ICG-001

BACKGROUND: Wingless and Int-related protein (Wnt) ligands are aberrantly expressed in patients with colorectal cancer (CRC). However, the aberrant level of Wnt ligands in serum have not been explored. Here, we aimed to identify the levels of WNT4 in serum and explored its oncogenic role in CRC. METHODS: The Oncomine database was used to analyze the relationship between WNT4 and the prognosis of CRC. ELISA was performed to measure WNT4 levels in serum and conditioned medium from fresh CRC tissues and adjacent normal tissues...

Our previous work demonstrated that Piwil2 reactivated by the human papillomavirus oncoproteins E6 and E7 may reprogram somatic cells into tumor-initiating cells (TICs), which contribute to cervical neoplasia lesions. Maintaining the stemness of TICs is critical for the progression of cervical lesions. Here, we determined that canonical Wnt signaling was aberrantly activated in HaCaT cells transfected with lentivirus expressing Piwil2 and in cervical lesion specimens of low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, and invasive carcinoma...

Endothelial-to-mesenchymal transition (EndMT) indispensable in embryogenesis also occurs in several human pathologies. Although transforming growth factor-β (TGFβ) has been demonstrated to induce EndMT, the type-I receptors (ALK-1 and ALK-5) responsible for TGFβ-induced EndMT is unclear. In the current study, we investigated the role of the Akt1 pathway in ALK1 and ALK5 expression regulation in response to TGFβ1 and TGFβ2 in human microvascular endothelial cells (HMECs). Whereas treatment with TGFβ1 and TGFβ2 or Akt1 gene silencing promoted EndMT accompanied by increased ALK5 expression and reduced ALK1 expression accompanied by increased expression of N-cadherin and reduced expression of eNOS in HMECs, treatment with ALK-5 inhibitor (SB431542) blunted these effects...

Although many studies have confirmed the relationship between obesity and endometrial cancer (EC), the molecular mechanism between obesity and EC progression has not been elucidated. Overexpression of fat mass and the obesity associated protein FTO leads to weight gain, although recently it has been discovered that FTO can serve as a demethylase which erases N6-methyladenosine (m6A) modification and regulates the metabolization of mRNAs. In this study, we found high expression of FTO in metastatic EC and that this action promote both metastasis and invasion in vivo and in vitro...

Cancer chemotherapy can significantly impair the bone formation and cause myelosuppression; however, their recovery potentials and mechanisms remain unclear. This study investigated the roles of the β-catenin signaling pathway in bone and bone marrow recovery potentials in rats treated with antimetabolite methotrexate (MTX) (five once-daily injections, 0.75 mg/kg) with/without β-catenin inhibitor indocyanine green (ICG)-001 (oral, 200 mg/kg/day). ICG alone reduced trabecular bone volume and bone marrow cellularity...

Diffuse intrinsic pontine gliomas (DIPG) are the most aggressive brain tumors in children with 5-year survival rates of only 2%. About 85% of all DIPG are characterized by a lysine-to-methionine substitution in histone 3, which leads to global H3K27 hypomethylation accompanied by H3K27 hyperacetylation. Hyperacetylation in DIPG favors the action of the Bromodomain and Extra-Terminal (BET) protein BRD4, and leads to the reprogramming of the enhancer landscape contributing to the activation of DIPG super enhancer-driven oncogenes...

Advanced oxidative protein products (AOPPs) are novel uremic toxins whose concentrations continuously increases in patients with chronic kidney disease (CKD). Epithelial-to-mesenchymal transition (EMT) of tubular cells is the main mechanism underlying CKD pathogenesis. Studies have shown that AOPPs can induce EMT and promote renal fibrosis. However, the mechanism through which AOPPs induce tubular cell-EMT is poorly understood. In this study, we aimed to clarify the mechanisms underlying AOPP-induced EMT in human kidney proximal tubular (HKC-8) epithelial cells...

Hypospadias and urethral stricture are common urological diseases which seriously affect voiding function and life quality of the patients, yet current clinical treatments often result in unsatisfactory clinical outcome with frequent complications. In vitro experiments confirmed that ICG-001 (a well-established Wnt signaling inhibitor) could effectively suppress fibroblast proliferation and fibrotic protein expression. In this study, we applied a novel drug-delivering nanoyarn scaffold in urethroplasty in dog model, which continuously delivers ICG-001 during tissue reconstruction, and could effectively promote urethral recovery and resume fully functional urethra within 12 weeks...

The Wnt signaling pathway is one of the major signaling pathways used by cancer stem cells (CSC). Ecotropic Viral Integration Site 1 (EVI1) has recently been shown to regulate oncogenic development of tumor cells by interacting with multiple signaling pathways, including the Wnt signaling. In the present study, we found that the Wnt modulator ICG-001 could inhibit the expression of EVI1 in nasopharyngeal carcinoma (NPC) cells. Results from loss-of-function and gain-of-function studies revealed that EVI1 expression positively regulated both NPC cell migration and growth of CSC-enriched tumor spheres...

Background: Meningiomas with Neurofibromin 2 gene mutations ( NF2 -mutant meningiomas) account for ~40% of the sporadic meningiomas. However, there is still no effective drug treatment for the disease. Methods: Expression profile of Merlin protein was explored through immunohistochemistry in a meningioma patient cohort ( n = 346). A 20-agent library covering a wide range of meningioma relevant targets was tested using meningioma cell lines IOMM-Lee ( NF2 wildtype) and CH157-MN ( NF2 deficient)...

