High Signal Transducer And Activator Of Transcription 3 Expression Research Articles

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.

A STAT3 Degrader Demonstrates Pre-Clinical Efficacy in Venetoclax Resistant Acute Myeloid Leukemia

Introduction: Acute Myeloid leukemia (AML) is an aggressive hematological malignancy resulting from the transformation of immature myeloid progenitor cells followed by an uncontrolled clonal proliferation and accumulation of the transformed cells. AML is the most common myeloid malignancy in the elderly [1]. Venetoclax (Ven) is a selective inhibitor of the anti-apoptotic BCL2 protein. Ven is FDA approved in combination with hypomethylating agents (HMA's) or low dose cytarabine for the treatment of de-novo AML in patients > 75 years or those ineligible for standard induction therapies. Despite the recent FDA approval of HMA/Ven and other novel therapies, 5-year survival in newly diagnosed AML remain less than 30% and disease relapse is inevitable without a bridge to allogeneic stem cell transplantation [2]. Signal transducer and activator of transcription 3 (STAT3) belonging to the STAT family of transcription factors is well known to be inappropriately activated in several malignancies [3]. On stimulation by cytokines such as IL-6, STAT3 undergoes dimerization and phosphorylation. Phosphorylation at Tyr 705 leads to its translocation to the nucleus whereas phosphorylation at Ser 727 translocates it to the mitochondria [4]. Previous data from our lab demonstrated de-methylation and overexpression of STAT3 in MDS & AML stem cells, that is associated with an adverse prognosis [5]. We have also reported that STAT3 controls several important leukemic drivers such as the anti-apoptotic protein myeloid cell leukemia-1 (MCL1). MCL1 overexpression is the central mechanism of resistance to BCL2 inhibition (Ven) in AML [5]. While MCL1 is a well-known direct transcriptional target of STAT3, the role of STAT3 in venetoclax resistance (Ven-res) is unknown. Methods & Results: To understand the role of STAT3 in Venetoclax resistance (Ven-res), Ven-res AML cell lines (MOLM-13, MV-4-11) as well as a Ven-res large cell lymphoma cell line (SU-DHL-1) were generated, which exhibited increased levels of both total STAT3, phospho-STAT3 and its downstream effector, MCL1, when compared to their parental cell lines (Fig. 1A). Data from > 90 AML patients treated with prior Ven also showed high expression of total STAT3 along with enhanced phosphorylation for p Ser727 and p Tyr-705 STAT3, that strongly correlated with worse overall survival (OS) and reduced remission duration (RemDur) (p<0.05). A highly specific potent heterobifunctional degrader of STAT3 (degrader) resulted in a dose dependent and selective degradation of STAT3 in both parental and Ven-res hematological malignancy cell lines. Treatment with degrader showed a significant (>60%) decrease in p Tyr-705 as wellas p Ser-727 STAT3 levels in MOLM-13 parental as well as MOLM-13 Ven-res cells. STAT3 degradation also led to induction of apoptosis in both parental and Ven-res AML cell lines (p < 0.001). Importantly, colony assay of Ven-res AML patient samples showed effective degradation of STAT3 (>90%) together with the increased erythroid and myeloid differentiation (~ 2 fold) on treatment with degrader. Interestingly, no differentiation was observed in healthy samples, suggesting the specificity of the degrader to AML stem and progenitor cells. In patients with Ven-res AML, erythroid colony counts were seen to increase (~1.5 fold) with a concomitant decrease in myeloid colony counts (>2.5 fold), on treatment with degrader. This observation supports the clinical significance of our studies in AML patients with anemia. Although BH3 profiling of Ven-res MOLM-13 supports an increased dependency on MCL1, we have observed that treatment with degrader led to ~20% reduction in the MCL1 dependent mitochondrial depolarization. Additionally, cell derived xenograft (CDX) models of Ven-res showed significant reduction of p Tyr-705 STAT3(~60%), total STAT3 (>90%) and MCL1 (~70%), on treatment with STAT3 degrader - KT-333 (currently in an early phase clinical trial:NCT05225584), as early as week 2 (Fig 1B). Significant decrease in intracellular STAT3 in the spleen cells was also observed (p < 0.05), with ongoing survival analysis. Conclusion: Our study suggests that targeting STAT3 and the downstream MCL1 represents a novel and effective strategy for Ven-resistant AML patients in clinic, with strong mechanistic rationales that can spur further clinical development of STAT3 degraders especially given the significant side effects of direct MCL1 inhibitors.

