Kido Tatsuo, Lau Yun-Fai Chris
1Division of Cell and Developmental Genetics, Department of Medicine, Veterans Affairs Medical Center, University of California, San Francisco, 4150 Clement Street, San Francisco, CA 94121 USA.
2Institute for Human Genetics, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143 USA.
Cell Biosci. 2019 Mar 4;9:22. doi: 10.1186/s13578-019-0287-x. eCollection 2019.
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.
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.
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.
肝癌是全球癌症死亡的主要原因之一，男性患者的发病率和死亡率显著更高。尽管性激素及其受体可能导致这种性别差异，但情况并不完整。Y染色体男性特异性区域上的基因可能在这种癌症中起作用。TSPY是Y染色体（GBY）上性腺母细胞瘤位点的推定基因，在一部分男性肝细胞癌（HCC）中异位表达。尽管各种研究表明TSPY表达与患者预后不良相关，且其过表达促进各种癌细胞系的细胞增殖，但尚不清楚TSPY如何影响HCC患者的临床结局。确定TSPY作用的下游基因和途径将为其在这种致命癌症中男性占优势的情况提供新的见解。
为了确定TSPY对HCC的影响，将TSPY转基因导入HCC细胞系HuH-7，并通过RNA测序转录组分析进行研究。结果表明，TSPY上调了与细胞周期和细胞活力相关的各种基因，并抑制了与细胞死亡相关的基因。为了将实验观察结果与临床标本的结果相关联，参考癌症基因组图谱（TCGA）中TSPY表达沉默的男性HCC的转录组，分析了TSPY高表达的男性HCC的转录组。比较分析确定了49个基因，这些基因在过表达TSPY的HuH-7细胞和TSPY高表达的临床标本之间表现出平行的表达模式。在这49个基因中，16个可能的下游基因可能与HCC患者的生存率相关。主要上调的靶点是细胞周期相关基因和生长因子受体基因，包括CDC25B和HMMR，其表达水平与患者生存率呈负相关。相反，PPARGC1A、SLC25A25和SOCS2随着TSPY表达而下调，对HCC患者具有良好的预后。
我们证明，TSPY可能通过差异上调男性HCC患者中促癌基因的表达并下调抗癌基因的表达来加剧HCC的肿瘤发生，从而导致这种致命癌症中男性占优势。
Zotero 插件
