Signal Transducer And Activator Of Transcription 3 Axis Research Articles

Circular RNA RHOT1 promotes progression and inhibits ferroptosis via mir-106a-5p/STAT3 axis in breast cancer.

To explore the effect of circRHOT1 on breast cancer progression and the underlying mechanism. Significantly, our data revealed that the depletion of circRHOT1 was able to repress the proliferation and induce the apoptosis of breast cancer cells. CircRHOT1 knockdown could remarkably inhibit the invasion and migration in the breast cancer cells. Meanwhile, the depletion of circRHOT1 enhanced the erastin-induced inhibition effect on cell growth of breast cancer cells. The circRHOT1 knockdown notably increased the levels of reactive oxygen species (ROS), iron, and Fe2+ in breast cancer cells. Mechanically, circRHOT1 was able to sponge microRNA-106a-5p (miR-106a-5p) and inhibited ferroptosis by down-regulating miR-106a-5p in breast cancer cells. Besides, miR-106a-5p induced ferroptosis by targeting signal transducer and activator of transcription 3 (STAT3) in the system. Moreover, the overexpression of STAT3 and miR-106a-5p inhibitor could reverse circRHOT1 knockdown-mediated breast cancer progression. Functionally, circRHOT1 promoted the tumor growth of breast cancer in vivo. In conclusion, we discovered that circRHOT1 contributed to malignant progression and attenuated ferroptosis in breast cancer by the miR-106a-5p/STAT3 axis. Our finding provides new insights into the mechanism by which circRHOT1 promotes the development of breast cancer. CircRHOT1 and miR-106a-5p may serve as potential targets for breast cancer therapy.

MiR-199a-5p-HIF-1α-STAT3 Positive Feedback Loop Contributes to the Progression of Non-Small Cell Lung Cancer.

Background: Non-small cell lung cancer (NSCLC) is the most common malignancy worldwide. MiR-199a-5p has been reported to play important roles in multiple tumors, inclusive of NSCLC. However, little is definitively known pertaining to its explicit mechanism of action in NSCLC.Methods: The expressions of miR-199a-5p and hypoxia-inducible factor-1α (HIF-1α) mRNA were quantified employing qRT-PCR. H1299 and A549 cells were transiently transfected with miR-199a-5p mimics or inhibitors. Then, CCK-8 assays, flow cytometry analysis, and Transwell assay were performed for detecting cell proliferation, cell cycle, apoptosis, migration, and invasion of NSCLC cells, respectively. HIF-1α, signal transducer and activator of transcription 3 (STAT3), and p-STAT3 expressions were detected via Western blotting. Bioinformatic analysis and dual-luciferase assay were performed to investigate the interactions among miR-199a-5p, HIF-1α, and STAT3. Xenograft models were established with nude mice for further analyzing the bevacizumab resistance of NSCLC cells.Results: MiR-199a-5p expression was markedly attenuated in NSCLC tissues and cell lines. Overexpression of miR-199a-5p repressed the proliferation, migration, and invasion but induced the apoptosis of NSCLC cells. HIF-1α was identified as a direct target of miR-199a-5p. There was a positive feedback loop among miR-199a-5p, HIF-1α, and STAT3. Co-transfection of HIF-1α or STAT3 overexpression plasmids counteracted the effects of miR-199a-5p. In vivo experiments indicated that the feedback loop was in association with the bevacizumab resistance of NSCLC cells.Conclusion: MiR-199a-5p blocked the progression of NSCLC and sensitized NSCLC cells to bevacizumab by suppressing HIF-1α and STAT3, while the HIF-1α/STAT3 axis suppressed the expression of miR-199a-5p, which forms a positive feedback loop to promote the sustaining progression of NSCLC.

Neem leaf glycoprotein salvages T cell functions from Myeloid-derived suppressor cells-suppression by altering IL-10/STAT3 axis in melanoma tumor microenvironment.

Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune functions. We have observed that an immunomodulator, neem leaf glycoprotein (NLGP), inhibits tumor-resident MDSCs and enhances antitumor CD8+ T cell immunity. NLGP inhibits the number as well as functions of tumor-resident MDSCs (Gr1±CD11b±) and enhances antitumor CD8± T cell immunity by downregulating arginase 1 and inducible nitric oxide synthase production in MDSCs. Accordingly, decreased T cell anergy and helper to regulatory T cell conversion have been observed in the presence of NLGP, which ultimately augments T cell functions. Mechanistically, NLGP-mediated rectification of T cell suppressive functions of MDSCs was primarily associated with downregulation of the interleukin (IL)-10/signal transducer and activator of transcription 3 (STAT3) signaling axis within the tumor microenvironment, as confirmed by knockdown of STAT3 (by STAT3-siRNA) and using IL-10-/- mice. Thus, NLGP-mediated suppression of MDSC functions in tumor hosts is appeared to be another associated effective mechanism for the eradication of murine melanoma by NLGP.

Aloperine Inhibits Proliferation and Promotes Apoptosis in Colorectal Cancer Cells by Regulating the circNSUN2/miR-296-5p/STAT3 Pathway.

BackgroundAloperine can regulate miR-296-5p/Signal Transducer and Activator of Transcription 3 (STAT3) pathway to inhibit the malignant development of colorectal cancer (CRC), but the regulatory mechanism is unclear. This study explored the upstream mechanism of Aloperine in reducing CRC damage from the perspective of the circRNA-miRNA-mRNA regulatory network.MethodsAfter treatment with gradient concentrations of Aloperine (0.1 mmol/L, 0.2 mmol/L, 0.4 mmol/L, 0.8 mmol/L and 1 mmol/L) for 24 hours, changes in CRC cell proliferation and apoptosis were detected by functional experiments. Data of the differential expression of miR-296-5p in CRC patients and healthy people were obtained from Starbase. The effects of Aloperine on 12 differentially expressed circRNAs were detected. The binding of miR-296-5p with NOP2/Sun RNA methyltransferase 2 (circNSUN2) and STAT3 was predicted by TargetScan and confirmed through dual-luciferase experiments. The expressions of circNSUN2, miR-296-5p and STAT3 as well as apoptosis-related genes in CRC cells were detected by qRT-PCR and Western blot as needed. Rescue experiments were conducted to test the regulatory effects of circNSUN2, miR-296-5p and STAT3 on CRC cells.ResultsAloperine at a concentration gradient inhibited proliferation and promoted apoptosis in CRC cells. The abnormally low expression of miR-296-5p in CRC could be upregulated by Aloperine. Among the differentially expressed circRNAs in CRC, only circNSUN2 not only targets miR-296-5p, but also can be regulated by Aloperine. The up-regulation of circNSUN2 offset the inhibitory effect of Aloperine on cancer cells. The rescue experiments finally confirmed the regulation of circNSUN2/miR-296-5p/STAT3 axis in CRC cells.ConclusionBy regulating the circNSUN2/miR-296-5p/STAT3 pathway, Aloperine prevents the malignant development of CRC cells.

Circular RNA hsa_circ_0000117 accelerates the proliferation and invasion of gastric cancer cells by regulating the microRNA-337-3p/signal transducer and activator of transcription 3 axis

ABSTRACT Circular RNA hsa_circ_0000117 is reportedly increased in Gastric cancer (GC), however, its role is unexplored. Hsa_circ_0000117 expression and function in GC was investigated using standard cell phenotypic and expression assays. Pull-down and luciferase reporter assays also elucidated hsa_circ_0000117 mechanisms. In the present study, we observed increased hsa_circ_0000117 and signal transducer and activator of transcription 3 (STAT3) expression, while microRNA-337-3p (miR-337-3p) was decreased in GC cells. Depleted hsa_circ_0000117 decreased GC proliferation and invasion. Hsa_circ_0000117 was also identified as a miR-337-3p sponge. Also, STAT3 was identified as a miR-337-3p target. Similarly, rescue assays indicated STAT3 overexpression (or miR-337-3p inhibition) reversed hsa_circ_0000117 effects in GC progression. Thus, our data suggested hsa_circ_0000117 exhibited oncogene properties in combination with the hsa_circ_0000117/miR-337-3p/STAT3 axis in GC, potentially providing a new therapeutic target for GC. Abbreviations GC: gastric cancer; STAT3: Signal transducer and activator of transcription 3; circRNA: Circular RNA; miRNA: microRNA; DMEM: Dulbecco’s modified Eagle’s medium; FBS: fetal bovine serum; PVDF: polyvinylidene fluoride; CCK-8: Cell counting kit-8; qRT-PCR: Quantitative real-time PCR; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis; TNM: TNM Classification of Malignant Tumors; mTOR: mechanistic target of rapamycin; ANOVA: one-way analysis of variance

IL-6 in inflammation, autoimmunity and cancer.

IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6-STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6-STAT3 axis is a critical target for treating diseases.

Long noncoding RNA LINC00324 promotes retinoblastoma progression by acting as a competing endogenous RNA for microRNA-769-5p, thereby increasing STAT3 expression.

Long intergenic non–protein-coding RNA 324 (LINC00324) is abnormally expressed in multiple human cancer types and plays an important role in cancer initiation and progression. This study showed that LINC00324 was expressed at higher levels in retinoblastoma (RB) tumors and cell lines than in control samples. Increased LINC00324 expression closely correlated with the TNM stage, optic nerve invasion, and shorter overall survival among patients with RB. The knockdown of LINC00324 decreased RB cell proliferation, colony formation, migration, and invasion, and promoted apoptosis and cell cycle arrest in vitro as well as hindered tumor growth in vivo. With respect to the mechanism, LINC00324 acted as a competing endogenous RNA for microRNA-769-5p (miR-769-5p) in RB cells. The mRNA of signal transducer and activator of transcription 3 (STAT3) was identified as a direct target of miR-769-5p in RB cells. Rescue experiments indicated that restoration of STAT3 expression attenuated the tumor-suppressive actions of miR-769-5p in RB cells. Downregulation of miR-769-5p or restoration of STAT3 almost completely reversed the effects of LINC00324 knockdown on RB cells. Our findings describe a novel RB-related LINC00324–miR-769-5p–STAT3 axis that is implicated in the malignancy of RB in vitro and in vivo. This study may point to innovative therapeutic targets in RB.

IcarisideII facilitates the differentiation of ADSCs to SCs via let-7i/STAT3 axis to preserve erectile function

BackgroundIcarisideII (ICAII) could promote the differentiation of adipose tissue-derived stem cells (ADSCs) to Schwann cells (SCs), leading to improvement of erectile function (EF) and providing a realistic therapeutic option for the treatment of erectile dysfunction (ED). However, the underlying molecular mechanisms of ADSCs and ICAII in this process remain largely unclear.MethodsADSCs were treated with different concentrations of ICAII. Cell proliferation was determined by MTT assay. qRT-PCR and western blot were performed to detect expressions of SCs markers, signal transducer and activator of transcription-3 (STAT3), and microRNA-let-7i (let-7i). Luciferase reporter assay was conducted to verify the regulatory relationship between let-7i and STAT3. The detection of intracavernosal pressure (ICP) and the ratio of ICP/mean arterial pressure (MAP) were used to evaluate the EF in bilateral cavernous nerve injury (BCNI) rat models.ResultsICAII promoted cell proliferation of ADSCs in a dose-dependent manner. The mRNA and protein levels of SCs markers were increased by ICAII treatment in a dose-dependent manner in ADSCs. Moreover, let-7i was significantly decreased in ICAII-treated ADSCs and upregulation of let-7i attenuated ICAII-induced promotion of SCs markers. In addition, STAT3 was a direct target of let-7i and upregulated in ICAII-treated ADSCs. Interestingly, overexpression of STAT3 abated the let-7i-mediated inhibition effect on differentiation of ADSCs to SCs and rescued the ICAII-mediated promotion effect on it. Besides, combination treatment of ADSCs and ICAII preserved the EF of BCNI rat models, which was undermined by let-7i overexpression.ConclusionICAII was effective for preserving EF by promoting the differentiation of ADSCs to SCs via modulating let-7i/STAT3 pathway.