Cyclometalated iridium(III) complexes as anti-breast cancer and anti-metastasis agents via STAT3 inhibition

Breast cancer is the most commonly diagnosed cancer and second‑leading cause of cancer deaths in women. Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting breast cancer cell proliferation, invasion, angiogenesis, and metastasis, and the high expression of STAT3 is related to the occurrence and poor chemotherapy sensitivity of breast cancer. Iridium(III) complexes Ir-PTS-1– 4 containing a pterostilbene-derived ligand were synthesized to inhibit the STAT3 pathway in breast cancer. Ir-PTS-4 inhibited the proliferation of breast cancer cells by suppressing the expression of phosphorylated STAT3 and STAT3-related cyclin D1, arresting cell cycle in the S-phase, inducing DNA damage and reactive oxygen species (ROS) generation, eventually leading to autophagic cell death. The cell metastasis and invasion were also inhibited after Ir-PTS-4 treatment. Besides, Ir-PTS-4 exhibited excellent anti-proliferation activity in 3D multicellular tumor spheroids, showing potential for the treatment of solid tumors. This work presents the rational design of metal-based anticancer agents to block the STAT3 pathway for simultaneously inhibiting breast cancer proliferation and metastasis.

A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors.

Combined cancer immunotherapy and targeted therapy have proven to be effective against various cancers and therefore have recently become the focus of cancer research. Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT protein family of transcription factors. Several studies have shown that STAT3 can affect the prognosis of cancer patients by regulating immune microenvironment (IME). Therefore, STAT3 may have high research value for the development of combined immunotherapy/targeted therapy approaches for the treatment of cancer patients. We found differences in STAT3 expression between tumor and normal tissues. Kaplan-Meier survival and Cox regression analyses showed that high expression of STAT3 is associated with poor prognosis in low-grade glioma (LGG) patients. The results of the analysis of the area under the curve of the receiver operating characteristic curve further suggested that the expression of STAT3 is an effective way to evaluate the prognosis of patients with glioma. The results of the IME analysis revealed that the immune and matrix scores of LGGs were positively correlated with the expression of STAT3 (P < 0.05). The results of immune cell infiltration analysis showed that STAT3 was positively correlated with resting dendritic cells, eosinophils, neutrophils, M0 macrophages, M1 macrophages, CD4 memory resting T cells, and CD8 T cells in LGG patients, but negatively correlated with activated mast cells and M2 macrophages (P < 0.05). Our gene set enrichment analysis identified 384 enriched pathways. According to the enrichment scores, the top ten most significantly upregulated pathways were related to immune response. The top ten most significantly downregulated pathways were related to cell signal transduction and the regulation of cell survival, proliferation, and metabolism. Genetic alteration analysis showed that missense mutations in STAT3 account for the majority of mutations, and STAT3 mutations mostly occur in the Src homology domain. In conclusion overexpression of STAT3 can promote the development and growth of tumors by regulating IME, which is significantly related to the poor prognosis of cancer patients. Therefore, targeted inhibition of STAT3 expression may have high research value for the development of combined immunotherapy/targeted therapy approaches for the treatment of cancer patients.

