Abstract
Background: HOXA10 is a key transcriptional factor that regulates testis development as reported from previous transgenic mouse models and human inherited diseases. However, whether it also plays important roles in promoting the development of testicular cancer is not well-understood.Objective: To study the expression of HOXA10 and its regulated signaling pathways in testicular cancers.Design, Setting, and Participants: A tissue microarray was constructed with benign and cancerous testis. TCam2, NT-2, and NCCIT cell models were applied in this study.Intervention: Immunohistochemistry and immunofluorescence were performed to measure the expression and cellular localization of HOXA10 in testicular cancer tissues and cell models. Cell proliferation and cell cycling rates were determined by BrdU incorporation and flow cytometry assays. HOXA10 transcriptomes were profiled with Ampliseq RNA-seq in testicular cancer cells. Immunoblotting assays were used to detect HOXA10-regulated signaling.Results: HOXA10 is a nuclear protein in benign spermatocytes. Reduced nuclear expression and increased cytoplasmic expression of HOXA10 are associated with testicular cancers. These changes are consistent in both seminoma and non-seminoma. Enhanced HOXA10 expression in testicular cancer cell models inhibits cell proliferation and delays cell cycle progression through G2/M phases. These functions of HOXA10 mainly affect the TP53, cKit, STAT3, AKT, and ERK signaling pathways.Conclusions: Loss of nuclear functions of HOXA10 enhances proliferation of testicular cancer cells, suggesting that downregulation of HOXA10 transcription activity may promote the development of testicular cancers.
Highlights
Testicular germ cell tumor (TGCT) is the most common form of cancer in young men aged between 15 and 40 and the incidence has been increasing over the past few decades worldwide [1,2,3]
To investigate the cellular localization of HOXA10 protein in testis tissue, the whole sections of benign testis slides were incubated with a HOXA10 antibody and HOXA10 expression was evaluated by immunohistochemistry (IHC)
Since Sertoli cells are often difficult to be distinguished from spermatocytes, we used the androgen receptor (AR) as a Sertoli cell-specific marker
Summary
Testicular germ cell tumor (TGCT) is the most common form of cancer in young men aged between 15 and 40 and the incidence has been increasing over the past few decades worldwide [1,2,3]. TGCT likely develops from gonocytes that failed to HOXA10 Roles in Testicular Cancer differentiate into spermatogonia, showing similar patterns of gene expression to those of stem cells and intratubular germ-cell neoplasm [4]. HOXA10 is a key transcriptional factor that regulates testis development as reported from previous transgenic mouse models and human inherited diseases. Whether it plays important roles in promoting the development of testicular cancer is not well-understood
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