scholarly journals Curcumin-Mediated Apoptotic Cell Death in Papillary Thyroid Cancer and Cancer Stem-Like Cells through Targeting of the JAK/STAT3 Signaling Pathway

2020 ◽  
Vol 21 (2) ◽  
pp. 438 ◽  
Author(s):  
Abdul Q. Khan ◽  
Eiman I. Ahmed ◽  
Noor Elareer ◽  
Hamna Fathima ◽  
Kirti S. Prabhu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Signaling Pathway ◽  
Papillary Thyroid Cancer ◽  
Cell Lines ◽  
Janus Kinase ◽  
Dependent Manner ◽  
Papillary Thyroid ◽  
Cytotoxic Effects ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

The constitutive activation of Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signal transduction is well elucidated in STAT3-mediated oncogenesis related to thyroid cancer and is considered to be a plausible therapeutic target. Hence, we investigated whether curcumin, a natural compound, can target the JAK/STAT3 signaling pathway to induce cytotoxic effects in papillary thyroid cancer (PTC) cell lines (BCPAP and TPC-1) and derived thyroid cancer stem-like cells (thyrospheres). Curcumin suppressed PTC cell survival in a dose-dependent manner via the induction of caspase-mediated apoptosis and caused the attenuation of constitutively active STAT3 (the dephosphorylation of Tyr705–STAT3) without affecting STAT3. Gene silencing with STAT3-specific siRNA showed the modulation of genes associated with cell growth and proliferation. The cotreatment of PTC cell lines with curcumin and cisplatin synergistically potentiated cytotoxic effects via the suppression of JAK/STAT3 activity along with the inhibition of antiapoptotic genes and the induction of proapoptotic genes, and it also suppressed the migration of PTC cells by downregulating matrix metalloproteinases and the inhibition of colony formation. Finally, thyrospheres treated with curcumin and cisplatin showed suppressed STAT3 phosphorylation, a reduced formation of thyrospheres, and the downregulated expression of stemness markers, in addition to apoptosis. The current study’s findings suggest that curcumin synergistically enhances the anticancer activity of cisplatin in PTC cells as well as in cancer stem-like cells by targeting STAT3, which suggests that curcumin combined with chemotherapeutic agents may provide better therapeutic outcomes.

scholarly journals Diet-Induced Obesity Increases Tumor Growth and Promotes Anaplastic Change in Thyroid Cancer in a Mouse Model

Endocrinology ◽  
2013 ◽  
Vol 154 (8) ◽  
pp. 2936-2947 ◽  
Author(s):  
Won Gu Kim ◽  
Jeong Won Park ◽  
Mark C. Willingham ◽  
Sheue-yann Cheng
Keyword(s):  
Thyroid Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Thyroid Tumor ◽  
Janus Kinase ◽  
Histopathological Analysis ◽  
Diet Induced Obesity ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Recent epidemiological studies provide strong evidence suggesting obesity is a risk factor in several cancers, including thyroid cancer. However, the molecular mechanisms by which obesity increases the risk of thyroid cancer are poorly understood. In this study, we evaluated the effect of diet-induced obesity on thyroid carcinogenesis in a mouse model that spontaneously develops thyroid cancer (ThrbPV/PVPten+/− mice). These mice harbor a mutated thyroid hormone receptor-β (denoted as PV) and haplodeficiency of the Pten gene. A high-fat diet (HFD) efficiently induced the obese phenotype in ThrbPV/PVPten+/− mice after 15 weeks. Thyroid tumor growth was markedly greater and survival was significantly lower in ThrbPV/PVPten+/− mice fed an HFD than in controls fed a low-fat diet (LFD). The HFD increased thyroid tumor cell proliferation by increasing the protein levels of cyclin D1 and phosphorylated retinoblastoma protein to propel cell cycle progression. Histopathological analysis showed that the frequency of anaplasia of thyroid cancer was significantly greater (2.6-fold) in the HFD group than the LFD group. The HFD treatment led to an increase in parametrial/epididymal fat pad and elevated serum leptin levels in ThrbPV/PVPten+/− mice. Further molecular analyses indicated that the HFD induced more aggressive pathological changes that were mediated by increased activation of the Janus kinase 2-signaling transducer and activator of transcription 3 (STAT3) signaling pathway and induction of STAT3 target gene expression. Our findings demonstrate that diet-induced obesity exacerbates thyroid cancer progression in ThrbPV/PVPten+/− mice and suggest that the STAT3 signaling pathway could be tested as a potential target for the treatment of thyroid cancer.