Physical interaction between STAT3 and AP1 in cervical carcinogenesis: Implications in HPV transcription control

The constitutive activation and aberrant expression of Signal Transducer and Activator of Transcription 3 (STAT3) plays a key role in initiation and progression of cervical cancer (CaCx). How STAT3 influences HPV transcription is poorly defined. In the present study, we probed direct and indirect interactions of STAT3 with HPV16/18 LCR. In silico assessment of cis-elements present on LCR revealed the presence of potential STAT3 binding motifs. However, experimental validation by ChIP-PCR could not confirm any specific STAT3 binding on HPV16 LCR. Protein-protein interaction (PPI) network analysis of STAT3 with other host transcription factors that bind LCR, highlighted the physical association of STAT3 with c-FOS and c-JUN. This was further confirmed in vitro by co-immunoprecipitation, where STAT3 co-immunoprecipitated with c-FOS and c-JUN in CaCx cells. The result was supported by immunocytochemical analysis and colocalization of STAT3 with c-FOS and c-JUN. Positive signals in proximity ligation assay validated physical interaction and colocalization of STAT3 with AP1. Colocalization of STAT3 with c-FOS and c-JUN increased upon IL-6 treatment and decreased post-Stattic treatment. Alteration of STAT3 expression affected the subcellular localization of c-FOS and c-JUN, along with the expression of viral oncoproteins (E6 and E7) in CaCx cells. High expression of c-JUN in tumor tissues correlated with poor prognosis in both HPV16 and HPV18 CaCx cohort whereas high expression of STAT3 correlated with poor prognosis in HPV18 CaCx lesions only. Overall, the data suggest an indirect interaction of STAT3 with HPV LCR via c-FOS and c-JUN and potentiate transcription of viral oncoproteins.

Signal transducer and activator of transcription 3 and cancer associated fibroblasts jointly generate chemo-resistance and affect prognosis in epithelial ovarian cancer

Objective: To investigate the mechanism of signal transducer and activator of transcription 3 (STAT3) and cancer associated fibroblasts (CAF) jointly generate chemo-resistance in epithelial-ovarian cancer and their effect on prognosis. Methods: A total of 119 patients with high-grade ovarian serous cancer who received surgery in Cancer Hospital of Chinese Academy of Medical Sciences from September 2009 to October 2017 were collected. The clinico-pathological data and follow-up data were complete. Multivariate Cox regression model was used to analyze the prognostic factors. Ovarian cancer tissue chips of patients in our hospital were prepared. EnVision two-step method immunohistochemistry was used to detect the protein expression levels of STAT3, the specific markers of CAF activation, fibroblast activating protein (FAP), and type Ⅰ collagen (COL1A1) secreted by CAF. The relationship between the expression of STAT3, FAP, COL1A1 protein and drug resistance and prognosis of ovarian cancer patients was analyzed, and the correlation between the expression of three proteins was analyzed. These results were verified through the gene expression and prognostic information of human ovarian cancer tissues collected in the GSE26712 dataset of gene expression omnibus (GEO) database. Results: (1) Multivariate Cox regression model analysis showed that chemotherapy resistance was an independent risk factor for overall survival (OS) of ovarian cancer (P<0.001). (2) The expression levels of STAT3, FAP, and COL1A1 proteins in chemotherapy resistant patients were significantly higher than those in chemotherapy sensitive patients (all P<0.05). Patients with high expression of STAT3, FAP, and COL1A1 had significantly shorter OS than those with low expression (all P<0.05). According to the human ovarian cancer GSE26712 dataset of GEO database, patients with high expression of STAT3, FAP, and COL1A1 also showed shorter OS than patients with low expression (all P<0.05), the verification results were consistent with the detection results of ovarian cancer patients in our hospital. (3) Correlation analysis showed that the protein level of STAT3 was positively correlated with FAP and COL1A1 in our hospital's ovarian cancer tissue chips (r=0.47, P<0.001; r=0.30, P=0.006), the analysis of GEO database GSE26712 dataset showed that the expression of STAT3 gene and FAP, COL1A1 gene were also significantly positively correlated (r=0.31, P<0.001; r=0.52, P<0.001). Conclusion: STAT3 and CAF could promote chemotherapy resistance of ovarian cancer and lead to poor prognosis.

