High Signal Transducer And Activator Of Transcription 3 Research Articles

Identification of the molecular link: STAT3 is a shared key gene linking postmenopausal osteoporosis and sarcopenia.

This study explored the shared genetic traits and molecular interactions between postmenopausal osteoporosis (POMP) and sarcopenia, both of which substantially degrade elderly health and quality of life. We hypothesized that these motor system diseases overlap in pathophysiology and regulatory mechanisms. We analyzed microarray data from the Gene Expression Omnibus (GEO) database using weighted gene co-expression network analysis (WGCNA), machine learning, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to identify common genetic factors between POMP and sarcopenia. Further validation was done via differential gene expression in a new cohort. Single-cell analysis identified high expression cell subsets, with mononuclear macrophages in osteoporosis and muscle stem cells in sarcopenia, among others. A competitive endogenous RNA network suggested regulatory elements for these genes. Signal transducer and activator of transcription 3 (STAT3) was notably expressed in both conditions. Single-cell analysis pinpointed specific cells with high STAT3 expression, and microRNA (miRNA)-125a-5p emerged as a potential regulator. Experiments confirmed the crucial role of STAT3 in osteoclast differentiation and muscle proliferation. STAT3 has emerged as a key gene in both POMP and sarcopenia. This insight positions STAT3 as a potential common therapeutic target, possibly improving management strategies for these age-related diseases.

STAT3 Contributes a Favorable Response to Pembrolizumab Through IFN-γ-induced Apoptosis in Urothelial Cancer.

Pembrolizumab, a second-line therapy for platinum-refractory advanced urothelial carcinoma (UC), is needed to improve objective response rate. Hence, it is crucial to identify optimal predictive biomarkers of responses. This study aimed to clarify the predictive value and role of signal transducer and activator of transcription 3 (STAT3) in selecting patients with advanced UC who might benefit clinically from pembrolizumab therapy. We retrospectively analyzed 31 patients who received pembrolizumab therapy for UC. STAT3, phosphorylated STAT3 (p-STAT3), and PD-L1 expression were determined using tissue microarrays constructed from patient-derived specimens, and the association of these expression levels with overall survival was analyzed. We assessed the functional role of STAT3 in bladder cancer cell lines in response to interferon-gamma (IFN-γ). Patients with high STAT3 or p-STAT3 expression, and high platelet-to-lymphocyte ratio (PLR) (n=6) had a significantly shorter OS; in the other patients (n=25), high STAT3 or p-STAT3 expression was significantly associated with improved prognosis. IFN-γ-induced apoptosis was partially dependent on STAT3 in T24 cells but not in JMSU1 cells. In patients with advanced UC, STAT3 plays a key role in mediating the efficacy of pembrolizumab through apoptosis in response to IFN-γ.

Differential curcumin absorption and curcumin-induced STAT3 inhibition during 3T3-L1 cell adipogenesis in 2D and 3D cultures

It is increasingly considered that 3D cell culture systems are superior to 2D in evaluating health promoting effects of candidate molecules because they better mimic tissue-like structures, thus testing in such systems will increase their in vivo applicability. The present study sought to examine the potential usefulness of spheroid models for assessing the antiadipogenic effect of polyphenols. The major food polyphenols were compared for their antiadipogenic effects in 3T3-L1 cells grown in conventional 2D conditions and as 3D spheroids. Further, the study evaluated the effect of the cell culture environment on the inhibition of the adipogenesis-related signaling pathway mediated by curcumin (CUR), the most effective antiadipogenic polyphenol identified in 2D and 3D, and its cellular absorption rate. CUR treatment inhibited the activity of signal transducer and activator of transcription 3 (STAT3) in cells cultured in both conditions; however, it was more effective in 2D. Notably, 3T3-L1 preadipocytes in a 3D cell culture system maintained high STAT3 activity and CCAAT/enhancer-binding protein alpha (C/EBPα) expression compared with a 2D system. Additionally, the cellular absorption rate was lower in 3D cultures. Thus, different cellular absorption rates, innate STAT3 activity, and C/EBPα expression levels may contribute to the difference in CUR efficacy. This study demonstrated that the STAT3 inhibition at least partly contributes to antiadipogenic effect of CUR. Moreover, it showed that the presentation of cells in 3D significantly alters activation of intracellular signaling pathways and absorption rate of CUR. Therefore, 3D spheroid models are valuable tools to evaluate the anti-adipogenicity of candidate molecules.

