CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFκB signaling pathways.

Chaoqun Wang,Hao Chen,Zhiming Cai,Hsiao Chang Chan,Kin Lam Fok

doi:10.18632/oncotarget.13624

Chaoqun Wang, Hao Chen + Show 3 more

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https://doi.org/10.18632/oncotarget.13624

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Abstract

CD147 null mutant male mice are infertile with arrested spermatogenesis and increased apoptotic germ cells. Our previous studies have shown that CD147 prevents apoptosis in mouse spermatocytes but not spermatogonia. However, the underlying mechanism remains elusive. In the present study, we aim to determine the CD147-regulated apoptotic pathway in mouse spermatocytes. Our results showed that immunodepletion of CD147 triggered apoptosis through extrinsic apoptotic pathway in mouse testis and spermatocyte cell line (GC-2 cells), accompanied by activation of non-canonical NFκB signaling and suppression of canonical NFκB signaling. Furthermore, CD147 was found to interact with TRAF2, a factor known to regulate NFκB and extrinsic apoptotic signaling, and interfering CD147 led to the decrease of TRAF2. Consistently, depletion of CD147 by CRISPR/Cas9 technique in GC-2 cells down-regulated TRAF2 and resulted in cell death with suppressed canonical NFκB and activated non-canonical NFκB signaling. On the contrary, interfering of CD147 had no effect on NFκB signaling pathways as well as TRAF2 protein level in mouse spermatogonia cell line (GC-1 cells). Taken together, these results suggested that CD147 plays a key role in reducing extrinsic apoptosis in spermatocytes, but not spermatogonia, through modulating NFκB signaling pathway.

Highlights

Spermatogenesis is a complicated process that involves a series of cellular events, stepping from spermatogonia, spermatocytes, spermatids to spermatozoa [1, 2]
Our results showed that immunodepletion of CD147 triggered apoptosis through extrinsic apoptotic pathway in mouse testis and spermatocyte cell line (GC-2 cells), accompanied by activation of non-canonical NFκB signaling and suppression of canonical NFκB signaling
Since CD147 interacts with TRAF2, we speculated that inference with CD147 could affect the expression of TRAF2, which in turn leads to extrinsic apoptosis

Summary

Introduction

Spermatogenesis is a complicated process that involves a series of cellular events, stepping from spermatogonia, spermatocytes, spermatids to spermatozoa [1, 2]. A large number of genes expressed in developing germ cells are eventually shown to be oncogenes, which induce tumorigenesis. Those genes are known as cancer/testis (CT) antigens [3]. It has been proposed that reactivation of gametogenic genes is one of the driving forces of tumorigenesis [4], and that the processes of cancer development and spermatogenesis shares critical similarities [5]. CD147 is expressed on the cell surface of spermatogonia and spermatocytes, and gradually increases www.impactjournals.com/oncotarget during the meiotic prophase [3, 16]. The lumens of the male reproductive system were filled with round degenerated cells, some of which were undergoing apoptosis [18]

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