Abstract 3556: MiR-506 suppresses tumor progression by reprogramming macrophage polarization in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancy owing to its aggressive nature and tumor-associated macrophages (TAMs) significantly promote disease progression by representing an immunosuppressive phenotype in PDAC. Macrophages could be functionally reprogrammed to opposite phenotype owning to different microenvironment and STAT3 (signal transducer and activator of transcription 3) activation may play an essential role in TAM polarization, directly contributing to local immunosuppression. Our recent study demonstrated that MiR-506 functioned as a tumor suppressor in many cancer types through the regulation of multiple pathways and directly targeted STAT3 in PDAC cells. In this study, we hypothesized that MiR-506 could affect tumor microenvironment and exert a tumor suppressive function in PDAC by reprograming TAM polarization through targeting STAT3 in TAM. Our results provided evidence that MiR-506 downregulation was associated with less immunosuppressive TAMs accumulation and better prognosis in human PDAC. MiR-506 could reduce the infiltration of immunosuppressive TAMs and inhibit the PDAC progression in mouse model. MiR-506 reprogramed macrophage polarization from an immunosuppressive phenotype to immune-activated phenotype through direct targeting the STAT3 axis. Silencing and inhibiting STAT3 recapitulated the effects of MiR-506. These findings expand the known mechanisms of MiR-506-mediated tumor suppression to reprogramming TAM polarization and suggest a strategy for using MiR-506 as an anti-STAT3 approach to PDAC immunotherapy. Citation Format: Longhao Sun, Qianqian Song, Weijun Tian, Zhixiang Zhang. MiR-506 suppresses tumor progression by reprogramming macrophage polarization in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3556.

HOXA11-AS regulates JAK-STAT pathway by miR-15a-3p/STAT3 axis to promote the growth and metastasis in liver cancer.

HOMEOBOX A11 (HOXA11) antisense RNA (HOXA11-AS), a newly identified long noncoding RNAs, is involved in the carcinogenic process of several human tumors. However, the role of HOXA11-AS in liver cancer progression is not well understood. This study used liver cancer tissues and cell lines (CSQT-2 and HCCLM3) to explore the potential mechanism of HOXA11-AS. Quantitative real-time polymerase chain reaction and Western blot were applied to evaluate the bio-molecules expression. Bioinformatics analysis, RNA pull down and luciferase report assay were applied to determine the molecules bind. MTT, transwell, and wound healing assay were used to measure the cell growth situation. HOXA11-AS was highly expressed in liver cancer tissues and cell lines, which was closely related with poor prognosis in patients with liver cancer. HOXA11-AS could act as a competing endogenous RNA for miR-15a-3p. Besides, miR-15a-3p negatively controlled its target molecule signal transducer and activator of transcription 3 (STAT3). Furthermore, a linear regression analysis and biological experiments showed a positive correlation between HOAX11-AS and STAT3. Moreover, HOAX11-AS overexpression activated the Janus kinase (JAK)-STAT pathway and thus promoted the growth, migration, and invasion of liver cancer cells, which might be through regulating miR-15a-3p/STAT3 axis. Our study suggested that HOAX11-AS could regulate the JAK-STAT signaling pathway by miR-15a-3p/STAT3 axis to promote the progression of liver cancer. Thus, HOXA11-AS may be regarded as an effective biomarker with diagnostic, prognostic, and therapeutic potentials for liver cancer.

Triptolide exerts an anti-tumor effect on non‑small cell lung cancer cells by inhibiting activation of the IL‑6/STAT3 axis.

Lung cancer is the leading cause of cancer‑associated mortality and current treatments are not sufficiently effective. Numerous studies have revealed that triptolide (TP), a classical traditional Chinese medicine compound widely used as an anti‑inflammatory and antirheumatic drug, also has an antitumor effect. This effect is hypothesized to be mediated by multiple pathways, with signal transducer and activator of transcription 3 (STAT3) possibly one of them. Evidence indicates that STAT3 participates in the initiation and progression of lung cancer during cell proliferation, apoptosis and migration; however, whether and how TP affects STAT3 and its targets remain unclear. In this study, the potential role of TP in the proliferation, apoptosis, and migration of non‑small cell lung cancer cell lines was investigated and evaluated the impact of TP on the interleukin‑6 (IL‑6)/STAT3 axis. The results showed that TP inhibited cell proliferation and migration and induced apoptosis. TP decreased the phosphorylation of STAT3, inhibited STAT3 translocation into the nucleus, and reduced the expression of STAT3 target genes involved in cell survival, apoptosis and migration, e.g. C‑myc, BCL‑2, myeloid cell leukemia‑1 (MCL‑1), and matrix metallopeptidase 9 (MMP‑9). Additionally, IL‑6‑induced activation of STAT3 target genes (e.g. MCL‑1 and BCL‑2) was attenuated by TP and homoharringtonine. In conclusion, the effect of TP on STAT3 signaling points to a promising strategy for drug development.