STAT3 Promotes Cell Proliferation by Potentiating the CCL4 Transcriptional Activity in Diffuse Large B-Cell Lymphoma

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and a candidate therapeutic option for human cancers. However, the underlying mechanism of STAT3 in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) is yet to be established. We studied here whether STAT3 contributes to C-C motif chemokine ligand (CCL4) transcription elevation in DLBCL. Our established protein-protein interactions network revealed the overexpression of STAT3 and CCL4 in DLBCL. Mechanistically, STAT3 activated CCL4 transcription to induce the Wnt/β-catenin pathway. The prognostic analysis exhibited that the overall survival of patients with high STAT3 and CCL4 were poorer than those with low STAT3 and CCL4 expression. In addition, silencing of STAT3 reverted the malignant phenotype in DLBCL cells. CCL4 overexpression partly weakened the si-STAT3-mediated antitumor effects on DLBCL cells. Tumor xenograft models showed that si-STAT3 inhibited tumor growth in vivo and decreased proliferative and mitogenic activities in tumor tissues, which was consistent with the in vitro data. Hence, this study provides new evidence that STAT3 and CCL4 may be new prognostic biomarkers and therapeutic targets for treating DLBCL.

STAT3/HIF-1\u03b1 signaling activation mediates peritoneal fibrosis induced by high glucose

BackgroundEpithelial-mesenchymal transition (EMT) of mesothelial cells is a key step in the peritoneal fibrosis (PF). Recent evidence indicates that signal transducer and activator of transcription 3 (STAT3) might mediate the process of renal fibrosis, which could induce the expression of hypoxia-inducible factor-1α (HIF-1α). Here, we investigated the effect of STAT3 activation on HIF-1α expression and the EMT of mesothelial cells, furthermore the role of pharmacological blockade of STAT3 in the process of PF during peritoneal dialysis (PD) treatment.MethodsFirstly, we investigated the STAT3 signaling in human peritoneal mesothelial cells (HPMCs) from drained PD effluent. Secondly, we explored the effect of STAT3 signaling activation on the EMT and the expression of HIF-1α in human mesothelial cells (Met-5A) induced by high glucose. Finally, peritoneal fibrosis was induced by daily intraperitoneal injection with peritoneal dialysis fluid (PDF) so as to explore the role of pharmacological blockade of STAT3 in this process.ResultsCompared with the new PD patient, the level of phosphorylated STAT3 was up-regulated in peritoneal mesothelial cells from long-term PD patients. High glucose (60 mmol/L) induced over-expression of Collagen I, Fibronectin, α-SMA and reduced the expression of E-cadherin in Met-5A cells, which could be abrogated by STAT3 inhibitor S3I-201 pretreatment as well as by siRNA for STAT3. Furthermore, high glucose-mediated STAT3 activation in mesothelial cells induced the expression of HIF-1α and the profibrotic effect of STAT3 signaling was alleviated by siRNA for HIF-1α. Daily intraperitoneal injection of high-glucose based dialysis fluid (HG-PDF) induced peritoneal fibrosis in the mice, accompanied by the phosphorylation of STAT3. Immunostaining showed that phosphorylated STAT3 was expressed mostly in α-SMA positive cells in the peritoneal membrane induced by HG-PDF. Administration of S3I-201 prevented the progression of peritoneal fibrosis, angiogenesis, macrophage infiltration as well as the expression of HIF-1α in the peritoneal membrane induced by high glucose.ConclusionsTaken together, these findings identified a novel mechanism linking STAT3/HIF-1α signaling to peritoneal fibrosis during long-term PD treatment. It provided the first evidence that pharmacological inhibition of STAT3 signaling attenuated high glucose-mediated mesothelial cells EMT as well as peritoneal fibrosis.

Expression of STAT3 and vasculogenic mimicry in gallbladder carcinoma promotes invasion and metastasis.

Surgical treatment of gallbladder carcinoma remains challenging, while targeted therapy has been demonstrated to have potential. In the present study, the effect of signal transducer and activator of transcription 3 (STAT3) expression and vasculogenic mimicry (VM) on the occurrence and development of gallbladder carcinoma was evaluated. A total of 72 patients with gallbladder carcinoma and 10 patients with chronic cholecystitis were examined. Immunohistochemical staining was performed to determine the positive expression rates of STAT3. Periodic acid Schiff CD34 double staining was performed to detect VM in the gallbladder carcinoma group. STAT3 expression and VM in gallbladder carcinoma tissues was compared among patients with different clinical characteristics. In postoperative patients with gallbladder cancer, the relationship of the postoperative recurrence time with STAT3 expression and VM was assessed. STAT3 expression in gallbladder carcinoma tissue was significantly higher than that in cholecystitis tissue (P<0.05). STAT3 expression levels and VM were positively correlated in gallbladder carcinoma tissue. STAT3 protein expression in gallbladder carcinoma tissues differed significantly among patients with different degrees of differentiation and clinical stages (P<0.05). Among the 51 patients who completed the 3-year follow-up, the mean time to relapse was 17.353 and 35.647 months in those with high and low STAT3 expression, respectively, with significant differences (P<0.05). The VM structure was detected in 47 cases (92.15%) and not detected in four cases (7.84%), which exhibited no immediate recurrence after surgery, and the difference in the mean postoperative recurrence time was significant (22.38 vs. 36.00 months, respectively; P<0.05). In gallbladder carcinoma tissues, a lower degree of differentiation, higher malignancy degree and higher clinical stage were associated with higher expression of STAT3 and VM. Thus, STAT3 may promote VM formation in the process of tumor occurrence, development and metastasis. Therefore, STAT3 as a regulatory target, may inhibit the proliferation and invasion of tumor cells and block the development of VM, thereby representing a suitable target for antitumor angiogenesis therapy.

Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors.

The cumulative evidence supports STAT3, a transcriptional mediator of oncogenic signaling, as a therapeutic target in cancer. The development of STAT3 inhibitors remain an active area of research as no inhibitors have yet to be approved for cancer treatment. In a continuing effort to develop more potent STAT3 inhibitors based on our previously identified hit compound 16w, a series of benzothiazole derivatives with unique binding mode in SH2 domain of STAT3 were designed, synthesized and biologically evaluated. Of note, compound B19 demonstrated excellent activity against IL-6/STAT3 signaling pathway with the IC50 value as low as 0.067μM as determined by a luciferase reporter assay. Moreover, multiple compounds displayed potent antiproliferative activity against MDA-MB-468 and JAK2 mutant HEL cell lines. Further biochemical study using Western blot assay indicated that B19 blocked the phosphorylation of STAT3 at Tyr 705 and Ser 727 and thus suppressed STAT3-mediated gene expression of c-MYC and MCL-1. Simultaneously, it induced cancer cell G2/M phase arrest and apoptosis both in MDA-MB-468 and HEL cell lines. Finally, molecular docking study along with surface plasmon resonance (SPR) and fluorescence polarization (FP) assays disclosed the binding mode of B19 in STAT3 SH2 domain. Taken together, our finding suggests that B19 is a promising therapeutic STAT3 inhibitor for cancer treatment.

Plasma soluble PD-L1 and STAT3 predict the prognosis in diffuse large B cell lymphoma patients.

Purpose: Diffuse large B cell lymphoma (DLBCL) is one of the most common B cell lymphomas, which displays heterogeneous pathologies. Programmed cell death 1/ programmed cell death ligand 1 (PD-1/PD-L1) plays an essential role in immunosuppression in multiple malignancies. Signal transducer and activator of transcription 3 (STAT3)-positive patients also have an independently inferior clinical outcome. However, there are no reports on the effect of plasma soluble PD-L1 (sPD-L1) combined with plasma STAT3 on the prognosis of DLBCL. In this study, we investigate the relationships between plasma sPD-L1 combined with STAT3 and clinical prognosis of DLBCL.Methods: Levels of plasma sPD-L1 and STAT3 were quantified using ELISA in eighty-seven DLBCL patients. Multiplexed immunofluorescence staining was performed to visualize the expression of PD-L1 in twenty-nine matched FFPE specimens from all patients.Results: The survival analysis revealed that the progression-free survival (PFS) and overall survival (OS) in high sPD-L1 level group were poorer than that in low sPD-L1 level group (PFS, P < 0.001; OS, P < 0.001). Similarly, the PFS and OS in high STAT3 level group were also poorer than that in low STAT3 level group. Multivariate cox regression analysis showed that both high sPD-L1 and high STAT3 levels were the independent prognostic factors negatively affecting survival. In addition, patients with DLBCL having high levels of both sPD-L1 and STAT3 had a worse outcome than those patients having any one high or low levels of both (P < 0.001).Conclusions: We therefore revealed that high levels of plasma sPD-L1 and STAT3 are associated with inferior outcome for DLBCL patients, suggesting that combined measurement of their levels in plasma may be a promising prognostic strategy for DLBCL patients.

A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma.

Medulloblastoma is the most common malignant brain tumor in children and represents 20% of all pediatric central nervous system neoplasms. While advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represent a major health care burden and have led to ongoing efforts to find effective targeted treatments. There is a well-recognized male bias in medulloblastoma diagnosis, although the mechanism remains unknown. Herein, we identify a sex-specific role for the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) in the Sonic Hedgehog (SHH) medulloblastoma subgroup. Specific deletion of Stat3 from granule cell precursors in a spontaneous mouse model of SHH medulloblastoma completely protects male, but not female mice from tumor initiation. Segregation of SHH medulloblastoma patients into high and low STAT3 expressing cohorts shows that low STAT3 expression correlates with improved overall survival in male patients. We observe sex specific changes in IL-10 and IL-6 expression and show that IL-6 stimulation enhances SHH-mediated gene transcription in a STAT3-dependent manner. Together these data identify STAT3 as a key molecule underpinning the sexual dimorphism in medulloblastoma.

