Natasha Hill

Lipid metabolism plays a significant role in the regulation of various critical pathways within cells, where enhanced lipid metabolism is a hallmark of cancer cell metabolism. The Hippo signalling pathway poses as an important signalling pathway that governs tissue growth control and tumorigenesis. The effector of the Hippo signalling pathway, Yes-associated protein (YAP), serves as a central regulator for this growth control. Once a tissue develops to its correct size, YAP is phosphorylated and inactivated within the cytoplasm by the activation of the Hippo pathway, where its inactivation results in YAP nucleus translocation. This allows its dephosphorylation, modulating various cellular behaviours such as cellular proliferation and the inhibition of apoptosis. Moreover, it has been established that YAP is positively regulated by the extracellular matrix (ECM). The interplay between the Hippo signalling pathway, the ECM, and lipid metabolism, however, is not entirely clear. Thus, this study illustrates a novel link between the Hippo signalling pathway, the ECM, and lipid metabolism. Furthermore, the project identifies a novel ECM complex which is dependent upon lipids and regulates YAP in a positive manner.

Overactive bladder (OAB) is a urological symptom complex defined by urinary urgency. It can have a devastating impact on an individual’s quality of life and leads to significant financial cost. Insulin-like growth factor 1 (IGF-1) is a protein hormone involved in a broad range of processes including cell proliferation and differentiation. IGF-1 is also regulated through alternative splicing. While the primary IGF-1Ea transcript is highly expressed in liver, the alternative IGF-1Ec transcript encodes the proteolytically-derived MGF peptide and has been primarily studied in skeletal muscle. MGF has been shown to stimulate satellite cell proliferation following tissue mechanical stretch or injury, but the role of MGF in smooth muscle, such as the detrusor muscle of the bladder, has been little explored. The aim of this study was to explore the expression of MGF in bladder biopsies from patients with OAB and age-matched controls. We show using immunohistochemistry that MGF is widely expressed in bladder tissue. Quantification of MGF expression by western blot showed that average MGF expression is more than doubled in OAB biopsies compared to controls (mean MGF in OAB=0.51±0.1, n=23; mean MGF in controls=0.22±0.07, n=9; p=0.05). Furthermore, there is an inverse correlation between MGF protein levels and symptom severity, as determined by the urodynamic parameter maximum cystometric capacity (correlation=0.53, p=0.03 n=16). MGF expression was highest in OAB biopsies with strong expression of the muscle cell marker DES . Combined with our observation that MGF induces cell proliferation in primary bladder cultures, our data suggests that high MGF expression in OAB patients may represent an attempted protective response in the bladder.