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Signal transducer and activator of transcription（STAT）is a unique protein family that binds to DNA,coupled with tyrosine phosphorylation signaling pathways,acting as a transcriptional regulator to mediate a variety of biological effects.Cerebral ischemia and reperfusion can activate STATs signaling pathway,but no studies have confirmed whether STAT activation can be verified by diffusion-weighted magnetic resonance imaging（DWI）in rats after cerebral ischemia/reperfusion.Here,we established a rat model of focal cerebral ischemia injury using the modified Longa method.DWI revealed hyperintensity in parts of the left hemisphere before reperfusion and a low apparent diffusion coefficient.STAT3 protein expression showed no significant change after reperfusion,but phosphorylated STAT3 expression began to increase after 30 minutes of reperfusion and peaked at 24 hours.Pearson correlation analysis showed that STAT3 activation was correlated positively with the relative apparent diffusion coefficient and negatively with the DWI abnormal signal area.These results indicate that DWI is a reliable representation of the infarct area and reflects STAT phosphorylation in rat brain following focal cerebral ischemia/reperfusion.

Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5‐fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X‐linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor β receptor 2‐mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling. Metformin and phenformin decreased the expression of pro‐apoptotic proteins by inhibiting STAT3 phosphorylation at Ser‐727 and suppressed invasion and migration by inhibiting TGFBR2‐mediated signaling

Background Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in several malignancies. Here, we define the correlation between STAT3 expression and lymph node micrometastasis of early‐stage non‐small cell lung cancer. Then we highlight some possibilities associated with developing a way to detect tumor micrometastasis and an anticancer drug that might therapeutically inhibit the STAT3 signaling pathway. Methods The samples were collected from 50 patients with early‐stage non‐small cell lung cancer and 50 patients with benign lung tumors. Mucin 1 mRNA expression was evaluated to determine lymph node micrometastasis status. STAT3 mRNA, STAT3 protein, and phosphorylated STAT3 protein expression were evaluated through reverse transcription polymerase chain reaction, western blot, and immunohistochemistry, respectively. Measurement data was represented as mean ± standard deviation, and the t‐rest or F‐test were used. The χ2‐test was used in enumeration data. Logistic regression analysis was carried out to determine the independent risk factors influencing lymph node micrometastasis. Results STAT3 mRNA and proteins expression were correlated with lymph node micrometastasis (P < 0.05). Logistic regression analysis revealed STAT3 protein overexpression and the differentiation degree of tumors were independent risk factors for lymph node micrometastasis. Conclusion Overexpression of STAT3 might promote lymphatic micrometastasis of early‐stage non‐small cell lung cancer and might be a clinical predictor of lymph node micrometastasis.

Interleukin-6 (IL-6) is a multifunctional glycoprotein that regulates the growth of some tumors, including prostate carcinomas due to signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinases 1/2 (ERK1/2), and AKT signaling pathways. Hesperetin, as a flavanone, has several biological properties such as antitumor and anti-inflammatory. This study was carried out to evaluate the biological effects of hesperetin on the IL-6 gene expression and phosphorylated STAT3, AKT, and ERK1/2 signaling pathways in PC3 prostate cancer (PC) cells. In this study, we used real-time quantitative polymerase chain reaction (RT-qPCR) and ELISA to evaluate IL-6 gene expression and IL-6 protein secretion, respectively, in the treated PC3 cells with 0, 400, 450, and 500 μM of hesperetin. Cell survival studies were done by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after 48 h treatment with hesperetin, and cell apoptosis was determined by flow cytometry. The protein levels of activated signaling molecules (pSTAT3, pAKT, and pERK1/2) analyzed by immunoprecipitation technique. Hesperetin-treated PC3 cells resulted in reduction of cell viability. Hesperetin led to the elevation of phosphorylated STAT3, ERK1/2, and AKT signaling proteins after 48 h in a dose-dependent manner as compared to the control cells. IL-6 gene expression, as well as protein level, significantly increased ( < 0.05) in a dose-dependent pattern in treated PC3 with hesperetin compared to the control cells. Further, hesperetin exposure resulted in the induction of cell cycle arrest at G0/G1 phase. Hesperetin in PC3 cells led to elevation IL-6 gene expression, IL-6 protein secretion, pSTAT3, pERK1/2 and pAKT intracellular signaling proteins. Our results indicate that hesperetin treatment leads to the inhibition of cell proliferation and the induction of cell cycle arrest at the G1 phase. Hesperetin can be considered a potent agent which synchronizes and stops cell cycle at G0/G1 phase to apply suitable chemotherapeutic agents and radiotherapy in PC cells. This study evaluates biological effects of hesperetin on the cell cycle, interleukin-6 gene expression and some phosphorylated signaling pathways in PC3 prostate cancer cells. Hesperetin resulted in the inhibition of cell proliferation via inducing G0/G1 phase arrest in spite of the elevation of interleukin-6 gene expression and phosphorylated AKT, STAT3, and ERK1/2 intracellular signaling proteins. Therefore, hesperetin can be considered a potent agent which synchronizes and stop cell cycle at G0/G1 phase so that suitable chemotherapeutic agents can be applied in PC3 prostate cancer cells. PC: Prostate cancer, IL-6: Interleukin-6, STAT3: Signal transducer activator of transcription 3, ERK1/2: Extracellular signal-regulated kinases 1/2, IC50: Inhibitory concentration of 50%.