Abstract 844: β IV -spectrin Regulates Cardiac Fibroblast Phenotype, Fibrosis, and Cardiac Function

Increased fibrosis is associated with cardiac dysfunction and arrhythmias. Activation of quiescent cardiac fibroblasts (CFs) occurs in response to injury although the underlying mechanistic pathways remain unclear. The cytoskeletal protein β IV -spectrin has been shown to control targeting and activity of the multifunctional transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) for maladaptive remodeling. The mechanism linking spectrin dysfunction to altered STAT3 signaling, fibrosis, and function remains unknown. The objective of this study was to investigate the role of stress-induced disruption of β IV -spectrin/STAT3 complex in modulating CF phenotype, fibrosis, and cardiac function. Cardiac function (echocardiography) and fibrosis (Masson’s trichrome) were evaluated in adult wildtype (WT) and qv 4J mice expressing truncated β IV -spectrin lacking STAT3 interaction. A subset of WT mice were subjected to 6 wks of transaortic constriction (TAC) to induce heart failure. From these groups, CFs were isolated from ventricles and analyzed for STAT3 localization, gene expression, and activity. CFs were treated with selective STAT3 inhibitor S3I-201 (100μM) or transfected for 72 hrs with β IV -spectrin fragment from repeat 10 to C-terminus (β IV,10-C , contains STAT3 binding motif). Ejection fraction was decreased in qv 4J and WT TAC relative to WT baseline (49.5±0.85% vs 34.9±2.2% vs 63.2±0.60% respectively, p&lt;0.05, N=5. Ventricular fibrosis was augmented in qv 4J and WT TAC compared to WT baseline (2.4±0.09% vs 3.2±0.25% vs 0.48±0.01% respectively, p&lt;0.05, N=5). qv 4J CFs showed STAT3 mislocalization (49.7±10.7% nuclear accumulation vs 5.3±.1.8% in WT, p&lt;0.05, N=5) with higher STAT3 transcriptional activity (2.6±0.17-fold increase over WT, p&lt;0.05, N=9). In parallel, qv 4J CFs displayed elevated expression of fibrotic genes associated with CF activation. At the functional level, qv 4J CFs showed increased proliferation (1.9±0.19-fold increase over WT at 24 hrs, p&lt;0.05, N=4). STAT3 inhibition with S31-201 or transfection with β IV,10-C normalized gene expression and proliferation in qv 4J CFs compared to WT. These studies identify a requirement of β IV -spectrin for normal STAT3 signaling and quiescent phenotype in CFs.

Prognostic values and clinical implications of programmed cell death-ligand 1 (PD-L1), fork head transcription factor P-1 (FOXP-1) and signal transducer and activator of transcription-3 (STAT-3) expression in diffuse large B-cell lymphoma (DLBCL); an immunohistochemical study

ContextPD-L1 is an inhibitory ligand that functions as an essential immune checkpoint. FOXP-1 is a member of the FOXP family. STAT-3 plays a critical role in regulation of cell proliferation and survival. The detailed expression of the three markers together in DLBCL tissues and their prognostic value in patients with DLBCL were not fully investigated.Aim was to assess the expression of PD-L1, FOXP-1 and STAT-3 in diffuse large B-cell lymphoma (DLBCL) and to correlate their expression with the pathological findings, prognostic parameters and clinical implications of patients.MethodsPD-L1, FOXP-1 and STAT-3 were assessed in DLBCL tissues derived from 50 patients using immunohistochemistry. Patients were followed up for 3 years for response to therapy progression, recurrence and survival.ResultsHigh PD-L1 expression was associated with bone marrow involvement (p = 0.004), extra-nodal involvement (p = 0.006) and advanced stage (p = 0.003). High FOXP-1 expression was associated with presence of bone marrow involvement and high risk group (p < 0.001). High STAT-3 expression was associated with older age of the patient (p < 0.001), presence of bone marrow involvement (p = 0.002), extra-nodal involvement (p = 0.009), and high risk group (p = 0.005). High expression of PD-L1, FOXP-1 and STAT-3 was related to poor response to therapy, poor OS rate and RFS rates (p < 0.001).ConclusionHigh expression of PD-L1, FOXP-1 and STAT-3 was related poor prognosis in DLBCL patients.

STAT3 expression is a prognostic marker in upper urinary tract urothelial carcinoma.

Signal transducer and activator of transcription 3 (STAT3) plays a prominent role in the growth and invasion of several types of solid tumors. In this study, to assess the expression status and prognostic significance of the STAT3 pathway in upper urinary tract urothelial carcinoma (UTUC), we immunohistochemically stained for STAT3 and STAT3 pathway proteins, sphingosine-1-phosphate receptor 1 (S1PR1) and interleukin-6 (IL-6), in a tissue microarray containing 99 UTUC specimens. There were no significant associations between STAT3, S1PR1, or IL-6 expression pattern and tumor grade or pT stage. However, the patients with high STAT3 tumor had a significantly higher risk of both disease progression (p = 0.009) and cancer-specific mortality (p = 0.009), but not with tumors expressing S1PR1 or IL-6. High STAT3 expression in the nucleus was also associated with a significantly higher risk of both disease progression (p = 0.003) and cancer-specific mortality (p = 0.034). Multivariate analysis revealed that high STAT3 expression in the nucleus was significantly associated with cancer-specific survival after adjustment for pathological stage, lymph node involvement, lymphovascular invasion, and tumor grade (HR = 2.136, 95% CI = 1.009–4.767, p = 0.047). Our findings indicated that STAT3 could be a cancer-promoting factor and potentially a significant prognostic factor in UTUC.