LncRNA SNHG16 aggravates tumorigenesis and development of hepatocellular carcinoma by sponging miR-4500 and targeting STAT3.

Hepatocellular carcinoma (HCC) is the most common type of primary liver tumor and becomes a lethal malignancy on account of high mortality and increasing incidence. A growing body of studies has proved that long noncoding RNAs (lncRNAs) participate in the development of diverse cancers. Although it has been commonly accepted that SNHG16 is a procancer gene in numerous cancers, the regulatory mechanism of SNHG16 in HCC still needs more explorations. In this study, our results delineated that SNHG16 presented much higher expression levels in HCC tissues and cells, particularly in advanced stages of HCC. Enhanced SNHG16 expression was strongly related to poor prognosis. SNHG16 facilitated HCC progression by promoting cell proliferation, migration, invasion, and epithelial-mesenchymal transition process as well as inhibiting cell apoptosis. SNHG16 served as a sponge for miR-4500 in HCC and miR-4500 neutralized the influences of SNHG16 knockdown on HCC. SNHG16 was confirmed to compete with signal transducer and activator of transcription 3 (STAT3) to bind with miR-4500. SNHG16 aggravated the development of HCC via sponging miR-4500 so as to upregulate STAT3. In other words, this study was the first to investigate the potential mechanism of SNHG16 in HCC and verified SNHG16 exerted its carcinogenesis by miR-4500/STAT3 axis, suggesting SNHG16 may be a new underlying therapeutic target for HCC treatment.

Arsenic trioxide attenuates STAT-3 activity and epithelial-mesenchymal transition through induction of SHP-1 in gastric cancer cells

BackgroundWe investigated the effect of arsenic trioxide (ATO) for inhibition of signal transducer and activator of transcription 3 (STAT3) and epithelial-mesenchymal transition (EMT) in gastric cancer cells, and the role of SH2 domain-containing phosphatase-1 (SHP-1) during this process.MethodsWe used AGS cells, which showed minimal SHP-1 expression and constitutive STAT3 expression. After treatment of ATO, cellular migration and invasion were assessed by using wound closure assay, Matrigel invasion assay and 3-D culture invasion assay. To validate the role of SHP-1, pervanadate, a pharmacologic phosphatase inhibitor, and SHP-1 siRNA were used. Xenograft tumors were produced, and ATO or pervanadate were administered via intraperitoneal (IP) route.ResultsTreatment of ATO 5 and 10 μM significantly decreased cellular migration and invasion in a dose-dependent manner. Western blot showed that ATO upregulated SHP-1 expression and downregulated STAT3 expression, and immunofluorescence showed upregulation with E-cadherin (epithelial marker) and downregulation of Snail1 (mesenchymal marker) expression by ATO treatment. Anti-migration and invasion effect and modulation of SHP-1/STAT3 axis by ATO were attenuated by pervanadate or SHP-1 siRNA. IP injection of ATO significantly decreased the xenograft tumor volume and upregulated SHP-1 expression, which were attenuated by co-IP injection of pervanadate.ConclusionOur data suggest that ATO inhibits STAT3 activity and EMT process by upregulation of SHP-1 in gastric cancer cells.

Long noncoding RNA TSLNC8 is a tumor suppressor that inactivates the interleukin-6/STAT3 signaling pathway.

TSLNC8 is a promising prognostic predictor for patients with HCC, and the TSLNC8-transketolase-STAT3 axis is a potential therapeutic target for HCC treatment. (Hepatology 2018;67:171-187).