Prognostic significance of STAT3 gene expression in patients with glioblastoma tumors: a study from Western India

ObjectiveGlioblastoma Multiforme (GBM), a devastating the most common primary malignant intracranial brain tumors. In India, the incidence of this malignancy is escalating, however, there are very few studies on this tumor entity from Indian population. The present study sought to investigate the prevalence and prognostic significance of Signal Transducer and Activator of Transcription 3 (STAT3) gene expression in GBM patients from Western India.MethodSTAT3 gene expression using real-time PCR was detected in total 55 GBM patients. The impact of STAT3 aberrant expression on progression-free survival (PFS) and overall (OS) was analysed using univariate and multivariate survival analysis. The data were analysed using SPSS statistical software and p value ≤0.05 was considered as significant.ResultsThe aberrant STAT3 expression was found in 85% (47/55) of patients with -1.12 fold change down-regulation in 49% (23/47) and 3.36 fold change up-regulation was noted in 51% (24/47) of patients. In wild type IDH tumors (n=30), down regulation and up regulation of STAT3 was noted in 63% and 27% of patients, respectively, whereas, for IDH mutant GBM tumors (n=25), the incidence of low expression and high expression of STAT3 was noted in 16% and 68% of patients, respectively. Thus, we found that incidence of STAT3 down regulation was significantly high in patients with IDH wild type tumors, whereas, in IDH mutant GBM tumors, the incidence of up-regulated STAT3 was significantly high (P=0.021, χ2=12.81, r=+0.310). In Kaplan-Meier univariate survival analysis, a part from age (P=0.006), tumor location (P=0.025), and KPS score (P=0.002), co-detection of STAT3 up regulation and presence of IDH mutation (P=0.030) remained significant prognostic factors for PFS and OS. In multivariate survival analysis also, co-detection of STAT3 high expression and presence of IDH mutation remained independent prognosticators for PFS (HR=6.45, 95% CI=1.32-31.40, P=0.021) and OS (HR=8.69, 95% CI=1.66-45.51, P=0.010).ConclusionFor GBM tumors, STAT3 up-regulation and presence of IDH mutations together predicts better survival. This reflects unique molecular etiology for GBM patients. Therefore, they would be useful in the future for targeted therapy and for clinicians they would be useful for better patient management. However, study on a larger sample size is required for validation.

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.

Dual PLK1 and STAT3 inhibition promotes glioblastoma cells apoptosis through MYC

Glioblastoma (GBM) is the deadliest primary brain tumor that is highly resistant to current treatments. Polo-like kinase 1 (PLK1) and signal transducer and activator of transcription 3 (STAT3) are highly expressed in gliomas, especially GBM. Previous studies have shown reciprocal activation between PLK1 and STAT3 and that they regulate the same pools of MYC downstream. We have demonstrated that PLK1 and STAT3 levels are elevated in gliomas compared with those in normal brain tissues, and high expression of both PLK1 and STAT3 is associated with poor prognosis in TCGA. Moreover, there was direct or indirect reciprocal regulation between PLK1 and STAT3. Furthermore, we found that PLK1 and STAT3 can regulate the same pools of MYC downstream. Compared to monotherapy, combined treatment of glioma cells with PLK1 and STAT3 inhibitors, BI2536 and Stattic, respectively, showed lower expression of MYC, synergistic induction of cell invasion and apoptosis in vitro, and tumor inhibition in xenografts. PLK1 and STAT3 were able to directly regulate the expression of MYC and induce apoptosis of glioma cells through the regulation of MYC. These findings may help develop a therapeutic strategy for dual inhibition of PLK1 and STAT3 against the tumorigenesis of glioma.

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.

Meta-analysis of STAT3 and phospho-STAT3 expression and survival of patients with breast cancer.