SiRNA interfering STAT3 enhances DDP sensitivity in cervical cancer cells.

Signal transducer and activator of transcription 3 (STAT3) is an important regulatory protein in the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, which regulates cell proliferation, apoptosis, and other biological processes. It is closely related to tumor occurrence, progress, and resistance. Cisplatin (DDP) resistant cervical cancer cell line was established by shock induction to investigate the role of STAT3 in cervical cancer cells drug resistance. The expression of STAT3 in different chemotherapy response cervical cancer tissues was compared. The cervical cancer was divided into two groups upon STAT3 median level. Cervical cancer cell inhibitory rate by DDP treatment was compared. Western blot was used to detect STAT3 and phosphorylated STAT3 (p-STAT3) expressions in CaSki and CaSki/DDP cells. Cell apoptosis rate was tested by flow cytometry. CaSki/DDP cells were divided into small interfere RNA-normal control (siRNA-NC) group and siRNA-STAT3 group. Cell proliferation was evaluated by EdU staining. The rate of STAT3 over-expression in cervical cancer patients with no significant chemotherapy response was markedly higher than that with a significant response. The inhibitory effect of DDP on tumor cells derived from patients with low STAT3 expression was significantly higher, while the apoptosis rate was apparently lower than that of CaSki/DDP cells from patients with high STAT3 expression. siRNA-STAT3 transfection significantly reduced the expressions of STAT3 and p-STAT3, decreased cell proliferation, and enhanced cell apoptosis in CaSki/DDP cells. STAT3 over-expression is associated with DDP resistance in cervical cancer. Decreasing STAT3 can significantly promote the apoptosis of cervical cancer CaSki cells and decrease the DDP resistance.

MP18-10 STAT3 EXPRESSION IS A PROGNOSTIC MARKER IN UPPER URINARY TRACT UROTHELIAL CARCINOMA

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma I1 Apr 2018MP18-10 STAT3 EXPRESSION IS A PROGNOSTIC MARKER IN UPPER URINARY TRACT UROTHELIAL CARCINOMA Kazutoshi Fujita, Kyosuke Matsuzaki, Satoshi Nojima, Kentaro Jingushi, Taigo Kato, Atsushi Kawashima, Takeshi Ujike, Akira Nagahara, Motohide Uemura, Seiji Yamaguchi, Hiroaki Fushimi, Eiji Morii, Hiroshi Miyamoto, Ryoichi Imamura, and Norio Nonomura Kazutoshi FujitaKazutoshi Fujita More articles by this author , Kyosuke MatsuzakiKyosuke Matsuzaki More articles by this author , Satoshi NojimaSatoshi Nojima More articles by this author , Kentaro JingushiKentaro Jingushi More articles by this author , Taigo KatoTaigo Kato More articles by this author , Atsushi KawashimaAtsushi Kawashima More articles by this author , Takeshi UjikeTakeshi Ujike More articles by this author , Akira NagaharaAkira Nagahara More articles by this author , Motohide UemuraMotohide Uemura More articles by this author , Seiji YamaguchiSeiji Yamaguchi More articles by this author , Hiroaki FushimiHiroaki Fushimi More articles by this author , Eiji MoriiEiji Morii More articles by this author , Hiroshi MiyamotoHiroshi Miyamoto More articles by this author , Ryoichi ImamuraRyoichi Imamura More articles by this author , and Norio NonomuraNorio Nonomura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.586AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Signal transducer and activator of transcription 3 (STAT3) plays a prominent role in the growth and invasion of several types of solid tumors. STAT3 are activated via Sphingosine-1-phosphate receptor 1(S1PR1) or IL-6. In this study, we evaluated the expression status of STAT3 pathway proteins, STAT3, S1PR1, and IL-6, in upper urinary tract urothelial carcinoma (UTUC) and analyzed their prognostic significance. METHODS A UTUC tissue microarray (TMA) was constructed with spotted triplicate tumor samples from 99 patients who underwent radical nephroureterectomy performed. Immunohistochemical staining was performed on using a primary antibody to STAT3, S1PR1 and IL-6. RESULTS There were no significant associations between STAT3, S1PR1, or IL-6 expression pattern and tumor grade or pT stage. However, the patients with high STAT3 tumor had a significantly higher risk of both disease progression (p=0.009) and cancer-specific mortality (p=0.009) than those with low STAT3 tumor. High STAT3 expression in the nucleus was also associated with a significantly higher risk of both disease progression (p=0.003) and cancer-specific mortality (p=0.034). Multivariate analysis revealed that high STAT3 expression in the nucleus was significantly associated with cancer-specific survival after adjustment for pathological stage, lymph node involvement, lymphovascular invasion, and tumor grade (HR=2.136, 95% CI=1.009-4.767, p=0.047). CONCLUSIONS Our findings indicated that STAT3 could be a cancer-promoting factor and potentially a significant prognostic factor in UTUC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e216-e217 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Kazutoshi Fujita More articles by this author Kyosuke Matsuzaki More articles by this author Satoshi Nojima More articles by this author Kentaro Jingushi More articles by this author Taigo Kato More articles by this author Atsushi Kawashima More articles by this author Takeshi Ujike More articles by this author Akira Nagahara More articles by this author Motohide Uemura More articles by this author Seiji Yamaguchi More articles by this author Hiroaki Fushimi More articles by this author Eiji Morii More articles by this author Hiroshi Miyamoto More articles by this author Ryoichi Imamura More articles by this author Norio Nonomura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Girdin protein: A potential metastasis predictor associated with prognosis in lung cancer.