MIAT promotes proliferation and hinders apoptosis by modulating miR-181b/STAT3 axis in ox-LDL-induced atherosclerosis cell models

BackgroundPlenty of lncRNAs and microRNAs have been identified to be critical mediators in the progression of atherosclerosis (AS). Myocardial infarction-associated transcript (MIAT) were aberrantly high expressed and closely associated with the pathogenesis of AS. However, its molecular mechanism has not been well characterized. MethodsThe expression patterns of MIAT and microRNA-181b (miR-181b) in clinical samples and cells were measured by RT-qPCR assays. Luciferase reporter assay and RIP assays were used to manifest the potential interaction between MIAT, miR-181b and signal transducer and activator of transcription 3 (STAT3). Cell Counting Kit-8 (CCK-8), Propidium Iodide (PI) staining, Terminal dexynucleotidyl transferase(TdT)-mediated dUTP nick end labeling (TUNEL) and western blot assays were carried out to detect cell proliferation, cell cycle distribution, apoptosis, and STAT3 protein level, respectively. ResultsMIAT expression was up-regulated and miR-181b expression was down-regulated in AS patients serum and oxidized low-density lipoprotein (ox-LDL) induced AS cells model. MIAT facilitated cell proliferation, accelerated cell cycle progression and inhibited apoptosis in ox-LDL-induced AS cell lines, while this effect was partly reversed by miR-181b overexpression. Moreover, MIAT enhanced STAT3 expression through sequestering miR-181b as a molecular sponge. Furthermore, MiR-181b hindered cell growth, induced cell cycle arrest and promoted apoptosis by directly targeting STAT3. ConclusionMIAT performed as an induction factor of AS by regulating miR-181b/STAT3 axis in ox-LDL-induced AS cell lines, offering a new insight into the potential application of MIAT in AS treatment.

The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist, counteracts hepatocarcinogenesis through cAMP-PKA-EGFR-STAT3 axis.

Epidemiological studies have demonstrated a close association of type 2 diabetes and hepatocellular carcinoma (HCC). Exenatide (Ex-4), a potent diabetes drug targeting glucagon-like peptide-1 receptor (GLP-1R), is protective against non-alcoholic fatty liver disease (NAFLD). However, the Ex-4 function and GLP-1R status have yet been explored in HCC. Herein we investigated the effect of Ex-4 in diethylnitrosamine (DEN)-treated mice consuming control or high-fat high-carbohydrate diet. Administration of Ex-4 significantly improved obesity-induced hyperglycemia and hyperlipidemia and reduced HCC multiplicity in obese DEN-treated mice, in which suppressed proliferation and induced apoptosis were confined to tumor cells. The tumor suppression effects of Ex-4 were associated with high expression of GLP-1R and activation of cyclic AMP (cAMP) and protein kinase A (PKA). Importantly, Ex-4 also downregulated epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3), which lie downstream of cAMP-PKA signaling, resulting in suppression of multiple STAT3-targeted genes including c-Myc, cyclin D1, survivin, Bcl-2 and Bcl-xl. The growth inhibitory effects of Ex-4 were consistent in GLP-1R-abundant hepatoma cell lines and xenograft mouse model, wherein both PKA and EGFR had obligatory roles in mediating Ex-4 functions. In addition, Ex-4 also effectively suppressed inflammatory and fibrotic phenotypes in mice fed with methionine-choline-deficient (MCD) diet and choline-deficient ethionine-supplemented (CDE) diet, respectively. In summary, Ex-4 elicits protective functions against NAFLD and obesity-associated HCC through cAMP-PKA-EGFR-STAT3 signaling, suggesting its administration as a novel approach to reduce HCC risk in diabetic patients.

MicroRNA-148a suppresses proliferation and invasion potential of non-small cell lung carcinomas via regulation of STAT3