ObjectiveThe prognostic value of signal transducer and activator of transcription 3 (STAT3) and phospho-STAT3 in breast cancer remains controversial in heterogeneous. The objective of this meta-analysis was to evaluate STAT3 and phospho-STAT3 expression on the prognosis of breast cancer patients.Materials and MethodsPubMed, Cochrane Central Register of Controlled Trials, Embase, Web of Science, Chinese CNKI, and Wan Fang were searched up to 19th June 2017. Studies which investigated the STAT3 or phospho-STAT3 expression of patients with breast cancer on the basis of patient survival data or survival curve were eligible.ResultsThis meta-analysis involves 12 studies and 4513 female patients with breast cancer. No clear relationship exists between overall survival (OS) and high expression of STAT3 and p-STAT3 (hazard ratio [HR] = 0.95, 95% confidence interval [CI]: 0.62–1.46, p > 0.05). p-STAT3 expression is unrelated to disease-free survival (HR = 0.69, 95% CI: 0.18–2.55, p = 0.573). Notably, the pooled effect predicts better breast cancer-specific survival with p-STAT3 overexpression (HR = 0.68, 95% CI: 0.59–0.78, I2 = 30.9%, p < 0.001). Results of subgroup analyses show that STAT3 overexpression indicates shorter OS (HR = 1.87, 95% CI: 1.42–2.45, p < 0.001) when excluding the heterogeneity test. Meanwhile, p-STAT3-positive patients have a significantly higher OS than their counterparts (HR = 0.72, 95% CI: 0.57–0.91, p < 0.01).ConclusionsPositive STAT3 expression may indicate poor OS. However, p-STAT3, as a potential molecular biomarker for predicting chemotherapeutic effect, appears to have better prognostic value than STAT3.

High Expression of STAT3 in Subcutaneous Adipose Tissue Associates with Cardiovascular Risk in Women with Rheumatoid Arthritis.

Despite the predominance of female patients and uncommon obesity, rheumatoid arthritis (RA) is tightly connected to increased cardiovascular morbidity. The aim of this study was to investigate transcriptional activity in the subcutaneous white adipose tissue (WAT) with respect to this disproportionate cardiovascular risk (CVR) in RA. CVR was estimated in 182 female patients, using the modified Systematic Coronary Risk Evaluation scale, and identified 93 patients with increased CVR. The overall transcriptional activity in WAT was significantly higher in patients with CVR and was presented by higher serum levels of WAT products leptin, resistin and IL-6 (all, p < 0.001). CVR was associated with high WAT-specific transcription of the signal transducer and activator of transcription 3 (STAT3) and the nuclear factor NF-kappa-B p65 subunit (RELA), and with high transcription of serine-threonine kinase B (AKT1) in leukocytes. These findings suggest Interleukin 6 (IL-6) and leptin take part in WAT-specific activation of STAT3. The binary logistic regression analysis confirmed an independent association of CVR with IL-6 in serum, and with STAT3 in WAT. The study shows an association of CVR with transcriptional activity in WAT in female RA patients. It also emphasizes the importance of STAT3 regulatory circuits for WAT-related CVR in RA.

Quantification of STAT3 and VEGF expression for molecular diagnosis of lymph node metastasis in breast cancer

Background:Axillary lymph node metastasis is associated with increased risk of regional recurrence, distant metastasis, and poor survival in breast malignant neoplasm. Expression of signal transducer and activator of transcription 3 (STAT3) is significantly associated with tumor formation, migration, and invasion in various cancers. In addition, vascular endothelial growth factor (VEGF) expression could promote angiogenesis and increase the risk of tumorigenesis. To determine correlations among STAT3 expression, VEGF, and clinicopathological data on lymph node involvement in breast cancer patients after surgery.Methods:The mRNA expression levels of STAT3 and VEGFs were measured in 45 breast invasive ductal carcinoma tissues, 45 peritumoral tissues, and 45 adjacent nontumor tissues by real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Postoperative pathological examination revealed explicit axillary lymph node involvement in all patients.Results:Average mRNA levels of STAT3 and VEGFs were the highest in breast invasive ductal carcinoma tissues, followed by peritumoral tissues. High expression of STAT3 showed significant positive correlation with high axillary lymph node involvement and progesterone receptor (PR), VEGF-C, VEGF-D, and vascular endothelial growth factor receptor (VEGFR)-3 expression. The expression levels of STAT3, VEGF-C, and VEGFR-3 were significantly higher in the tumor tissues of patients with axillary lymph node metastasis than in those of patients without the metastasis. Expression levels of VEGF-C and VEGFR-3 were also significantly higher in peritumoral tissues of patients with axillary lymph node metastasis. Positive correlations were found between STAT3 and VEGF-C/-D mRNA levels.Conclusion:These data suggest that STAT3/VEGF-C/VEGFR-3 signaling pathway plays an important role in carcinogenesis and lymph-angiogenesis. Our findings suggest that STAT3 may be a potential molecular biomarker for predicting the involvement of axillary lymph nodes in breast cancer, and therapies targeting STAT3 may be important for preventing breast cancer metastasis.