Cholangiocarcinoma (CCA) is a malignant biliary tract tumor with an extremely poor prognosis. There is an urgent demand to explore novel therapeutic strategies. L-fucose has been confirmed to participate in anti-inflammation and antitumor activities. However, the effect of L-fucose on the progression of CCA has not been well investigated. This study aimed to determine whether L-fucose induced the inhibition of CCA and its possible mechanism. The anti-growth activity was determined using Cell Counting Kit-8 assay, colony formation assays, Annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI) assay, and cell cycle analysis. The anti-metastasis activity was determined by wound healing, transwell, and invasion assays. The anti-angiogenesis activity was determined by tube formation and transwell assays. MicroRNAs that may be involved in the L-fucose-induced CCA inhibition was analyzed using bioinformatics methods. The preclinical therapeutic efficacy was mainly estimated by ultrasound in xenograft nude mouse models. Differences were analyzed via Student's t test or one-way analysis of variance. L-Fucose induced apoptosis and G0/G1 cell cycle arrest, inhibited cell epithelial-mesenchymal transition of CCA cells, and additionally inhibited tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner, leading to a decrease in cell proliferation, metastasis, and angiogenesis. Mechanistically, L-fucose induced microRNA-200b (miR-200b) upregulation, and mitogen-activated protein kinase 7 (MAPK7) downregulation was found to be targeted by miR-200b, with decreased cell proliferation and metastasis. Additionally, phosphorylated signal transducer and activator of transcription 3 was found to be downregulated after L-fucose treatment. Finally, in vivo experiments in CCA xenograft models also confirmed the antitumor properties of L-fucose. L-Fucose inhibited the progression of CCA via the miR-200b/MAPK7 and signal transducer and activator of transcription 3 signaling pathways.

Signal transducer and activator of transcription 3 (STAT3) and mucin 1 (MUC1) are associated with development, progression and a poor prognosis in several types of cancer. The present study investigated the levels of STAT3 and MUC1 in patients with non-small cell lung cancer (NSCLC) following surgery. In total, 98 patients with NSCLC were enrolled into the study. STAT3, phosphorylated (p)-STAT3 and MUC1 expression in NSCLC specimens obtained from patients were investigated using immunohistochemical analysis. Enumeration results were analyzed using the χ2 test or Fisher's exact probability test. Spearman's rank correlation was used to analyze correlations between STAT3, p-STAT3 and MUC1 expression. Univariate analysis was conducted using the Kaplan-Meier estimator curve method and Cox regression multivariate analysis was performed in order to determine prognostic factors. Results demonstrated that STAT3 and p-STAT3 expression was identified in 82 and 51 patients, respectively. Furthermore, the expression of MUC1 was identified in 61/98 cases (62.2%) and STAT3 expression was significantly associated with pathological tumor-node-metastasis stage (pTNM; P<0.01). p-STAT3 expression was associated with pathological type (P<0.01), pathological lymph nodes (pN; P<0.01) and pTNM (P<0.05). MUC1 expression was associated with pathological type (P<0.05), pathological tumor pT (P<0.05), pN (P<0.01) and pTNM (P<0.01). STAT3 expression was positively associated with p-STAT3 expression (P<0.05) and p-STAT3 expression was positively associated with MUC1 expression (P<0.01). Overall, the results identified that the 3-year survival rate was 56.1% and was significantly associated with the degree of differentiation (P<0.05), pT (P<0.01), pN (P<0.01), pTNM stage (P<0.01), p-STAT3 expression (P<0.01) and MUC1 expression (P<0.05). Results obtained from the Cox multivariate regression analysis demonstrated that pN and p-STAT3 expression were independent factors associated with the 3-year survival rate.

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.

The cancer-testis (CT) family of antigens are expressed in multiple types of malignant neoplasm and are silent in normal tissues, apart from the testis. Immunotherapy targeting CT antigens is a promising therapeutic strategy for treatment of solid tumors. One member of this family, melanoma-associated antigen A4 (MAGE-A4), has been demonstrated to be expressed in melanomas and lung cancer. Patients with tumors expressing the MAGE-A4 antigen exhibit specific cellular and humoral immune responses to the antigen, resulting in a favorable prognosis. Conversely, the expression of MAGE-A4 is associated with poor survival in lung cancer. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells, which are upregulated in the cancer microenvironment. Little is known regarding any potential correlation between the expression of MAGE-A4 antigens and the accumulation of MDSCs. The present study aimed to examine the association between circulating MDSC levels and MAGE-A4 expression in a mouse model of Lewis lung cancer. The expression of MAGE-A4 in tumor cells or tissues was evaluated using western blotting, while the percentage of MDSCs (CD11b+Gr-1+) in the blood was detected by flow cytometry. In addition, the suppressive capacity of MDSCs and the effectiveness of MDSC depletion were assessed in C57BL/6 tumor-bearing mice. MDSCs were demonstrated to upregulate MAGE-A4 expression via the phosphosphorylated-signal transducer and activator of transcription 3705 pathway, while depletion of MDSCs decreased the tumor growth rate, prolonged median survival and enhanced the recognition of MAGE-A4 by CD8+ T cells. These findings indicated that immunotherapeutic strategies involving induction of cytotoxic T lymphocytes that target MAGE-A4, in combination with MDSC depletion, may be an effective approach to immunotherapy for cancer types with high expression of MAGE-A4.