scholarly journals LINC00893 Inhibits The Progression of Prostate Cancer Through miR-3173-5p/SOCS3/JAK2/STAT3 Pathway

2021 ◽  
Author(s):  
Chuigong Yu ◽  
Yu Fan ◽  
Yu Zhang ◽  
Lupeng Liu ◽  
Gang Guo
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Janus Kinase ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Background: Prostate cancer (PCa) is one of the most common malignant tumors in the male urinary system. In recent years, the morbidity and mortality of PCa have been increasing due to the limited effects of existing treatment strategies. Long non-coding RNA (lncRNA) LINC00893 inhibits the proliferation and metastasis of papillary thyroid cancer (PTC) cells, but its role in PCa has not been reported. Our study aims to clarify the role and underlying mechanism of LINC00893 in regulating the progression of PCa.Methods: We analyzed LINC00893 expression through TCGA database. We also collected 66 paires of PCa tissues and matched para-cancerous tissues as well as cell lines and assessed LINC00893 expression. Subsequently, we conducted gain-of-function assays to confirm the role of LINC00893 in PCa. CCK-8, EdU, colony information and transwell assays were implemented to detect cell proliferation, colony formation and metastasis abilities, respectively. RT-qPCR and western blot assays were used to quantify the expression of mRNA and protein. Dual-luciferase reporter, RNA-binding protein immunoprecipitation (RIP) and RNA pull down assays were conducted to evaluate the interaction of molecules. Spearman correlation coefficient analysis was conducted to detect the correlation between molecules.Results: We found that the LINC00893 expression in PCa tissues and cell lines was upregulated compared with matched controls, and patients with low expression of LINC00893 suffered a low overall survival rate. Overexpression of LINC00893 hindered the proliferation, epithelial-mesenchymal transition (EMT) as well as metastasis of PCa cells in vitro and in vivo. In terms of mechanism, suppressor of cytokine signaling 3 (SOCS3)/Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway occupied a central position in the regulation of PCa progression by LINC00893. LINC00893 weakened the inhibition role of miR-3173-5p on SOCS3 expression through functioning as a miR-3173-5p sponge, which inhibited the JAK2/STAT3 signaling pathway. Conclusions: LINC00893 suppresses the progression of prostate cancer through miR-3173-5p/SOCS3/JAK2/STAT3 pathway. our data uncovers a novel mechanism by which LINC00893 hinders the progression of PCa, which enriches the molecular network of LINC00893 regulating the PCa progression and laies a theoretical foundation for PCa targeted therapy.

scholarly journals SUN-132 KLF5 Is a Poor Prognostic Marker and Therapeutic Target for Middle Eastern Papillary Thyroid Carcinoma

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Khawla S Al-Kuraya ◽  
Abdul K Siraj ◽  
Pratheeshkumar Poyil ◽  
Divya Padmaja ◽  
Sandeep Kumar Parvathareddy ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Critical Role ◽  
Dependent Manner ◽  
Papillary Thyroid ◽  
Inhibition Of Proliferation ◽  
Over Expression

