen species (ROS) in the mitochondria damages mitochondrial components, including membranes, proteins and mitochondrial DNA (mtDNA), and triggers the mitochondrial pathway of apoptosis. The functionality of some damaged mitochondria can be restored by fusion with normally functioning mitochondria, but when severely damaged, mitochondria are segregated from the remaining functional mitochondrial network through fission and are eventually degraded via mitochondrial autophagy, also called as mitophagy. In this review, we describe the functions and mechanisms of mitochondrial fission, fusion, oxidative stress and mitophagy in the development and progression of NAFLD.

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Section: Agingmentioning

confidence: 99%

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Toan

Zhou

2020

Aging

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“…Mao et al 40 found that MLT inhibited EMT and migration in breast cancer through disturbing the AKT-Ser473/GSK-3β-Ser9/β-catenin/SNAIL axis. Liu et al 41 showed that MLT inhibited β-catenin activation and stemness in chordoma through decreasing the phosphorylation level of Y86/Y333/Y654 residues in β-catenin. Chao et al 42 found that MLT decreased EMT and metastasis in lung cancer through targeting the β-catenin/TWIST axis.…”

Section: Discussionmentioning

confidence: 99%

Melatonin suppresses chronic restraint stress-mediated metastasis of epithelial ovarian cancer via NE/AKT/β-catenin/SLUG axis

Wang

Sun

et al. 2020

Cell Death Dis

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Chronic stress has been shown to facilitate progression of epithelial ovarian cancer (EOC), however, the neuro-endocranial mechanism participating in this process still remains unclear. Here, we reported that chronic restraint stress (CRS) promoted the abdominal implantation metastasis of EOC cells and the expression of epithelial–mesenchymal transition-related markers in tumor-bearing mouse model, including TWIST, SLUG, SNAIL, and β-catenin. We observed that β-catenin co-expressed with SLUG and norepinephrine (NE) in tumor tissues obtained from nude mice. Further ex vivo experiments revealed that NE promoted migration and invasion of ovarian cancer cells and SLUG expression through upregulating expression and improving transcriptional function of β-catenin in vitro. A human phosphor-kinase array suggested that NE activated various kinases in ovarian cancer cells, and we further confirmed that AKT inhibitor reduced NE-mediated pro-metastatic impacts and activation of the β-catenin/SLUG axis. Furthermore, the expression levels of NE and β-catenin were examined in ovarian tumor tissues by using tumor tissue arrays. Results showed that the expression levels of both NE and β-catenin were associated with poor clinical stage of serous EOC. Moreover, we found that melatonin (MLT) effectively reduced the abdominal tumor burden of ovarian cancer induced by CRS, which was partially related to the inhibition of the NE/AKT/β-catenin/SLUG axis. Collectively, these findings suggest a novel mechanism for CRS-mediated ovarian cancer metastasis and MLT has a potential therapeutic efficacy against ovarian cancer.

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“…Chordoma is a rare malignant bone tumor with a high recurrence rate. 30 The characteristics of the growth mode and location of chordoma make it difficult to completely remove the tumor. Due to the chemical resistance of chordoma, the clinical effects of radiotherapy and chemotherapy are unsatisfactory because there is no effective drug treatment.…”

Section: Discussionmentioning

confidence: 99%

GSK-3β Regulates the Expression of P21 to Promote the Progression of Chordoma

Chen¹,

Zuo

et al. 2021

CMAR

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Purpose: Chordoma is a rare malignant bone tumor transformed from the remnants of notochord. It is characterized as highly aggressive and locally invasive, difficult to be completely removed by surgery, and has a poor clinical prognosis. Glycogen synthase kinase 3 beta (GSK-3β) is involved in many cellular processes. GSK-3β overexpression has been shown to promote the development of many cancers, according to previous studies. However, the role of GSK-3β in chordoma remains unclear. Methods: Immunohistochemistry (IHC) and Western blotting (WB) were performed on clinical specimens to measure GSK-3β expression in chordoma, and immunofluorescence and quantitative real-time polymerase chain reaction (QRT-PCR) were performed to examine the expression of GSK-3β and P21 in cell lines. Cell proliferation was detected by the CCK-8 assay and colony formation analysis, cell migration and invasion checked by Transwell experiments, and cell apoptosis was determined by Annexin V/propidium iodide staining. P21 was predicted as a downstream target gene of GSK-3β using STRING and UNIHI databases. Moreover, we used immunoprecipitation to confirm that GSK-3β and P21 interacted with each other. The double luciferase reporter gene assay showed that GSK-3β could regulate the promoter activity of P21. Finally, the role of the GSK-3β -P21 pathway in chordoma tumorigenesis was analyzed in vivo in nude mice. Results: Our study showed that GSK-3β was significantly higher in chordoma tissues than in paracancer tissues, and siRNA knockdown of GSK-3β inhibited chordoma cell proliferation and promoted cell apoptosis. Additionally, our research found that GSK-3β bound and downregulated the expression of the P21 gene, and the expression of silencing P21 partially reversed the inhibitory effect of knockdown GSK-3β on chordoma. Furthermore, xenografts showed that knockdown GSK-3β inhibited the formation of chordomas in vivo. Conclusion:Our results indicated that the GSK-3β-P21 axis may be an important signaling pathway for the occurrence and development of chordoma, providing a new therapeutic target for the clinical treatment of this disorder.

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MTNR1B loss promotes chordoma recurrence by abrogating melatonin‐mediated β‐catenin signaling repression

Cited by 21 publications

References 51 publications

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease

Melatonin suppresses chronic restraint stress-mediated metastasis of epithelial ovarian cancer via NE/AKT/β-catenin/SLUG axis

GSK-3β Regulates the Expression of P21 to Promote the Progression of Chordoma

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