Role of STAT3 in the pathogenesis of nasopharyngeal carcinoma and its significance in anticancer therapy

Si, Yishimei; Xǔ, Jǐnjīng; Meng, Linghui; Wu, Yuanqing; Qi, Jianwei

doi:10.3389/fonc.2022.1021179

Cited by 6 publications

(6 citation statements)

References 82 publications

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“…NPC is a metastasis-prone malignancy with the highest metastatic rate among head and neck cancers 45 . More than 70% of patients present with locoregionally advanced disease, and distant metastasis is the main cause of treatment failure 46 , 47 . Although radiotherapy, combined with chemotherapy are effective therapies for NPC, they have side effects, including hearing loss and cranial nerve damage, resulting in NPC patients being unable to complete these therapies, leading to therapeutic failure 48 .…”

Section: Discussmentioning

confidence: 99%

Berberine-mediated Ferroptosis through System Xc^-/GSH/GPX4 Axis Inhibits Metastasis of Nasopharyngeal Carcinoma

Wu,

Jia,

Tang

et al. 2024

J. Cancer

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Nasopharyngeal carcinoma (NPC) is a malignant tumor that is highly prevalent in Southeast China, and its metastasis remains an unresolved clinical problem. Ferroptosis, a type of nonapoptotic cell death, is a critical pathway in tumor metastasis. Berberine (BBR), a plant alkaloid, has been explored as a potential anti-NPC metastatic agent; however, the underlying mechanisms are unknown. Here, we showed that BBR exerted its anti-metastasis role by inhibiting system Xc - /GSH/GPX4 axis-driven ferroptosis. The present study demonstrated for the first time that BBR induced ferroptosis in NPC cells by increasing reactive oxygen species, lipid peroxidation and cellular Fe 2+ and that the ferroptosis inhibitors Ferrostatin-1 and Deferoxamine mesylate rescued BBR-induced NPC cell death. Moreover, the ferroptotic characteristics of BBR-treated NPC cells were observed using transmission electron microscopy. Mechanistically, system Xc - (SLC7A11 and SLC3A2) and GSH levels were found to be suppressed after treatment with BBR. We demonstrated that the system Xc - /GSH/GPX4 axis was a critical mediator of BBR-induced ferroptosis. Furthermore, GPX4, a key inhibitor of lipid peroxidation, was greatly suppressed by BBR at both protein and mRNA levels. Molecular docking results showed a strong interaction between GPX4 and BBR. Notably, GPX4 overexpression reversed the effect of BBR-induced ferroptosis in NPC cells. Finally, BBR-mediated inhibition of NPC metastasis was validated in vivo using a mouse model. Taken together, our data suggest that BBR induced ferroptosis of NPC cells via suppressing the system Xc - /GSH/GPX4 axis, provides new insights into the mechanism of BBR anti-NPC metastasis.

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Section: Discussmentioning

confidence: 99%

Berberine-mediated Ferroptosis through System Xc^-/GSH/GPX4 Axis Inhibits Metastasis of Nasopharyngeal Carcinoma

Wu,

Jia,

Tang

et al. 2024

J. Cancer

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“…Continued investigation into the interaction between MAPK/ERK/MEK/JNK pathways and the TME is essential to formulate effective therapeutic strategies. Targeting JAK/STAT Previous studies have investigated the role of JAK/STAT3 in NPC initiation, progression, and metastasis, as well as associated with advanced stages of NPC [ 271 , 272 ]. The activation of STAT3 has been detected in 70.5% of NPC patients, and LMP1 has been suggested to play role in this activation by enhancing its dimerization and DNA binding in B-cells [ 271 , 273 ].…”

Section: Molecular Aberrations Exploitation In Npc For Precision Medi...mentioning

confidence: 99%

“…Notably, the JAK/STAT3 signalling exhibited markedly elevated levels in NPC (60.2% and 70.9%), contrasting with the figures observed in chronic nasopharyngitis (12.8% and 14.1%) [ 274 ]. Moreover, high activation of this pathway is associated with poor prognosis [ 271 , 272 ]. NPC patients with elevated JAK2/STAT3 expression experienced notably reduced survival times.…”

Section: Molecular Aberrations Exploitation In Npc For Precision Medi...mentioning

confidence: 99%

Precision medicine in nasopharyngeal carcinoma: comprehensive review of past, present, and future prospect

Siak,

Heng,

Teoh

et al. 2023

J Transl Med

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Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with high propensity for lymphatic spread and distant metastasis. It is prominent as an endemic malignancy in Southern China and Southeast Asia regions. Studies on NPC pathogenesis mechanism in the past decades such as through Epstein Barr Virus (EBV) infection and oncogenic molecular aberrations have explored several potential targets for therapy and diagnosis. The EBV infection introduces oncoviral proteins that consequently hyperactivate many promitotic pathways and block cell-death inducers. EBV infection is so prevalent in NPC patients such that EBV serological tests were used to diagnose and screen NPC patients. On the other hand, as the downstream effectors of oncogenic mechanisms, the promitotic pathways can potentially be exploited therapeutically. With the apparent heterogeneity and distinct molecular aberrations of NPC tumor, the focus has turned into a more personalized treatment in NPC. Herein in this comprehensive review, we depict the current status of screening, diagnosis, treatment, and prevention in NPC. Subsequently, based on the limitations on those aspects, we look at their potential improvements in moving towards the path of precision medicine. The importance of recent advances on the key molecular aberration involved in pathogenesis of NPC for precision medicine progression has also been reported in the present review. Besides, the challenge and future outlook of NPC management will also be highlighted.