Abstract Thyroid cancer is the second most common malignancy among females in Saudi Arabia, with Papillary thyroid carcinoma (PTC) accounting for 80-90%. The Kruppel-like factor 5 (Klf5) is a transcription factor that play a critical role in cell transformation, proliferation and oncogenesis. Immunohistochemical analysis of KLF5 was performed in 1219 PTC cases. KLF5 over-expression was noted in 65.1% (793/1219) of PTCs, and was significantly associated with tall-cell variant (p <0.0001), extrathyroidal extension (p = 0.0003), lymph node metastasis (p < 0.0001) and stage IV tumors (p < 0.0001). Significant association was also noted with HIF-1α over-expression (p = 0.0492). Interestingly, KLF5 over-expressing tumors showed poor disease-free survival (p = 0.0066). Functional studies in PTC cell lines showed that KLF5 co-immunoprecipitated with HIF-1α. Knockdown of KLF5 decreased the expression of HIF-1α while KLF5 was not affected by HIF-1α inhibition, suggesting that KLF5 is a functional upstream of HIF-1α. Down-regulation of KLF5 using specific inhibitor, ML264 or siRNA inhibited cell invasion and migration. In addition, treatment of PTC cell lines with ML264 resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. Furthermore, silencing of KLF5 significantly decreased the self-renewal ability of spheroids generated from PTC cells. Our findings confer that KLF5 may be a potential therapeutic target for the treatment of papillary thyroid cancer.

A natural product phillygenin suppresses osteosarcoma growth and metastasis by regulating the SHP-1/JAK2/STAT3 signaling

2021 ◽  
Vol 85 (2) ◽  
pp. 307-314
Author(s):  
Xiaomin Ding ◽  
Danqing Lu ◽  
Jianbo Fan
Keyword(s):  
Cell Growth ◽  
Signaling Pathway ◽  
Janus Kinase ◽  
Potential Candidate ◽  
Osteosarcoma Cell ◽  
Cancer Cell Growth ◽  
Functional Roles ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

ABSTRACT Osteosarcoma represents one of the most devastating cancers due to its high metastatic potency and fatality. Osteosarcoma is insensitive to traditional chemotherapy. Identification of a small molecule that blocks osteosarcoma progression has been a challenge in drug development. Phillygenin, a plant-derived tetrahydrofurofuran lignin, has shown to suppress cancer cell growth and inflammatory response. However, how phillygenin plays functional roles in osteosarcoma has remained unveiled. In this study, we showed that phillygenin inhibited osteosarcoma cell growth and motility in vitro. Further mechanistic studies indicated that phillygenin blocked STAT3 signaling pathway. Phillygenin led to significant downregulation of Janus kinase 2 and upregulation of Src homology region 2 domain-containing phosphatase 1. Gene products of STAT3 regulating cell survival and invasion were also inhibited by phillygenin. Therefore, our studies provided the first evidence that phillygenin repressed osteosarcoma progression by interfering STAT3 signaling pathway. Phillygenin is a potential candidate in osteosarcoma therapy.

scholarly journals Expression of the NEK family in normal and cancer tissue: an immunohistochemical study

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Talita Diniz Melo-Hanchuk ◽  
Mariana Bonjiorno Martins ◽  
Lucas Leite Cunha ◽  
Fernando Augusto Soares ◽  
Laura Sterian Ward ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Protein Kinases ◽  
Papillary Thyroid Cancer ◽  
Tumour Size ◽  
Lung Tumour ◽  
Cancer Tissue ◽  
Dependent Manner ◽  
Papillary Thyroid ◽  
Multiple Cancer ◽  
Specificity And Sensitivity

Abstract Background The NEK serine/threonine protein kinases are involved in cell cycle checkpoints, DNA damage repair, and apoptosis. Alterations in these pathways are frequently associated with cell malignant cellular transformations. Thyroid cancer is the most common malignant tumour in the endocrine system. Despite good treatment methods, the number of cases has increased significantly in recent years. Here, we studied the expression of NEK1, NEK2, NEK3, and NEK5 in different types of normal and malignant tissues, using tissue microarray analysis, and identified NEKs as potential markers in thyroid malignancy. Methods The studied cases comprised multiple cancer tissue microarrays, including breast, colon, esophagus, kidney, lung, pancreas, prostate, stomach, thyroid and uterine cervix, as well as 281 patients who underwent thyroid resection for thyroid cancer or thyroid nodules. The expression of NEK1, NEK2, NEK3, and NEK5 was analyzed by immunohistochemistry. The expression pattern was evaluated in terms of intensity by two methods, semiquantitative and quantitative, and was compared between normal and cancer tissue. Results We analysed the expression of each member of the NEK family in a tissue-dependent manner. Compared to normal tissue, most of the evaluated proteins showed lower expression in lung tumour. However, in the thyroid, the expression was higher in malignant tissue, especially for NEK 1, NEK3 and NEK5. Concerning characteristics of the thyroid tumour, such as aggressiveness, NEK1 expression was higher in tumours with multifocality and in patients with lymph node metastasis. NEK3 expression was stronger in patients with stage II, that involved metastasis. NEK5, on the other hand, showed high expression in patients with invasion and metastasis and in patients with tumour size > 4 cm. Furthermore, this work, demonstrated for the first time a high specificity and sensitivity of over-expression of NEK1 in classical and follicular variants of papillary thyroid cancer and NEK3 in tall-cell papillary thyroid cancer. Conclusion Taken together, the NEK protein kinases emerge as important proteins in thyroid cancer development and may help to identify malignancy and aggressiveness features during diagnosis. Trial registration This study was retrospectively registered.  www.accamargo.org.br/cientistas-pesquisadores/comite-de-etica-em-pequisa-cep.

