Noncanonical IL6 Signaling-Mediated Activation of YAP Regulates Cell Migration and Invasion in Ovarian Clear Cell Cancer.

Ovarian clear cell adenocarcinoma (OCCA) is characterized by a particularly poor response to conventional chemotherapy and a short overall survival time in women with established disease. The development of targeted treatments for OCCA relies on a better understanding of its molecular characteristics. IL6 is strongly expressed in OCCA and may therefore provide a novel therapeutic target.

and Mutations Co-occur and Cooperate in Low-Grade Serous Ovarian Carcinomas.

Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator and in , and RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in and Missense mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant and proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer.

Inhibiting the system x/glutathione axis selectively targets cancers with mutant-p53 accumulation.

TP53, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of SLC7A11, a component of the cystine/glutamate antiporter, system x, through binding to the master antioxidant transcription factor NRF2.

Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition.

Cyclin E1 () amplification is associated with primary treatment resistance and poor outcome in high-grade serous ovarian cancer (HGSC). Here, we explore approaches to target -amplified cancers and potential strategies to overcome resistance to targeted agents. To examine dependency on in -amplified HGSC, we utilized siRNA and conditional shRNA gene suppression, and chemical inhibition using dinaciclib, a small-molecule CDK2 inhibitor.

APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma.

Objectives: p53 is a critical tumour suppressor and is mutated in 70% of oesophageal adenocarcinomas (OACs), resulting in chemoresistance and poor survival. APR-246 is a first-in-class reactivator of mutant p53 and is currently in clinical trials. In this study, we characterised the activity of APR-246 and its effect on p53 signalling in a large panel of cell line xenograft (CLX) and patient-derived xenograft (PDX) models of OAC.

IGFBP-2 - taking the lead in growth, metabolism and cancer.

The activity of the Insulin-like Growth Factors (IGFs) ligands elicited via their receptors and transduced by various intracellular signal pathways is modulated by the IGF Binding Proteins (IGFBPs). Among all the IGFBPs, IGFBP-2 has been implicated in the regulation of IGF activity in most tissue and organs. Besides binding to IGFs in the circulation these IGF-regulatory activities of IGFBP-2 involve interactions with components of the extracellular matrix, cell surface proteoglycans and integrin receptors.

Desert hedgehog is a mammal-specific gene expressed during testicular and ovarian development in a marsupial.

Background: Desert hedgehog (DHH) belongs to the hedgehog gene family that act as secreted intercellular signal transducers. DHH is an essential morphogen for normal testicular development and function in both mice and humans but is not present in the avian lineage. Like other hedgehog proteins, DHH signals through the patched (PTCH) receptors 1 and 2.

IGFBP-2 at the interface of growth and metabolism--implications for childhood obesity.

The growth hormone/insulin-like growth factor-I (IGF-I) axis is at the centre of normal human childhood growth. Six well characterised binding proteins (IGFBP-1 to IGFBP-6) act as general carriers of IGF-I, but they also modulate IGF-I bioavailability and activity in a tissue-specific, and developmentally appropriate, manner. Recent findings also point to several binding proteins possessing specific 'lGF-independent' actions and, in particular, there is now substantial evidence linking IGFBP-2 with nutritional status and insulin sensitivity.

IGFBP-2 enhances VEGF gene promoter activity and consequent promotion of angiogenesis by neuroblastoma cells.

IGF binding protein (IGFBP)-2 is one of the most significant genes in the signature of major aggressive cancers. Previously, we have shown that IGFBP-2 enhances proliferation and invasion of neuroblastoma cells, suggesting that IGFBP-2 activates a protumorigenic gene expression program in these cells. Gene expression profiling in human neuroblastoma SK-N-SHEP (SHEP)-BP-2 cells indicated that IGFBP-2 overexpression activated a gene expression program consistent with enhancement of tumorigenesis.

Peripubertal aromatase inhibition in male rats has adverse long-term effects on bone strength and growth and induces prostatic hyperplasia.

Aromatase inhibitors have been increasingly used in boys with growth retardation to prolong the duration of growth and increase final height. Multiple important roles of oestrogen in males point to potential adverse effects of this strategy. Although the deleterious effects of aromatase deficiency in early childhood and adulthood are well documented, there is limited information about the potential long-term adverse effects of peripubertal aromatase inhibition.