SPIN1 is a proto-oncogene and SPIN3 is a tumor suppressor in human seminoma

Damian Mikolaj Janecki,Bogna Kuczynska,Maciej Kurpisz,Riko Kitazawa,Barbara Ginter-Matuszewska,Tomasz Kolanowski,Anna Spik,Maciej Jerzy Smialek,Marcin Sajek,Maciej Kotecki,Jadwiga Jaruzelska

doi:10.18632/oncotarget.25977

Damian Mikolaj Janecki, Bogna Kuczynska + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.25977

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Abstract

SPIN1 is necessary for normal meiotic progression in mammals. It is overexpressed in human ovarian cancers and some cancer cell lines. Here, we examined the functional significance and regulation of SPIN1 and SPIN3 in the TCam-2 human seminoma cell line. We found that while SPIN1 overexpression reduced apoptosis in these cells, SPIN3 overexpression induced it. Similarly, SPIN1 upregulated and SPIN3 downregulated CYCD1, which is a downstream target of the PI3K/AKT pathway and contributes to apoptosis resistance in cancer cell lines. It appears that SPIN1 is pro-oncogenic and SPIN3 acts as a tumor suppressor in TCam-2 cells. To our knowledge, this is the first report of SPIN3 tumor suppressor activity. However, both SPIN1 and SPIN3 stimulated cell cycle progression. In addition, using luciferase reporters carrying SPIN1 or SPIN3 mRNA 3′UTRs, we found that PUM1 and PUM2 targeted and repressed SPINs. We also found that PUM1 itself strongly stimulated apoptosis and moderately slowed cell cycle progression in TCam-2 cells, suggesting that PUM1, like SPIN3, is a tumor suppressor. Our findings suggest that acting, at least in part, through SPIN1 and SPIN3, PUM proteins contribute to a mechanism promoting normal human male germ cell apoptotic status and thus preventing cancer.

Highlights

Apoptosis and cell cycle progression are crucial processes that regulate human germ cell numbers
Because SPIN1 mediates PI3K/AKT signaling to promote apoptosis resistance in cancer cell lines [20], we performed real-time qRT-PCR to test whether SPIN1 or SPIN3 affected the downstream targets of that pathway
The present study describes two proteins, SPIN1 and SPIN3, that play opposite roles in regulating apoptosis in the human seminoma cell line, TCam-2

Summary

Introduction

Apoptosis and cell cycle progression are crucial processes that regulate human germ cell numbers. These processes are critical for fertility, and play pivotal roles in cancer [1, 2]. Elucidating the mechanisms behind these processes will improve our understanding of both infertility and germ cell tumors. Some genes that strongly influence germ cell apoptosis and cell cycle progression are posttranscriptionally regulated by PUM (pumilio) proteins [4, 5]. PUM proteins are well described, highly conserved factors that target mRNAs by binding short nucleotide consensus motifs (UGUANAUA; pumilio binding elements, or PBEs) located in the 3’ untranslated region (3ʹUTR) [6]. The two PUM paralogues in mammals, PUM1 and PUM2, are very similar in structure [8], and PUM1 is important for mammalian germ cell development [9]

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