JAB1-STAT3 activation loop is associated with recurrence following 5-fluorouracil-based adjuvant chemotherapy in human colorectal cancer.

Jun activation domain-binding protein 1 (JAB1) has been shown to have multiple roles in tumorigenesis, including the degradation of tumor suppressor proteins such as p53, Smad7, Runx3 and the cyclin-dependent kinase inhibitor p27Kip1, and the activation of oncogenic transcription factors, such as c-Jun and hypoxia-inducible factor-1α. In addition, our previous study revealed that JAB1 positively regulates signal transducer and activator of transcription 3 (STAT3) DNA-binding activity in human colon cancer cells. In turn, the oncogenic transcription factor STAT3 positively regulates JAB1 expression, indicative of a positive feedback loop. Furthermore, high JAB1 expression is associated with a poor prognosis in numerous malignant carcinomas. However, the association between JAB1 expression and prognosis in colorectal cancer remains unclear. The aim of the present study was to elucidate the association between JAB1 and STAT3 expression and recurrence in colorectal cancer. In the present study, it was found that high JAB1 expression in primary colorectal cancer tissues is an independent predictor of recurrence following 5-fluorouracil (5-FU)-based adjuvant chemotherapy in colorectal cancer patients, and that high expression of both JAB1 and STAT3 in primary colorectal cancer tissues is associated with a lower recurrence-free survival rate following 5-FU-based adjuvant chemotherapy compared to high expression of only JAB1 or STAT3. Overall, these results suggest that JAB1 is a novel predictive marker of recurrence following 5-FU-based adjuvant chemotherapy in colorectal cancer patients, and that the JAB1-STAT3 activation loop may be a potential therapeutic target in recurrent colorectal cancer following 5-FU-based adjuvant chemotherapy.

Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC.

Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non–small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) and Src-YES-associated protein 1 (YAP1) signaling are dually activated during EGFR TKI treatment to limit therapeutic response. Methods: We used MTT and clonogenic assays, immunoblotting, and quantitative polymerase chain reaction to evaluate the efficacy of EGFR TKI alone and in combination with STAT3 and Src inhibition in three EGFR-mutant NSCLC cell lines. The Chou-Talalay method was used for the quantitative determination of drug interaction. We examined tumor growth inhibition in one EGFR-mutant NSCLC xenograft model (n = 4 mice per group). STAT3 and YAP1 expression was evaluated in tumors from 119 EGFR-mutant NSCLC patients (64 in an initial cohort and 55 in a validation cohort) by quantitative polymerase chain reaction. Kaplan-Meier and Cox regression analyses were used to assess the correlation between survival and gene expression. All statistical tests were two-sided. Results: We discovered that lung cancer cells survive initial EGFR inhibitor treatment through activation of not only STAT3 but also Src-YAP1 signaling. Cotargeting EGFR, STAT3, and Src was synergistic in two EGFR-mutant NSCLC cell lines with a combination index of 0.59 (95% confidence interval [CI] = 0.54 to 0.63) for the PC-9 and 0.59 (95% CI = 0.54 to 0.63) for the H1975 cell line. High expression of STAT3 or YAP1 predicted worse progression-free survival (hazard ratio [HR] = 3.02, 95% CI = 1.54 to 5.93, P = .001, and HR = 2.57, 95% CI = 1.30 to 5.09, P = .007, respectively) in an initial cohort of 64 EGFR-mutant NSCLC patients treated with firstline EGFR TKIs. Similar results were observed in a validation cohort. Conclusions: Our study uncovers a coordinated signaling network centered on both STAT3 and Src-YAP signaling that limits targeted therapy response in lung cancer and identifies an unforeseen rational upfront polytherapy strategy to minimize residual disease and enhance clinical outcomes.