BACKGROUND: Although cyclic AMP-response element binding protein-binding protein (CBP)/β-catenin signaling is known to promote proliferation and fibrosis in various organ systems, its role in the activation of pancreatic stellate cells (PSCs), the key effector cells of desmoplasia in pancreatic cancer and fibrosis in chronic pancreatitis, is largely unknown. METHODS: To investigate the role of the CBP/β-catenin signaling pathway in the activation of PSCs, we have treated mouse and human PSCs with the small molecule specific CBP/β-catenin antagonist ICG-001 and examined the effects of treatment on parameters of activation...

Myocardial fibrosis is the pathological consequence of injury-induced fibroblastto-myofibroblast transition, resulting in increased stiffness and diminished cardiac function. Histone modification has been shown to play an important role in the pathogenesis of cardiac fibrosis. Here, we identified H3K27me3 demethylase JMJD3/KDM6B promotes cardiac fibrosis via regulation of fibrogenic pathways. Using neonatal rat cardiac fibroblasts (NRCF), we show that the expression of endogenous JMJD3 is induced by angiotensin II (Ang II), while the principle extracellular matrix (ECM) such as fibronectin, CTGF, collagen I and III are increased...

Background Given known inefficiencies in reprogramming of fibroblasts into mature induced cardiomyocytes (iCMs), we sought to identify small molecules that would overcome these barriers to cardiac cell transdifferentiation. Methods and Results We screened alternative combinations of compounds known to impact cell reprogramming using morphologic and functional cell differentiation assays in vitro. After screening 6 putative reprogramming factors, we found that a combination of the histone deacetylase inhibitor sodium butyrate, the WNT inhibitor ICG-001, and the cardiac growth regulator retinoic acid (RA) maximally enhanced iCM generation from primary rat cardiac fibroblasts when combined with administration of the cardiodifferentiating transcription factors Gata4, Mef2C, and Tbx5 (GMT) compared with GMT administration alone (23±1...

PURPOSE: The canonical wnt pathway with its central signaling molecule β-catenin is important for tissue development and homeostasis and its dysregulation leads to many diseases including pathologies of the cardiovascular system. Inhibition of the wnt pathway has the potential to protect against cardiac allograft vasculopathy (CAV), because it reduces the proliferation of smooth muscle cells (SMCs), which is a main pathomechanism of CAV and causes neointima formation and vessel occlusion...

BACKGROUND: The transforming growth factor β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) has been proven associated with the pathogenesis of asthmatic airway remodeling, in which the Wnt/β-catenin pathway plays an important role, notably with regard to TGF-β1. Recent studies have shown that 1α, 25-dihydroxyvitamin D3(1α, 25(OH)2D3) inhibits TGF-β1-induced EMT, although the underlying mechanism have not yet been fully elucidated. METHODS: Alveolar epithelial cells were exposed to 1α, 25(OH)2D3, ICG-001, or a combination of both, followed by stimulation with TGF-β1...

Introduction: Dysregulation of BCAT1 has been implicated in carcinogenesis. However, its clinical significance and biological roles in human non-small cell lung cancer (NSCLC) are not clear. Methods: Immunohistochemistry was used to examine the protein expression of BCAT1 in 107 cases of lung cancer tissues. Biological roles and potential mechanisms of BCAT1 were examined using MTT, colony formation assay, Matrigel invasion assay, Western blot, RNA-sequencing, and luciferase reporter assay...

Osteoarthritis (OA) is one of the most prevalent joint disorders globally. Patients suffering from OA are often obese and adiposity is linked to chronic inflammation. In the present study, the potential of using exosomes isolated from adipose‑derived stem cells (ADSCs) as a therapeutic tool for reducing chronic inflammation and promoting chondrogenesis was investigated using patient‑derived primary cells. First, it was tested whether patient‑derived ADSCs could differentiate into chondrogenic and osteogenic lineages...

INTRODUCTION: Human periodontal ligament stem cells (hPDLSCs) are stem cells found near the tooth periodontal ligament. These cels are involved in the regeneration of the periodontal ligament and alveolar bone during orthodontic treatment and chronic periodontitis. OBJECTIVES: The Homeobox gene HOXA10 regulates the osteogenic differentiation of stem cells. However, the role of HOXA10 in hPDLSCs remains unclear. Therefore, we studied the effects of HOXA10 on human PDLSC osteogenic differentiation in vitro ...

The transcription factor β-catenin is able to induce tolerogenic/anti-inflammatory features in different types of dendritic cells (DCs). Monocyte-derived dendritic cells (moDCs) have been widely used in dendritic cell-based cancer therapy, but so far with limited clinical efficacy. We wanted to investigate the hypothesis that aberrant differentiation or induction of dual pro- and anti-inflammatory features may be β-catenin dependent in moDCs. β-catenin was detectable in both immature and lipopolysaccharide (LPS)-stimulated DCs...

Epidermal growth factor receptor (EGFR) is a major driver of head and neck cancer, a devastating malignancy with a major sub-site in the oral cavity manifesting as oral squamous cell carcinoma (OSCC). EGFR is a glycoprotein receptor tyrosine kinase (RTK) whose activity is upregulated in >80% OSCC. Current anti-EGFR therapy relies on the use of cetuximab, a monoclonal antibody against EGFR, although it has had only a limited response in patients. Here, we uncover a novel mechanism regulating EGFR activity, identifying a role of the nuclear branch of the Wnt/β-catenin signaling pathway, the β-catenin/CBP axis, in control of post-translational modification of N-glycans on the EGFR...