The Role of an NFκB-STAT3 Signaling Axis in Regulating the Induction and Maintenance of the Pluripotent State

AbstractMedulloblastoma (MB) is a high-grade pediatric brain malignancy that originates from neuronal precursors located in the posterior cranial fossa. In this study, we evaluated the role of STAT3 and IL-6 in a tumor microenvironment mediated drug resistance in human MBs. We established that the Group 3 MB cell line, Med8A, is chemosensitive (hence Med8A-S), and this is correlated with a basal low phosphorylated state of STAT3, while treatment with IL-6 induced robust increases in pY705-STAT3. Via incremental selection with vincristine, we derived the stably chemoresistant variant, Med8A-R, that exhibited multi-drug resistance, enhanced IL-6 induced pY705-STAT3 levels, and increased IL6R expression. Consequently, abrogation of STAT3 or IL6R expression in Med8A-R led to restored chemosensitivity to vincristine, highlighting a prominent role for canonical IL-6/STAT3 signaling in acquired drug resistance. Furthermore, Med8A-S subjected to conditioning exposure with IL-6, termed Med8A-IL6+ cells, exhibited enhanced vincristine resistance, increased expression of pY705-STAT3 and IL6R, and increased secretion of IL-6. When cocultured with Med8A-IL6+ cells, Med8A-S cells exhibited increased pY705-STAT3 and increased IL-6 secretion, suggesting a cytokine feedback loop responsible for amplifying STAT3 activity. Similar IL-6 induced phenomena were also observed in the Group 3 MB cell lines, D283 and D341, including increased pY705-STAT3, drug resistance, IL-6 secretion and IL6R expression. Our study unveiled autocrine IL-6 as a promoter of STAT3 signaling in development of drug resistance, and suggests therapeutic benefits for targeting the IL-6/STAT3 signaling axis in Group 3 MBs.

Download Full-text

Resistin Induces LIN28A-Mediated Let-7a Repression in Breast Cancer Cells Leading to IL-6 and STAT3 Upregulation

Cancers ◽

10.3390/cancers13184498 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4498

Author(s):

Sachin Kumar Deshmukh ◽

Sanjeev Kumar Srivastava ◽

Haseeb Zubair ◽

Mohammad Aslam Khan ◽

Ajay Pratap Singh ◽

...

Keyword(s):

Breast Cancer ◽

In Silico Analysis ◽

Stat3 Signaling ◽

Expression Of Genes ◽

Signaling Axis ◽

Reporter Assays ◽

Underlying Mechanisms ◽

Cell Phenotypes ◽

Silico Analysis

Downregulation of the Let-7 family of microRNAs (miRNAs) has been reported in several cancers, including breast malignancy; however, underlying mechanisms are not completely understood. Resistin is an important component of the tumor microenvironment, having a functional impact on the tumor cell phenotypes. Here, we examined the role of resistin in the regulation of Let-7 miRNAs and studied its downstream consequences. We found that resistin treatment led to the reduced expression of Let-7 family miRNAs in breast cancer (BC) cells, with the highest downregulation reported for Let-7a. Furthermore, resistin induced the expression of LIN28A, and its silencing abrogated resistin-mediated Let-7a suppression. Let-7a restoration or LIN28A silencing abolished the resistin-induced growth, clonogenicity, and sphere-forming ability of BC cells. Restoration of Let-7a also suppressed the resistin-induced expression of genes associated with growth, survival, and stemness. Pathway analysis suggested STAT3 as a putative central node associated with Let-7a-mediated gene regulation. In silico analysis identified STAT3 and its upstream modifier, IL-6, as putative Let-7a gene targets, which were later confirmed by 3′UTR-reporter assays. Together, our findings demonstrate a novel resistin/LIN28A/Let-7a/IL-6/STAT3 signaling axis supporting the growth and stemness of BC cells.

Download Full-text

Protective and anti-inflammatory role of REG1A in inflammatory bowel disease induced by JAK/STAT3 signaling axis

International Immunopharmacology ◽

10.1016/j.intimp.2020.107304 ◽

2021 ◽

Vol 92 ◽

pp. 107304

Author(s):

Hongli Mao ◽

Jinlin Jia ◽

Jinxiu Sheng ◽

Shanfeng Zhang ◽

Kaida Huang ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Stat3 Signaling ◽

Signaling Axis ◽

Inflammatory Bowel ◽

Anti Inflammatory

Download Full-text

346-LB: The Role of STAT3 Signaling toward a-to-ß Reprogramming within the Adult Pancreas

Diabetes ◽

10.2337/db19-346-lb ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 346-LB

Author(s):

YUKA WAKABAYASHI ◽

TAKESHI MIYATSUKA ◽

LUKA SUZUKI ◽

MIWA HIMURO ◽

TAKEHIRO KATAHIRA ◽

...

