ABSTRACT
Introduction: Cellular neurothekeoma is a benign tumor that mainly occurs in young children and adolescents. The aberrant expression of transcription factor E3 (TFE3) has not been reported in cellular neurothekeoma previously. Case report: We report four cellular neurothekeoma with aberrant immunohistochemical expression of TFE3 protein. The fluorescence in situ hybridization (FISH) showed no TFE3 gene rearrangement or amplification. Discussion/Conclusion: TEF3 protein expression may not be related to TFE3 gene translocation in cellular neurothekeoma. TFE3 may be a potential pitfall in diagnosis, for several malignant tumors in children also express TFE3. The aberrant expression of TFE3 may offer insights into cellular neurothekeoma etiology, and associated molecular mechanisms.
Subject(s)
Neurothekeoma , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Neurothekeoma/diagnosis , Neurothekeoma/geneticsABSTRACT
Gastric cancer is one of the most common malignant cancers globally. Chemotherapy resistance remains a major obstacle in the treatment of gastric cancer, and the molecular mechanisms underlying drug resistance are still not well understood. We previously reported that Zipper interacting protein kinase (ZIPK), also known as death-associated protein kinase3, exerts an oncogenic effect on gastric cancer via activation of Akt/NF-κB signaling and promotion of stemness. Here, we explored the roles of ZIPK in cisplatin resistance. We report that ZIPK enhances cell proliferation and invasion and reduces the antitumor activity of cisplatin in gastric cancer. In addition, our western blot data suggest that ZIPK activated the IL-6/STAT3 signaling pathway. Furthermore, ZIPK increased the expression of IL-6 and multidrug-resistance genes. Using the STAT3 inhibitor stattic to block the IL-6/STAT3 signaling pathway strongly increased the sensitivity of ZIPK-expressed cells to cisplatin. In conclusion, ZIPK may play a role in cisplatin resistance through activation of the IL-6/ STAT3 signaling pathway. Inhibition of STAT3 in gastric cancer overexpressing ZIPK might have potential to improve the efficacy of cisplatin.
Subject(s)
Cisplatin/pharmacology , Death-Associated Protein Kinases/metabolism , Drug Resistance, Neoplasm , Interleukin-6/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction , Stomach Neoplasms/metabolism , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Death-Associated Protein Kinases/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Models, Biological , STAT3 Transcription Factor/antagonists & inhibitors , Signal Transduction/drug effects , Stomach Neoplasms/etiology , Stomach Neoplasms/pathologySubject(s)
Carcinoma, Squamous Cell , Mouth Neoplasms , Child , Humans , Mouth Floor , Mouth Neoplasms/diagnosis , Retrospective StudiesABSTRACT
Dysregulation of the balance between cell proliferation and cell death is a central feature of malignances. Death-associated protein kinase 3 (DAPK3) regulates programmed cell death including apoptosis and autophagy. Our previous study showed that DAPK3 downregulation was detected in more than half of gastric cancers (GCs), which was related to tumor invasion, metastasis, and poor prognosis. However, the precise molecular mechanism underlying DAPK3-mediated tumor suppression remains unclear. Here, we showed that the tumor suppressive function of DAPK3 was dependent on autophagy process. Mass spectrometry, in vitro kinase assay, and immunoprecipitation revealed that DAPK3 increased ULK1 activity by direct ULK1 phosphorylation at Ser556. ULK1 phosphorylation by DAPK3 facilitates the ULK1 complex formation, the VPS34 complex activation, and autophagy induction upon starvation. The kinase activity of DAPK3 and ULK1 Ser556 phosphorylation were required for DAPK3-modulated tumor suppression. The coordinate expression of DAPK3 with ULK1 Ser556 phosphorylation was confirmed in clinical GC samples, and this co-expression was correlated with favorable survival outcomes in patients. Collectively, these findings indicate that the tumor-suppressor roles of DAPK3 in GC are associated with autophagy and that DAPK3 is a novel autophagy regulator, which can directly phosphorylate ULK1 and activate ULK1. Thus, DAPK3 might be a promising prognostic autophagy-associated marker.
Subject(s)
Autophagy-Related Protein-1 Homolog/metabolism , Autophagy/physiology , Death-Associated Protein Kinases/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Stomach Neoplasms/genetics , Adaptor Proteins, Vesicular Transport/metabolism , Animals , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation , Death-Associated Protein Kinases/metabolism , Female , Genes, Tumor Suppressor , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Microscopy, Electron, Transmission , Middle Aged , Phosphorylation , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: The incidence of thyroid cancer is fast increasing in both adults and children. The pediatric thyroid cancer had often already progressed to a more advanced stage of the disease at diagnosis. Early detection of pediatric thyroid cancer has been a problem for many years. Lipocalin-2 (Lcn2) has been reported to be over-expressed in cancers of diverse histological origin and it facilitates tumorigenesis by promoting survival, growth, and metastasis. METHODS: The plasma Lcn2 concentration of 28 Chinese papillary thyroid cancer (PTC) children and 24 healthy controls was measured. Immunostaining for Ki-67 of tumor tissue from PTC children was performed. The expression levels of Lcn2 and NFκB in PTC tissue and peri-carcinoma tissue of PTC children were measured through Western blot. RESULTS: The plasma concentration of Lcn2 was significantly elevated in pediatric PTC patients compared with healthy controls. Besides, the plasma Lcn2 concentration significantly correlated with clinical characteristics, NFκB level, and Ki-67 positive rate of nucleus in tissue of PTC. CONCLUSION: This is the first study to evaluate the plasma Lcn2 in pediatric PTC patients. It is possible that the plasma Lcn2 may be a new biomarker of pediatric thyroid cancer. Further studies are needed to explore the definite role and mechanism of Lcn2 in thyroid cancer, which will help to explore novel diagnostic or therapeutic strategies.
Subject(s)
Carcinoma/metabolism , Carcinoma/pathology , Lipocalin-2/blood , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology , Adolescent , Case-Control Studies , Child , Female , Humans , Male , NF-kappa B/metabolism , Transcriptional Activation , Up-RegulationABSTRACT
Zipper-interacting Protein Kinase (ZIPK) belongs to the death-associated protein kinase family. ZIPK has been characterized as a tumor suppressor in various tumors, including gastric cancer. On the other hand, ZIPK also promotes cell survival. In this study, both in vitro and in vivo assays indicated that ZIPK promoted cell growth, proliferation, migration, invasion, tumor formation and metastasis in nude mice. ZIPK induced epithelial-mesenchymal transition (EMT) with increasing expression of ß-catenin, mesenchymal markers, Snail and Slug, and with decreasing expression of E-cadherin. Furthermore, ZIPK activated the AKT/IκB/NF-κB pathway, which can promote EMT and metastasis. Additionally, ZIPK expression was detected in human primary gastric cancer and their matched metastatic lymph node samples by immunohistochemistry. Increased expression of ZIPK in lymph node metastases was significantly associated with stage VI and abdominal organ invasion. Survival analysis revealed that patients with increased ZIPK expression in metastatic lymph nodes had poor disease-specific survival. Taken together, our study reveals that ZIPK is a pro-oncogenic factor, which promotes cancer metastasis.