scholarly journals Carbon Ion Therapy Inhibits Esophageal Squamous Cell Carcinoma Metastasis by Upregulating STAT3 Through the JAK2/STAT3 Signaling Pathway

2020 ◽  
Vol 8 ◽  
Author(s):  
Hongtao Luo ◽  
Zhen Yang ◽  
Qiuning Zhang ◽  
Lihua Shao ◽  
Shihong Wei ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Signaling Pathway ◽  
Ion Beam ◽  
Ion Beams ◽  
Dependent Manner ◽  
Carbon Ion ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Carbon Ion Beam ◽  
Dose Dependent

Radiation therapy is an important component of the comprehensive treatment of esophageal cancer. However, conventional radiation resistance is one of the main reasons for treatment failure. The superiority of heavy ion radiation in physics and biology has been increasingly highlighted in radiation therapy research. The Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway plays an important role in the occurrence, development and metastasis of esophageal squamous cell carcinoma (ESCC) and is related to the development of resistance to ionizing radiation in ESCC. Therefore, the aim of the present study was to investigate the relationship between carbon ion inhibition of the proliferation and metastasis of esophageal carcinoma cells and the JAK2/STAT3 signaling pathway. The results demonstrated that carbon ion beams significantly reduced cell viability and stimulated apoptosis in human ESCC cells in a dose-dependent manner. In addition, carbon ion beams induced G2/M phase cell cycle arrest in ESCC cells and inhibited tumor metastasis in a dose-dependent manner. Additionally, poorly differentiated KYSE150 cells were more sensitive to the same carbon ion beam dose than moderately differentiated ECA109 cells. Carbon ion beam exposure regulated the relative expression of metastasis-related molecules at the transcriptional and translational levels in ESCC cells. Carbon ion beams also regulated CDH1 and MMP2 downstream of the STAT3 pathway and inhibited ESCC cell metastasis, which activated the STAT3 signaling pathway. This study confirmed the inhibition of cell proliferation and the metastatic effect of carbon ion beam therapy in ESCC cells.

STAT3, Constitutively Activated In ABC-Like DLBCL, Regulates Expression of the Prognostic Factor Cyclin D2

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 705-705
Author(s):  
Julie Marie Matthews ◽  
Yasodha Natkunam ◽  
Sathish Srinivasan ◽  
Matt Patricelli ◽  
Tyzoon Nomanbhoy ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
B Cell ◽  
Signaling Pathway ◽  
Tumor Cells ◽  
Cell Lines ◽  
Chip Assay ◽  
Cyclin D2 ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Cells Of Origin

