Elevated level of inhibin-α subunit is pro-tumourigenic and pro-metastatic and associated with extracapsular spread in advanced prostate cancer

Abstract

The biological function of inhibin-a subunit (INHa) in prostate cancer (PCa) is currently unclear. A recent study associated elevated levels of INHa in PCa patients with a higher risk of recurrence. This prompted us to use clinical specimens and functional studies to investigate the pro-tumourigenic and pro-metastatic function of INHa. We conducted a cross-sectional study to determine a link between INHa expression and a number of clinicopathological parameters including Gleason score, surgical margin, extracapsular spread, lymph node status and vascular endothelial growth factor receptor-3 expression, which are well-established prognostic factors of PCa. In addition, using two human PCa cell lines (LNCaP and PC3) representing androgen-dependent and -independent PCa respectively, we investigated the biological function of elevated levels of INHa in advanced cancer. (Wiater and Vale, 2003;Farnworth et al, 2007). This antagonistic effect of inhibin is amplified in the presence of the inhibin receptor, TGFb receptor III (TGFbRIII), also known as betaglycan.The first study that linked inhibin to reproductive cancers showed that serum inhibin increased in women with granulosa cell tumours of the ovary (Lappohn et al, 1989) and inhibin currently serves as a robust biomarker for this cancer. A direct biological function for inhibin in carcinogenesis was demonstrated by Matzuk et al (1992) when they created the inhibin-a subunit (INHa) knockout mouse. Both sexes developed gonadal sex-cord stromal tumours with high penetrance and developed tumours in their adrenal glands after castration, showing that INHa can act as a tumour suppressor. Subsequent mouse model studies revealed a complex network of interactions involving inhibin, activin and other modifiers in the development and progression of gonadal and adrenal tumours in INHa-deficient mice (reviewed in Risbridger et al, 2001). Although it is clear that total inhibin as a serum test has utility in the initial detection and prognosis of certain types of ovarian cancers, the biological function of inhibin in tumourigenesis is far from clear.We have observed both up-and down-regulation of INHa expression in prostate cancer (PCa) tissues dependent on the stage

Activin A induces apoptosis of mouse myeloma cells via the mitochondrial pathway

“…Activin A has been demonstrated to exert a primarily protective function, whereby it induces cell cycle arrest of patient-derived prostate cancer cells and non-invasive prostate cancer LNCaP cells. In contrast, activin A treatment resulted in an increase in proliferation of the more aggressive prostate cancer cell line, PC3, an apparent discrepancy (20)(21)(22). The tumor suppressive function of activin A is also observed in breast cancer, but activing A promotes cell proliferation and invasion in head and neck squamous cell carcinoma, resulting in a poor prognosis (8).…”

Peritubular myoid cell‐derived factors and its potential role in the progression of testicular germ cell tumours

“…Interestingly enough, alterations in transferrin and inhibin levels have been related with an increased invasiveness and poor prognosis in several tumour types (Mylonas et al. , 2005; Balanathan et al. , 2009; Park et al.…”

“…This androgen-dependent interaction between PTCs and Sertoli cells has been suggested to be mediated by PModS, a molecule secreted by PTCs that modulates the secretion of transferrin, inhibin and androgen-binding protein by Sertoli cells (Verhoeven et al, 2000), although other PTC-derived factors, such as IGF-I, bFGF and several cytokines, share most of the PModS effects on Sertoli cells, and thus could also participate in its functional regulation (Verhoeven et al, 2000). Interestingly enough, alterations in transferrin and inhibin levels have been related with an increased invasiveness and poor prognosis in several tumour types (Mylonas et al, 2005;Balanathan et al, 2009;Park et al, 2009;Habashy et al, 2010). Moreover, the analysis of the rodent model has shown that PTCs are also involved in the regulation of processes such as spermatogenesis and testicular development (Mackay & Smith, 2007) through the secretion of factors that includes Fibroblast Growth Factors (El Ramy et al, 2005), TGF-b (Konrad et al, 2000a) and ECM components (Ailenberg et al, 1988).…”

Inhibin-α subunit in normal and malignant human cervical tissue and cervical cancer cell lines

“…Meanwhile, loss of inhibin-α expression resulted in a poorer survival of endometrial cancer patients, suggesting a tumoursuppressor function in human endometrium (16). Additionally, a pro-tumourigenic and pro-metastatic function for inhibin-α in prostate cancer has been described (37). However, the exact molecular mechanism by which the inhibin-α subunit is implicated in carcinogenesis is still not clear.…”