Studies indicate that the AIM2 inflammasome plays an important role in tumor occurrence and development. The present study examined the prognostic significance of AIM2 expression and the correlation between AIM2 expression and p-STAT3 expression in hypopharyngeal squamous cell carcinoma (HSCC), which remain unknown. AIM2 and p-STAT3 were detected using immunohistochemistry (IHC) in 111 paraffin-embedded tissue samples from primary HSCC sites and 20 samples from matched adjacent non-malignant sites. Western blotting was utilized to investigate AIM2, p-STAT3 and total STAT3 in 5 pairs of fresh tissue samples. Western blotting indicated that AIM2 expression was significantly lower (P<0.05), but that p-STAT3 levels and the p-STAT3/STAT3 ratio were higher (P<0.01) in HSCC tissues than in adjacent normal hypopharyngeal tissues. IHC analysis of the 111 HSCC samples revealed low AIM2 and high p-STAT3 expression in 48 (43.2%) and 58 (52.3%) samples, respectively. High AIM2 expression and low p-STAT3 expression were detected in 13 (75%) and 18 (90%) adjacent normal hypopharyngeal tissue samples, respectively. In the HSCC samples, low AIM2 expression was closely related to lymph node metastasis and intravascular tumor thrombus (P<0.05). Kaplan-Meier survival curves revealed that low AIM2 levels were strongly associated with poor survival for HSCC patients (P<0.0001). Additionally, Cox proportional hazards regression models indicated that low AIM2 expression significantly predicted poor prognosis for HSCC patients (P<0.0001), and multivariate analysis revealed that AIM2 expression could be an independent prognostic factor for HSCC patients (P<0.0001). Furthermore, AIM2 expression was negatively correlated with p-STAT3 expression in the HSCC tissue samples, and combined analysis revealed that patients with low AIM2 and high p-STAT3 levels had the worst survival rate. Moreover, receiver operating characteristic (ROC) curve analysis confirmed that AIM2 was predictive of specific survival in all HSCC patients [area under the curve (AUC)=0.7160]. In conclusion, our data suggested that for HSCC patients, AIM2 and p-STAT3 expression detected via IHC could serve as a biomarker to predict tumor progression and as an independent prognostic factor.

BackgroundMouse models have shown that interleukin (IL)6 stimulates survival, proliferation and progression to cancer of intestinal epithelial cells via activation of signal transducers and activators of transcription 3 (STAT3).ObjectiveTo investigate the expression of IL6/phosphorylated STAT3 (p-STAT3)/suppressor of cytokine signalling 3 (SOCS3) in biopsy specimens from patients with ulcerative colitis (UC) and UC-related colorectal cancer (CRC) progression.MethodsBiopsy specimens from patients with inactive UC (n=18), active UC (n=28), UC with low-grade dysplasia (LGD) (n=9), UC with high-grade dysplasia (HGD) (n=7), UC-CRC (n=11) and sporadic CRC (n=14) were included. Biopsy specimens (n=9) from patients without colonic abnormalities served as control. The protein expression of IL6, p-STAT3 and SOCS3 was determined immunohistochemically.ResultsPatients with active UC had significantly more IL6 and p-STAT3-positive epithelial cells than both patients with inactive UC and controls (strong positive IL6: 53.6%, 11.1% and 0%, respectively; p-STAT3: 64.3%, 22.2% and 11.1%, respectively; all p≤0.012). SOCS3-positive cells were significantly increased in colonic epithelium of both inactive and active UC compared with controls (strong positive: 94.4%, 96.4% and 11.1%, respectively; both p<0.001). In dysplasia and cancer, significantly more epithelial cells expressed IL6 and p-STAT3 compared with controls (strong positive IL6: 72.7% and 0% respectively; p-STAT3: 54.5% and 11.1%, respectively; both p<0.05), whereas the proportion of SOCS3-positive cells in this progression reduced (LGD 33.3%; HGD 14.3%; UC-CRC 9.1%). In addition, methylation of the SOCS3 gene was detected in epithelial cells from UC-CRC biopsy specimens.ConclusionThe importance of IL6/p-STAT3 in patients with inflammation-induced CRC was demonstrated. Moreover, SOCS3 may be involved in UC pathogenesis and the absence of SOCS3 seems critical for CRC progression.