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The Y-linked proto-oncogene TSPY contributes to poor prognosis of the male hepatocellular carcinoma patients by promoting the pro-oncogenic and suppressing the anti-oncogenic gene expression

BACKGROUND: Liver cancer is one of the major causes of cancer death worldwide, with significantly higher incidence and mortality among the male patients. Although sex hormones and their receptors could contribute to such sex differences, the story is incomplete. Genes on the male-specific region of...

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Autores principales: Kido, Tatsuo, Lau, Yun-Fai Chris
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399826/
https://www.ncbi.nlm.nih.gov/pubmed/30867900
http://dx.doi.org/10.1186/s13578-019-0287-x
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author Kido, Tatsuo
Lau, Yun-Fai Chris
author_facet Kido, Tatsuo
Lau, Yun-Fai Chris
author_sort Kido, Tatsuo
collection PubMed
description BACKGROUND: Liver cancer is one of the major causes of cancer death worldwide, with significantly higher incidence and mortality among the male patients. Although sex hormones and their receptors could contribute to such sex differences, the story is incomplete. Genes on the male-specific region of the Y chromosome could play a role(s) in this cancer. TSPY is the putative gene for the gonadoblastoma locus on the Y chromosome (GBY) that is ectopically expressed in a subset of male hepatocellular carcinomas (HCCs). Although various studies showed that TSPY expression is associated with poor prognosis in the patients and its overexpression promotes cell proliferation of various cancer cell lines, it remains unclear how TSPY contributes to the clinical outcomes of the HCC patients. Identifying the downstream genes and pathways of TSPY actions would provide novel insights on its contribution(s) to male predominance in this deadly cancer. RESULTS: To determine the effects of TSPY on HCC, a TSPY transgene was introduced to the HCC cell line, HuH-7, and studied with RNA-Seq transcriptome analysis. The results showed that TSPY upregulates various genes associated with cell-cycle and cell-viability, and suppresses cell-death related genes. To correlate the experimental observations with those of clinical specimens, transcriptomes of male HCCs with high TSPY expression were analyzed with reference to those with silent TSPY expression from the Cancer Genome Atlas (TCGA). The comparative analysis identified 49 genes, which showed parallel expression patterns between HuH-7 cells overexpressing TSPY and clinical specimens with high TSPY expression. Among these 49 genes, 16 likely downstream genes could be associated with survival rates in HCC patients. The major upregulated targets were cell-cycle related genes and growth factor receptor genes, including CDC25B and HMMR, whose expression levels are negatively correlated with the patient survival rates. In contrast, PPARGC1A, SLC25A25 and SOCS2 were downregulated with TSPY expression, and possess favorable prognoses for HCC patients. CONCLUSION: We demonstrate that TSPY could exacerbate the oncogenesis of HCC by differentially upregulate the expression of pro-oncogenic genes and downregulate those of anti-oncogenic genes in male HCC patients, thereby contributing to the male predominance in this deadly cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13578-019-0287-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-63998262019-03-13 The Y-linked proto-oncogene TSPY contributes to poor prognosis of the male hepatocellular carcinoma patients by promoting the pro-oncogenic and suppressing the anti-oncogenic gene expression Kido, Tatsuo Lau, Yun-Fai Chris Cell Biosci Research BACKGROUND: Liver cancer is one of the major causes of cancer death worldwide, with significantly higher incidence and mortality among the male patients. Although sex hormones and their receptors could contribute to such sex differences, the story is incomplete. Genes on the male-specific region of the Y chromosome could play a role(s) in this cancer. TSPY is the putative gene for the gonadoblastoma locus on the Y chromosome (GBY) that is ectopically expressed in a subset of male hepatocellular carcinomas (HCCs). Although various studies showed that TSPY expression is associated with poor prognosis in the patients and its overexpression promotes cell proliferation of various cancer cell lines, it remains unclear how TSPY contributes to the clinical outcomes of the HCC patients. Identifying the downstream genes and pathways of TSPY actions would provide novel insights on its contribution(s) to male predominance in this deadly cancer. RESULTS: To determine the effects of TSPY on HCC, a TSPY transgene was introduced to the HCC cell line, HuH-7, and studied with RNA-Seq transcriptome analysis. The results showed that TSPY upregulates various genes associated with cell-cycle and cell-viability, and suppresses cell-death related genes. To correlate the experimental observations with those of clinical specimens, transcriptomes of male HCCs with high TSPY expression were analyzed with reference to those with silent TSPY expression from the Cancer Genome Atlas (TCGA). The comparative analysis identified 49 genes, which showed parallel expression patterns between HuH-7 cells overexpressing TSPY and clinical specimens with high TSPY expression. Among these 49 genes, 16 likely downstream genes could be associated with survival rates in HCC patients. The major upregulated targets were cell-cycle related genes and growth factor receptor genes, including CDC25B and HMMR, whose expression levels are negatively correlated with the patient survival rates. In contrast, PPARGC1A, SLC25A25 and SOCS2 were downregulated with TSPY expression, and possess favorable prognoses for HCC patients. CONCLUSION: We demonstrate that TSPY could exacerbate the oncogenesis of HCC by differentially upregulate the expression of pro-oncogenic genes and downregulate those of anti-oncogenic genes in male HCC patients, thereby contributing to the male predominance in this deadly cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13578-019-0287-x) contains supplementary material, which is available to authorized users. BioMed Central 2019-03-04 /pmc/articles/PMC6399826/ /pubmed/30867900 http://dx.doi.org/10.1186/s13578-019-0287-x Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Kido, Tatsuo
Lau, Yun-Fai Chris
The Y-linked proto-oncogene TSPY contributes to poor prognosis of the male hepatocellular carcinoma patients by promoting the pro-oncogenic and suppressing the anti-oncogenic gene expression
title The Y-linked proto-oncogene TSPY contributes to poor prognosis of the male hepatocellular carcinoma patients by promoting the pro-oncogenic and suppressing the anti-oncogenic gene expression
title_full The Y-linked proto-oncogene TSPY contributes to poor prognosis of the male hepatocellular carcinoma patients by promoting the pro-oncogenic and suppressing the anti-oncogenic gene expression
title_fullStr The Y-linked proto-oncogene TSPY contributes to poor prognosis of the male hepatocellular carcinoma patients by promoting the pro-oncogenic and suppressing the anti-oncogenic gene expression
title_full_unstemmed The Y-linked proto-oncogene TSPY contributes to poor prognosis of the male hepatocellular carcinoma patients by promoting the pro-oncogenic and suppressing the anti-oncogenic gene expression
title_short The Y-linked proto-oncogene TSPY contributes to poor prognosis of the male hepatocellular carcinoma patients by promoting the pro-oncogenic and suppressing the anti-oncogenic gene expression
title_sort y-linked proto-oncogene tspy contributes to poor prognosis of the male hepatocellular carcinoma patients by promoting the pro-oncogenic and suppressing the anti-oncogenic gene expression
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399826/
https://www.ncbi.nlm.nih.gov/pubmed/30867900
http://dx.doi.org/10.1186/s13578-019-0287-x
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