Lung cancer has the highest morbidity and mortality in the world, and non-small cell lung carcinomas (NSCLC) account for 80% of cases of lung cancer. The mechanism of NSCLC is still largely unknown, and finding novel targets is of great importance for the treatment of NSCLC. The current study was designed to evaluate the role of miR-148a in NSCLC cell proliferation and invasion and to investigate the possible molecular mechanisms. We found that miR-148a expression was decreased in NSCLC tissues and cell lines. Upregulation of miR-148a significantly decreased A549 cell proliferation, and downregulation of miR-148a significantly increased A549 cell proliferation. Upregulation of miR-148a markedly increased apoptotic cell death and inhibited cell invasion potential. Upregulation of miR-148a significantly decreased signal transducer and activator of transcription 3 (STAT3) expression and 3′-untranslated region luciferase activity. Downregulation of miR-148a significantly increased STAT3 expression. Overexpression of STAT3 significantly inhibited the effect of miR-148a on cell viability and invasion potential. In conclusion, we found that miR-148a inhibited NSCLC cell proliferation and invasion potential through the inhibition of STAT3. Our findings highlight miR-148a/STAT3 axis as a novel therapeutic target for the inhibition of NSCLC growth.

Sulforaphane improves chemotherapy efficacy by targeting cancer stem cell-like properties via the miR-124/IL-6R/STAT3 axis.

Gastric carcinoma (GC) is the second leading cause of cancer-related mortality worldwide. The efficacy of standard chemotherapy for GC, such as cisplatin (CDDP), is dissatisfactory partly due to the toxic/side-effects. Sulforaphane (SFN), which exhibits effective anti-cancer functions, is a phytochemical converted from cruciferous plants. Our present study aimed to identify whether SFN could enhance the anti-cancer effects of low-dose CDDP and to determine the underlying mechanisms. Herein, co-exposure of SFN and CDDP significantly inhibited the viabilities of gastric cancer cells. For the molecular mechanisms, CDDP alone increased the cancer stem cell (CSC)-like properties in gastric cancer cells via activating the interleukin-6 (IL-6)/IL-6 receptor (IL-6R)/signal transducer and activator of transcription 3 (STAT3) signaling. However, SFN could activate the microRNA-124 (miR-124), which directly targets the 3′-untranslated regions (UTR) of the IL-6R and STAT3. Moreover, knockdown of miR-124 eliminated the effects of SFN on CSC-like properties in GC cells, and in turn enhanced the anti-cancer effects of low-dose CDDP. These findings not only suggested a mechanism whereby SFN enhanced the anti-cancer functions of CDDP, but also helped to regard SFN as a potential chemotherapeutic factor in gastric cancer.

IL-6/STAT3/ARF: the guardians of senescence, cancer progression and metastasis in prostate cancer.

Prostate cancer is one of the most prevalent forms of cancer in men worldwide. It remains a clinical challenge to identify lethal metastatic prostate cancers, which escape standard therapeutic intervention. Aberrant interleukin-6 (IL-6) / signal transducer and activator of transcription-3 (STAT3) signalling and loss of p53 occur during prostate cancer progression to metastatic disease. The abnormality of the IL-6/STAT3/p53 axis is frequently accompanied by other genetic alterations; however, its potential role as an important mediator of oncogenic reprogramming, invasion and metastatic transformation remains unknown. The failure of anti-IL-6 treatments is still unexplained and may be due to an incomplete understanding of the mechanism of the in vivo role of IL-6/STAT3 in prostate cancer. The identification of the alternative reading frame protein (ARF) / murine double minute protein (MDM2) / p53 tumour suppressor pathway potentially involving the IL-6/STAT3 axis as a restricting factor in prostate cancer deficient in the tumour suppressor phosphatase and tensin homologue (PTEN) opened new avenues to currently available therapies. This review summarises the current knowledge on the role of crucial pathways driving prostate cancer progression as well as metastatic disease and discusses the potential use of novel specific target molecules and how it can be exploited to avoid overtreatment and increase quality of life.

Engaged for survival

In normal tissues or tumors, cells have extensive opportunities for adhesion to their neighbors. This state is mimicked by dense cell cultures. In this review, we integrate some recent findings on a key signal transducer, STAT3 (signal transducer and activator of transcription-3), whose activity is dramatically increased following cadherin-mediated cell to cell adhesion. Cadherin engagement, favored in dense cell cultures, causes a dramatic increase in total Rac/Cdc42 protein levels through inhibition of proteasomal degradation, which is followed by activation of IL-6 and STAT3. The cadherin/Rac/IL-6/STAT3 axis offers a potent survival signal that is a prerequisite for neoplastic transformation, as well as normal tissue function.