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Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas

¹ Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia² Departments of Biochemistry and Molecular Biology, Monash University, Building 77 Level 1, Wellington Road, Clayton, Victoria 3800, Australia³ Australian Research Council Centre of Excellence in Biotechnology and Development, Australia⁴ University Department of Growth and Reproduction, Rigshospitalet, DK-2100, Copenhagen, Denmark⁵ Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia

Correspondence should be addressed to K L Loveland at School of Biomedical Sciences, Building 77, Level 1, Wellington Road, Monash University, Clayton, Victoria 3800, Australia; Email: kate.loveland{at}med.monash.edu.au

Activin is a pleiotropic growth factor belonging to the transforming growth factor-β (TGFB) superfamily of signaling molecules. Regulated activin signaling is known to influence several steps in rodent male gamete differentiation. TGFB ligand isoforms, TGFB1–B3, also influence germ cell survival in the rodent testis at the onset of spermatogenesis and around the time of puberty. Given the importance of regulated activin and TGFB signaling in testis development and function, we sought to investigate the cellular production sites of activin/TGFB-signaling modulators in normal and dysfunctional adult human testes samples. Signaling transducers phosphorylated SMAD2/3, and signaling modulators SMAD6, MAN-1, inhibin (INHA), and β-glycan were detected in Bouins fixed, paraffin–embedded adult human testis sections using immunohistochemistry. Additional samples examined were from testicular cancer patients and from normal men subjected to gonadotropin suppression with androgen-based contraceptives. Our findings identify distinct differences between normal and gonadotropin-deprived human testis in the expression and cellular localization of activin/TGFB-signaling modulators. The presence of a nuclear phosphorylated SMAD2/3 signal in all analyzed seminoma specimens indicated active activin/TGFB signaling. Moreover, a subset of seminoma specimens exhibited selective enhanced expression of β-glycan (4 out of 28 seminoma tumors), INHA (6 out of 28), and MAN-1 (6 out of 28), highlighting potential functional differences between individual tumors in their capacity to regulate activin/TGFB signaling. Within the heterogenous nonseminomas, expression of signaling modulators was variable and reflected the degree of somatic differentiation. Thus, synthesis of activin and TGFB-signaling modulators may be affected by spermatogenic disruption and altered hormone levels in the testis.