AbstractsBiology & Animal Science

Is activin-βc a tumour suppressor in the inhibin knockout mice?

by Francesco Elia Marino

Institution: University of Otago
Year: 0
Keywords: inhibin; activin; adrenal; testis; ovary; cachexia; tumour; musclewasting
Record ID: 1313115
Full text PDF: http://hdl.handle.net/10523/5560


Inhibins and activins are essential for normal reproductive and endocrine function. Previous literature showed that loss of INHA encoding for inhibin-α subunit in mice results in development of gonadal (sex-cord stromal) and adrenal tumourigenesis. However, a strong paradox has emerged regarding the function of INHA in human tumours primarily due to conflicting studies. A correlation has been found between the overexpression of activin-A by the tumours in the inhibin-deficient mice and severe cancer-associated cachexia, which has a profound impact on survival. Therefore, activin antagonism has been used to modulate the sex-cord stromal tumour growth rate both in vivo and in vitro. Recent work has shown that activin-C is an additional activin-A antagonist, despite being considered biologically redundant for several years. A preliminary study conducted in the inhibin-deficient mouse model, showed that overexpression of activin-βC has a beneficial effect, modulating sex-cord stromal tumours development and attenuating the cancer-associated cachexia phenotype. The overall objectives of this thesis were to clarify the incongruity regarding the inhibin-α subunit in human versus mouse and to further explore the biological function of activin-βC in vivo and in vitro defining its effect on gonadal, adrenal tumourigenesis and cancer-cachexia. Finally, this thesis wanted to clarify if activin-C is a tumour suppressor in the inhibin knockout mice. Initially this thesis re-evaluated the inhibin/activin pathway in human gonadal and adrenal cancers using contemporary protein and mRNA expression data for pathway components rather than inhibin-α alone. Clarification of the inhibin/activin expression profile in human cancers represented an essential part of the study in order to validate the in vivo findings described in the mouse model for potential translational applications. The study also described, for the first time, a comprehensive protein expression profile of activin-C in reproductive and adrenal cancers and its effect on a human granulosa cell line (COV434). The study then proceeded to determine whether overexpression of activin-βC modulated adrenal tumours in gonadectomised inhibin deficient mice. Male and female WT, ActC++, α-KO (INHAKO), and α-KO/ActC++ mice were gonadectomised and monitored up to 30 weeks of age. Markers of apoptosis and proliferation were assessed, and survival analyses were conducted in the castrated animals versus the sham operation control groups. Finally this thesis identified the potential molecular mechanism by which activin-C increased survival and modulated cancer-associated cachexia in the α-KO mice. Western blot analysis for the specific E3 ubiquitin ligase, atrogin-1 and MuRF1, effectors Smad-2/Smad-3 and myostatin was performed in the gastrocnemius muscle. Histopathology and survival analysis was conducted in animals from the same breeding cohort. The study also explored the impact of overexpression of activin-βC on the serum levels of activin-A, inflammatory cytokines (TNF-α, IL-6…