Keyword(s):

Stat3 Signaling

Download Full-text

Role of Regulatory Oncogenic or Tumor Suppressor miRNAs of PI3K/AKT Signaling Axis in the Pathogenesis of Colorectal Cancer

Current Pharmaceutical Design ◽

10.2174/1381612825666190110151957 ◽

2019 ◽

Vol 24 (39) ◽

pp. 4605-4610 ◽

Cited By ~ 7

Author(s):

Atena Soleimani ◽

Farzad Rahmani ◽

Gordon A. Ferns ◽

Mikhail Ryzhikov ◽

Amir Avan ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Suppressor ◽

Current Knowledge ◽

Akt Signaling ◽

Tumor Tissues ◽

Radio Therapy ◽

Signaling Axis ◽

Cancer Tumor ◽

Novel Biomarkers

Colorectal cancer (CRC) is the leading cause of cancer death worldwide and its incidence is increasing. In most patients with CRC, the PI3K/AKT signaling axis is over-activated. Regulatory oncogenic or tumor suppressor microRNAs (miRNAs) for PI3K/AKT signaling regulate cell proliferation, migration, invasion, angiogenesis, as well as resistance to chemo-/radio-therapy in colorectal cancer tumor tissues. Thus, regulatory miRNAs of PI3K/AKT/mTOR signaling represent novel biomarkers for new patient diagnosis and obtaining clinically invaluable information from post-treatment CRC patients for improving therapeutic strategies. This review summarizes the current knowledge of miRNAs’ regulatory roles of PI3K/AKT signaling in CRC pathogenesis.

Download Full-text

Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20092066 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2066 ◽

Cited By ~ 12

Author(s):

Namrata Khurana ◽

Suresh C. Sikka

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Signaling Pathways ◽

Critical Role ◽

Castration Resistant Prostate Cancer ◽

Form Complex ◽

Androgen Receptor Signaling ◽

Castration Resistant ◽

Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

Download Full-text

O-GlcNAcylation protein disruption by Thiamet G promotes changes on the GBM U87-MG cells secretome molecular signature

Clinical Proteomics ◽

10.1186/s12014-021-09317-x ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Maria Cecilia Oliveira-Nunes ◽

Glaucia Julião ◽

Aline Menezes ◽

Fernanda Mariath ◽

John A. Hanover ◽

...

Keyword(s):

Experimental Evidence ◽

Critical Role ◽

Molecular Signature ◽

Label Free ◽

Intercellular Signaling ◽

Tumor Aggressiveness ◽

Signaling Axis ◽

Literature Evidence ◽

Therapeutic Tools

AbstractGlioblastoma (GBM) is a grade IV glioma highly aggressive and refractory to the therapeutic approaches currently in use. O-GlcNAcylation plays a key role for tumor aggressiveness and progression in different types of cancer; however, experimental evidence of its involvement in GBM are still lacking. Here, we show that O-GlcNAcylation plays a critical role in maintaining the composition of the GBM secretome, whereas inhibition of OGA activity disrupts the intercellular signaling via microvesicles. Using a label-free quantitative proteomics methodology, we identified 51 proteins in the GBM secretome whose abundance was significantly altered by activity inhibition of O-GlcNAcase (iOGA). Among these proteins, we observed that proteins related to proteasome activity and to regulation of immune response in the tumor microenvironment were consistently downregulated in GBM cells upon iOGA. While the proteins IGFBP3, IL-6 and HSPA5 were downregulated in GBM iOGA cells, the protein SQSTM1/p62 was exclusively found in GBM cells under iOGA. These findings were in line with literature evidence on the role of p62/IL-6 signaling axis in suppressing tumor aggressiveness and our experimental evidence showing a decrease in radioresistance potential of these cells. Taken together, our findings provide evidence that OGA activity may regulate the p62 and IL-6 abundance in the GBM secretome. We propose that the assessment of tumor status from the main proteins present in its secretome may contribute to the advancement of diagnostic, prognostic and even therapeutic tools to approach this relevant malignancy.

Download Full-text

Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

Nature Communications ◽

10.1038/s41467-021-24853-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ian T. Stancil ◽

Jacob E. Michalski ◽

Duncan Davis-Hall ◽

Hong Wei Chu ◽

Jin-Ah Park ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Airway Epithelium ◽

Cell Types ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Airway Epithelia ◽

Chronic Lung Diseases ◽

Distal Airway ◽

Signaling Axis

AbstractThe airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

Download Full-text

Activation of FXR modulates SOCS3/Jak2/STAT3 signaling axis in a NASH-dependent hepatocellular carcinoma animal model

Biochemical Pharmacology ◽

10.1016/j.bcp.2021.114497 ◽

2021 ◽

pp. 114497

Author(s):

Yasmeen M Attia ◽

Rasha A Tawfiq ◽

Abdullah A Gibriel ◽

Aya A Ali ◽

Dina H Kassem ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Animal Model ◽

Stat3 Signaling ◽

Signaling Axis

Download Full-text

The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling

Nature Communications ◽

10.1038/s41467-021-24631-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Eui Jung Moon ◽

Stephano S. Mello ◽

Caiyun G. Li ◽

Jen-Tsan Chi ◽

Kaushik Thakkar ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Invasion ◽

Critical Role ◽

Metastatic Breast ◽

Breast Cancer Patients ◽

Invasion And Metastasis ◽

Stat3 Signaling ◽

Inducible Genes ◽

Transcriptional Target

AbstractHypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.

Download Full-text