The present study explored the relationship between Girdin protein expression and the survival rate of patients with lung carcinoma. A total of 334 lung cancer specimens, 20 benign lung disease tissue sections and 24 fresh tissues from patients with lung carcinoma were analyzed by immunohistochemistry and western blotting. Girdin protein was expressed in 130/334 (38.93%) of the cases examined. Girdin protein expression was correlated with tumor/node/metastasis stage (P<0.001), lymph node metastasis (P=0.001), distant metastasis (P<0.001) and specimen sites (P=0.034). Girdin expression was also correlated with signal transducer and activator of transcription 3 (STAT3) expression (P<0.001). Patients with high Girdin and STAT3 expression had a significantly poorer prognosis compared with those with low/high, high/low or low/low expression (P<0.001). In summary, Girdin may be a prognostic marker of lung cancer and serve as a biomarker for metastasis.

Abstract 5707: STAT3 and STAT5a are potential therapeutic targets in castration-resistant prostate cancer

Abstract Background: Currently, there is no effective pharmacotherapy for metastatic castration-resistant prostate cancer (mCRPC). The mechanisms underlying mCRPC are not clearly understood, thus hindering rational-based drug design. Evidence suggests that signal transducer and activator of transcription 3 (STAT3) and 5a/b (STAT5a/b), key components of the JAK/STAT pathway, play a significant role in aggressive PC. However, expression of STAT3/5 in prostate tumor samples have not been studied. Here, we evaluated the possible role of STAT3/5a in aggressive PC. Materials and Methods: Expression of STAT3 and STAT5a in high grade PC (HGPC, n=15) and in benign prostatic hyperplasia (BPH, n=15) tissue sections were evaluated by immunohistochemistry (IHC) according to the protocol approved by Institutional Review Board. Age ranged from 59 to 95 years (median = 81) in the former and 57 years to 86 years (median = 68 years) in the latter category. In addition, the effects of STAT inhibitor, Pimozide, on androgen-sensitive LNCaP and its castration-resistant subline C4-2 PC cell growth were assessed in vitro. Results: A strong nuclear immunoreactivity for STAT3 and STAT5a in 93% (n=14) and 80% (n=12) of HGPC cases, respectively, were observed. Only one BPH case showed strong STAT3 expression. Focal and weak positivity for STAT3 and STAT5a were noted in 47% (n=7) and 67% (n=10) of BPH cases. None of the BPH cases showed strong STAT5a expression. HGPC cases showed significantly higher STAT3 positivity compared with BPH (p=0.01). No significant differences were observed for STAT5a expression between HGPC and BPH group (p=0.4). However, multifocal or diffuse and strong STAT3 (p&amp;lt;0.0001) and STAT5a (p&amp;lt;0.0001) expression was significantly higher in HGRPC than BPH. Pimozide exposure significantly inhibited LNCaP cell proliferation at 10 μM and C4-2 cell proliferation at 20 μM concentration. Conclusion: Our results demonstrate that increased expression of STAT3 and STAT5a may serve as a predictive biomarker for efficacy of the JAK/STAT targeted therapy. Since JAK/STAT and androgen receptor signaling are functionally synergistic in contributing PC progression, the inhibition of JAK/STAT-alone or in combination with AR may lead to a novel treatment modality for mCRPC. Citation Format: Sambit K. Mohanty, Kader Yagiz, Luthringer Luthringer, Mahul B. Amin, Serhan Alkan, Bekir Cinar. STAT3 and STAT5a are potential therapeutic targets in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5707. doi:10.1158/1538-7445.AM2017-5707

STAT3 activation and risk of recurrence in meningiomas.