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“…NPC can be divided into three pathological subtypes: non-keratinized squamous, keratinized and basal-like squamous, among which non-keratinized squamous cell NPC accounts for more than 97% of NPC cases in Southeast Asia and southern China. 3 Cancer cells interact actively with their tumor microenvironment in the NPC as a multidimensional spatiotemporal unity of ecology and evolution pathological ecosystem, and even co-evolve on a cross-level basis. 4 As a result of the complex anatomy of the nasopharynx, atypical early symptoms, as well as the ease of invasion of lymph nodes and distant metastasis, most patients with NPC are already in advanced stages of the disease at the time of diagnosis.…”

Section: Introductionmentioning

confidence: 99%

“…Generally, NPC is a rare disease, with approximately 80,000 new patients testified each year, accounting for 0.7% of each malignant tumor. NPC can be divided into three pathological subtypes: non‐keratinized squamous, keratinized and basal‐like squamous, among which non‐keratinized squamous cell NPC accounts for more than 97% of NPC cases in Southeast Asia and southern China 3 . Cancer cells interact actively with their tumor microenvironment in the NPC as a multidimensional spatiotemporal unity of ecology and evolution pathological ecosystem, and even co‐evolve on a cross‐level basis 4 .…”

Section: Introductionmentioning

confidence: 99%

Relevance of pyroptosis‐associated genes in nasopharyngeal carcinoma diagnosis and subtype classification

Wang,

Zou,

Chen

et al. 2024

The Journal of Gene Medicine

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BackgroundNasopharyngeal carcinoma (NPC) is a highly aggressive and metastatic malignancy originating in the nasopharyngeal tissue. Pyroptosis is a relatively newly discovered, regulated form of necrotic cell death induced by inflammatory caspases that is associated with a variety of diseases. However, the role and mechanism of pyroptosis in NPC are not fully understood.MethodsWe analyzed the differential expression of pyroptosis‐related genes (PRGs) between patients with and without NPC from the GSE53819 and GSE64634 datasets of the Gene Expression Omnibus (GEO) database. We mapped receptor operating characteristic profiles for these key PRGs to assess the accuracy of the genes for disease diagnosis and prediction of patient prognosis. In addition, we constructed a nomogram based on these key PRGs and carried out a decision curve analysis. The NPC patients were classified into different pyroptosis gene clusters by the consensus clustering method based on key PRGs, whereas the expression profiles of the key PRGs were analyzed by applying principal component analysis. We also analyzed the differences in key PRGs, immune cell infiltration and NPC‐related genes between the clusters. Finally, we performed differential expression analysis for pyroptosis clusters and obtained differentially expressed genes (DEGs) and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.ResultsWe obtained 14 differentially expressed PRGs from GEO database. Based on these 14 differentially expressed PRGs, we applied least absolute shrinkage and selection operator analysis and the random forest algorithm to obtain four key PRGs (CHMP7, IL1A, TP63 and GSDMB). We completely distinguished the NPC patients into two pyroptosis gene clusters (pyroptosis clusters A and B) based on four key PRGs. Furthermore, we determined the immune cell abundance of each NPC sample, estimated the association between the four PRGs and immune cells, and determined the difference in immune cell infiltration between the two pyroptosis gene clusters. Finally, we obtained and functional enrichment analyses 259 DEGs by differential expression analysis for both pyroptosis clusters.ConclusionsPRGs are critical in the development of NPC, and our research on the pyroptosis gene cluster may help direct future NPC therapeutic approaches.

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Role of STAT3 in the pathogenesis of nasopharyngeal carcinoma and its significance in anticancer therapy

Cited by 6 publications

References 82 publications

Berberine-mediated Ferroptosis through System Xc^-/GSH/GPX4 Axis Inhibits Metastasis of Nasopharyngeal Carcinoma

Berberine-mediated Ferroptosis through System Xc^-/GSH/GPX4 Axis Inhibits Metastasis of Nasopharyngeal Carcinoma

Precision medicine in nasopharyngeal carcinoma: comprehensive review of past, present, and future prospect

Relevance of pyroptosis‐associated genes in nasopharyngeal carcinoma diagnosis and subtype classification

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Role of STAT3 in the pathogenesis of nasopharyngeal carcinoma and its significance in anticancer therapy

Cited by 6 publications

References 82 publications

Berberine-mediated Ferroptosis through System Xc-/GSH/GPX4 Axis Inhibits Metastasis of Nasopharyngeal Carcinoma

Berberine-mediated Ferroptosis through System Xc-/GSH/GPX4 Axis Inhibits Metastasis of Nasopharyngeal Carcinoma

Precision medicine in nasopharyngeal carcinoma: comprehensive review of past, present, and future prospect

Relevance of pyroptosis‐associated genes in nasopharyngeal carcinoma diagnosis and subtype classification

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Berberine-mediated Ferroptosis through System Xc^-/GSH/GPX4 Axis Inhibits Metastasis of Nasopharyngeal Carcinoma

Berberine-mediated Ferroptosis through System Xc^-/GSH/GPX4 Axis Inhibits Metastasis of Nasopharyngeal Carcinoma