Abstract Abstract 705 As the most common subtype of non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL) remains clinically heterogeneous. Genome-scale expression profiles have defined two distinct molecular subtypes of DLBCL: Germinal Center B-Cell like (GCB-like) and Activated B-Cell like (ABC-like), with separate postulated tumor cells of origin and different pathogenesis, e.g. activation of NF-kB and Signal Transducer and Activator of Transcription 3 (STAT3) in the ABC-like DLBCLs. These subtypes are also characterized by distinct clinical outcomes. Since global gene expression is not practical for routine prognosis determination, we established an IPI independent 6-gene model based on the expression of BCL6, LMO2, FN1, BCL2, SCYA3 and cyclin D2 (CCND2) genes, which was capable of predicting patients' survival. While some of these genes may merely reflect different postulated tumor cells of origin, others may represent distinct pathogenetic mechanisms. Herein we demonstrate that CCND2, whose expression correlates with shorter survival, is positively regulated by the STAT3 signaling pathway, activated in the ABC-like DLBCL. Immunohistochemical staining of phosphorylated STAT3 (pSTAT3) demonstrated strong positive pSTAT3 staining (greater than 30% of nuclei) in 85 of 204 (41.7%) primary DLBCLs. Hierarchical clustering analysis of 143 DLBCL specimens stained for GCB and ABC markers demonstrated that expression of the pSTAT3 protein correlated with the expression patterns of non-GCB markers MUM1/IRF4 and BCL2 but not with GCB-specific markers HGAL, BCL6, and CD10. However, pSTAT3 expression was not different between the GCB-like and non-GCB-like DLBCLs defined by Han's model (Hans et al, Blood 2004). Examination of pSTAT3 levels in GCB-like DLBCL cell lines (OCI-LY7, OCI-LY19, and Sud-HL6) and the ABC-like cell lines (OCI-LY3 and OCI-LY10) by Western blotting demonstrated its expression in OCI-LY3 and OCI-LY10 but not in other cell lines. pSTAT3 expression in these cells was confirmed by phospho-flow cytometry. Interestingly, pSTAT3 expressing cell lines also expressed high levels of Cyclin D2, while it was not detected by Western blotting in the DLBCL cell lines not expressing pSTAT3. Analysis of the CCND2 promoter showed a single potential STAT3 binding site. Chromatin immunoprecipitation (ChIP) assay confirmed specific binding of STAT3 to this site in the CCND2 promoter. BCL6 is reported to negatively regulate expression of CCND2 and to competitively bind to STAT3 binding sites. Consequently, using quantitative ChIP assay we measured BCL6 and STAT3 binding to the CCND2 promoter in Sud-HL6, Oci-LY7 and Oci-LY19 GCB-like and in Oci-LY3 and Oci-LY10 ABC-like DLBCL cell lines. Levels of the bound STAT3 and BCL6 proteins were significantly higher in the Oci-LY3 and Oci-LY10 cell lines compared to their GCB counterparts. Treatment with BCL6 peptide inhibitor (BPI) slightly increased CCND2 mRNA expression in both GCB-like and ABC-like DLBCL, confirming the inhibitory effect of BCL6 on the CCND2 expression. To examine the effect of pSTAT3 on Cyclin D2 in the physiological context, we have knocked-down expression of STAT3 and pSTAT3 by specific siRNA in the OCI-LY3 cell line. A 37% decrease in the total levels of STAT3 led to a 52% decrease in pSTAT3 and a 55% reduction in the Cyclin D2 protein levels and was associated with a statistically significant decrease in cell proliferation as measured by the MTT assay. Overall our results demonstrate that a constitutively active STAT3 signaling pathway contributes to the Cyclin D2 expression and proliferation of the ABC-like DLBCLs. These findings elucidate the mechanism regulating the expression of prognostic factor Cyclin D2 and link it to the STAT3 signaling pathway constitutively activated in ABC-like DLBCL. Disclosures: Patricelli: ActivX Biosciences: Employment. Nomanbhoy:ActivX Biosciences: Employment.

scholarly journals EphB3 Stimulates Cell Migration and Metastasis in a Kinase-dependent Manner through Vav2-Rho GTPase Axis in Papillary Thyroid Cancer

2016 ◽  
Vol 292 (3) ◽  
pp. 1112-1121 ◽  
Author(s):  
Jing-Jing Li ◽  
Zhi-Jian Sun ◽  
Yan-Mei Yuan ◽  
Fen-Fen Yin ◽  
Yao-Gang Bian ◽  
...  
Keyword(s):  
Cell Migration ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Rho Gtpase ◽  
Dependent Manner ◽  
Papillary Thyroid
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