Several studies have suggested that activation of signal transducer and activator of transcription 3 (STAT3) is associated with initiation, progression and metastasis of numerous types of malignancy. However, the role of the Janus kinase-interleukin 6-STAT3 signaling pathway in the pathogenesis and recurrence of meningiomas is unknown. The present study evaluated STAT3 activation by western blotting and immunohistochemistry and assessed its association with Ki-67 labeling in 13 cases of meningioma in which frozen tissue and ≥5.5-year follow-up information were available, and in formalin-fixed meningioma tissues from 14 cases with an 8.4-year follow-up. The results of the western blot analysis indicated that STAT3 phosphorylation was markedly higher in grade II meningiomas compared with that in grade I, with mean densitometric values of 8.6 and 1.7 following normalization to actin, respectively. High STAT3 phosphorylation/activation was identified in 2 of 3 recurrent World Health Organization (WHO) grade I meningiomas and 0 of 3 non-recurrent meningiomas. Strong STAT3 phosphorylation/activation signal was also found in 2 of 4 recurrent grade II meningiomas and 1 of 3 non-recurrent cases. According to the immunohistochemistry results, phospho-STAT3 was not increased in WHO grade II tumors compared with that in grade I tumors, and was not significantly different between recurrent and non-recurrent cases. Ki-67 labeling was significantly increased in grade II vs. grade I tumors, and was also significantly increased in recurrent compared with non-recurrent grade I meningiomas. The results of the current study suggest that, while detection of phosphorylated/activated STAT3 may be useful in isolated cases, identifying activation may be of little value in predicting recurrence.

MTE23.02 Biomarker Characterization: Challenges and Perspectives

Small molecule inhibitors are the current treatment for non-small-cell lung cancer (NSCLC), especially for tumors harboring an active mutation of epidermal growth factor receptor (EGFR). Approximately 90% of EGFR mutations are exon 19 deletions or exon 21 single-point L858R substitutions and are associated with sensitivity to EGFR tyrosine kinase inhibitors (EGFR TKIs), like gefitinib or erlotinib. However, less than 5% of EGFR-mutant NSCLC patients achieve a complete response to EGFR TKI and the overall median progression-free survival is no longer than 9-11 months. Accumulated studies report several mechanisms of early adaptive resistance that can occur as early as two hours after starting EGFR TKI therapy. The activation of signal transducer and activator of transcription 3 (STAT3) signaling is among these mechanisms of resistance. Furthermore, EGFR blockage enriches lung cancer stem cells through Notch3-dependent signaling pathway. We have previously demonstrated that NF-κB contributes to gefitinib resistance in EGFR-mutant NSCLC. The efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is jeopardized by the activation of signaling pathways. We examined the relevance of co-targeting EGFR, signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling. We conducted clinical and preclinical studies of key components of signaling pathways limiting EGFR TKI efficacy in EGFR-mutant NSCLC. High levels of STAT3 or YAP1 mRNA expression were associated with worse outcome to EGFR TKI in two independent cohorts of EGFR-mutant NSCLC patients. In the initial cohort of 64 patients, median progression-free survival was shorter among the patients with high STAT3 than among those with low STAT3 (hazard ratio [HR] for disease progression, 3·02; 95% confidence interval [CI], 1·54-5·93; P=0·0013). Median progression-free survival was shorter among the patients with high YAP1 than among those with low YAP1 (HR for disease progression, 2·57; 95%CI, 1·30-5·09; P=0·0067). The results were similar in the validation cohort of 55 patients. We demonstrated that gefitinib augments STAT3 signaling in EGFR-mutant NSCLC cells. Gefitinib with TPCA-1 (STAT3 inhibitor) blocked STAT3, but not the YAP1 phosphorylation on tyrosine residue 357 by Src family kinases (SFKs) that occurs downstream of IL-6. The triple combination of gefitinib, TPCA-1 and AZD0530 (SFK inhibitor) ablated both STAT3 and YAP1 phosphorylation and markedly and safely suppressed tumor growth. Added value of our research: We found that EGFR TKI therapy activates STAT3 and that EGFR blockage enriches lung cancer stem cells with up-regulation of the YAP1 and Notch downstream effectors connective tissue growth factor (CTGF) and hairy-enhancer of split-1 (HES1), respectively. We sought to demonstrate that EGFR TKI treatment cannot abrogate STAT3 and Src-YAP1-Notch activation in EGFR-mutant NSCLC cell lines, leading us to examine whether the combination of gefitinib with compounds targeting STAT3 and Src, suppresses the mechanisms of resistance. Nine days after gefitinib treatment, STAT3 mRNA level was significantly increased, as well as the fraction of ALDH positive cells. TPCA-1, a compound that targets STAT3, increases sensitivity to gefitinib in PC-9 and H1975 cells; however, neither gefitinib nor TPCA-1 inhibits Src or YAP1. The addition of the Src inhibitor, saracatinib, to the doublet of gefitinib and TPCA-1, was highly synergistic and abrogated STAT3, and Src-YAP1-Notch signaling. Implications: Treatment with single EGFR TKI can no longer be considered adequate for patients with EGFR mutant NSCLC. Our findings ultimately suggest that a clinical trial evaluating the co-targeted inhibition of STAT3 and Src is warranted. As a result, STAT3 and YAP1 mRNA levels could become important predictive biomarkers. We searched PubMed for English language reports published up to December, 2015 using the terms “non-small-cell lung cancer”, “STAT3”, “interleukin-6”, “NF-κB”, “aldehyde-dehydrogenase (ALDH)”, “integrin-linked kinase (ILK)”, “glycoprotein 130 (gp130)”, “Src-homology 2 domain-containing phosphatase 2 (SHP2)”, “the complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing protein-1 (CDCP1)”, “AXL”, “ephrin type-A receptor-2 (EphA2)”, “Src family kinases (SFK)”, “YES-associated protein 1 (YAP1)”, “Notch”, “cell migration, invasion and metastases” and “STAT3 inhibitors”. STAT3, EGFR TKI, YAP1, NSCLC