Abstract 265: Cotargeting EGFR, STAT3 and Src-Notch pathways: a promising approach to improve the efficacy of EGFR-TKIs in the treatment of NSCLC patients

Abstract Intrinsic or acquired resistance limits the clinical effectiveness of EGFR tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC) patients (p) with EGFR mutations. One of the signaling mediators downstream of activated EGFR is signal transducer and activator of transcription 3 (STAT3). Not only does gefitinib not inhibit STAT3, but it also augments STAT3 tyrosine phosphorylation. EGFR blockade enriches lung cancer stem cells (CSCs) through NOTCH3-dependent signaling. A co-receptor of IL-6 (gp130) associates with Src and triggers activation of YAP and NOTCH. Our study is designed with three parallel objectives: firstly, to demonstrate that single EGFR TKI treatment cannot abrogate STAT3 and Src in EGFR mutant NSCLC cell lines; secondly, to examine whether the combination of gefitinib with compounds that target STAT3, (TPCA-1) and Src (saracatinib), suppresses the mechanisms of resistance; thirdly, to identify biomarkers in clinical tumor samples that may help us predict the outcome of EGFR TKIs and design effective combination therapies. Cell viability assay (MTT), western blotting, quantitative-real time PCR (qRT-PCR) and aldefluor assay-flow cytometry were used. We found that gefitinib increases pSTAT3 Y705 in PC-9 cells (that harbor the exon 19 deletion) in a time- and dose-dependent manner. Nine days after gefitinib treatment STAT3 mRNA level was significantly elevated. PC-9 cells showed dramatic increase in the fraction of ALDH+ cells upon treatment with gefitinib. TPCA-1 increased sensitivity to gefitinib in the PC-9 cells. Combination of gefitinib with TPCA-1 abrogated pSTAT3 Y705 but neither inhibited pPaxillin Y118 (Src induced) and pYAP S127 nor prevented the increment in the ALDH+ CSCs subpopulation. The triple combination of gefitinib, TPCA-1 and saracatinib was highly synergistic and abrogated pSTAT3 Y705, pPaxillin Y118 and pYAP S127. We performed qRT-PCR at baseline tumor samples of 64 EGFR mutant NSCLC p treated with first line EGFR TKIs and found that high expression of STAT3 and YAP were significantly correlated with shorter median progression-free survival (mPFS). mPFS was 9.6 months (m) (95% CI, 5.9 to 14.1) for p with low STAT3 and 18.4m (95% CI, 8.8 to 30.2) for p with high STAT3 mRNA expression (P&amp;lt;0.001). mPFS was 9.6 months (95% CI, 7.7 to 15.2) for p with low YAP and 23.4 months (95% CI, 13.0 to 28.1) for p with high YAP mRNA expression (P = 0.005). A combined STAT3 and YAP risk group model was constructed since the mRNA expression of the 2 transcripts was weakly correlated (r = .0.15; P = 0.305). mPFS was 25.7 months for p with low STAT3 and YAP mRNA (95% CI, 8.5 to 60.9), 9.4 months for p with high STAT3 and YAP mRNA (95% CI, 2.8 to 15.2), and 14.1 months for others (95% CI, 8.2 to 23.4) (P = 0.004). Single EGFR TKI treatment can no longer be considered adequate for p with EGFR mutant lung cancer and a clinical trial co-targeting STAT3 and Src is warranted. Citation Format: Niki Karachaliou, Imane Chaib, Sara Pilotto, Jordi Codony, Xueting Cai, Xuefei Li, Ana Drozdowskyj, Carles Codony, Andrés Felipe Cardona, Guillermo López-Vivanco, Alain Vergnenègre, José Miguel Sánchez, Mariano Provencio, Filippo de Marinis, Enric Carcereny, Noemí Reguart, Rosario García-Campelo, Silvia Marin, Cristina Teixido, Isabella Sperduti, Sonia Rodríguez, Roger Estrada, Raimon Puig de la Bellacasa, José Luis Ramírez, Miguel Angel Molina-Vila, Caicun Zhou, Peng Cao, Patrick Ma, Trever Bivona, Rafael Rosell. Cotargeting EGFR, STAT3 and Src-Notch pathways: a promising approach to improve the efficacy of EGFR-TKIs in the treatment of NSCLC patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 265.