P3.02b-047 Co-Activation of STAT3 and YAP1 Signaling Pathways Limits EGFR Inhibitor Response in Lung Cancer: Topic: EGFR Clinical

EGFR tyrosine kinase inhibitors (TKIs) induce early activation of several signaling pathways. Interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) hyper-activation occur following EGFR TKI therapy in EGFR-mutant NSCLC cells. We explored the relevance of co-targeting EGFR, STAT3 and Src-YES-associated protein 1 (YAP1) signaling in EGFR-mutant NSCLC. We combined in vitro and in vivo approaches to explore whether concomitant activation of STAT3 and Src-YAP1 can limit the effectiveness of EGFR TKIs in EGFR-mutant NSCLC cells and xenograft models. In two cohorts of EGFR-mutant NSCLC patients, we examined messenger RNA (mRNA) gene expression within signaling pathways, leading to EGFR TKI resistance. Gefitinib suppressed EGFR, ERK1/2 and AKT phosphorylation but increased STAT3 phosphorylation (pSTAT3-Tyr705). In EGFR mutant cells, gefitinib plus TPCA-1 (STAT3 inhibitor) abolished pSTAT3-Tyr705 but not the YAP1 phosphorylation on tyrosine 357 by Src family kinases (SFKs). The triple combination of gefitinib, TPCA-1 and AZD0530 (SFK inhibitor) ablated both STAT3 and YAP1 phosphorylation and was highly synergistic, according to the combination index. In two EGFR mutant xenograft mouse models, the triple combination of gefitinib, TPCA-1 and AZD0530 markedly and safely suppressed tumor growth. High levels of STAT3 or YAP1 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 9.6 (95%CI, 5.9-14.1) and 18.4 months (95% CI, 8.8-30.2) for patients with high and low STAT3 mRNA, respectively (p<0.001), (HR for disease progression, 3.02; 95% CI, 1.54-5.93; p=0.0013). Median PFS was 9.6 (95% CI, 7.7-15.2) and 23.4 months (95%CI, 13.0-28.1) for patients with high and low YAP1 mRNA, respectively (p=0.005), (HR for disease progression, 2.57; 95% CI, 1.30-5.09; p=0.0067). The results were similar in the validation cohort of 55 EGFR-mutant NSCLC patients treated with first-line EGFR TKI in the Department of Oncology of Shanghai Pulmonary Hospital. Our study reveals that STAT3 and Src-YAP1 signaling activation occurs following single EGFR TKI in EGFR-mutant NSCLC. STAT3 and YAP1 mRNA levels were significantly predictive of progression-free survival in the original as well as in the validation cohort of EGFR-mutant NSCLC patients. Co-targeting STAT3 and Src in combination with EGFR TKI could substantially improve survival.

STAT3 overexpression promotes metastasis in intrahepatic cholangiocarcinoma and correlates negatively with surgical outcome.

Signal transducer and activator of transcription 3 (STAT3) promotes tumor progression in many types of cancer. In this study, we analyzed the prognostic value of this marker in human intrahepatic cholangiocarcinoma (ICC). Using real-time PCR, western blot and immunohistochemistry assays, we found that STAT3 is overexpressed in ICC patients. STAT3 expression correlated with several clinicopathological features, including tumor size, pathological satellite, vascular invasion, undifferentiated-type histology, lymph node metastasis and TNM stage in two independent cohorts of ICC patients. Patients with high STAT3 levels had a poor prognosis in terms of overall survival (OS) and disease-free survival (DFS). Multivariate survival analysis indicated that STAT3 is an independent prognostic factor for OS and DFS. Furthermore, we observed that STAT3 overexpression promotes the invasion, metastasis and proliferation of ICC cells in vitro and in vivo, and also promotes STAT3 phosphorylation. These findings suggest that STAT3 expression correlated negatively with surgical outcome and inhibition of STAT3 expression may constitute a novel target for the treatment of ICC patients.