Testis‐specific protein Y‐linked 1 activates PI3K/AKT and RAS signaling pathways through suppressing IGFBP3 expression during tumor progression

摘要

The testis‐specific protein, Y‐linked 1 (TSPY1), a newly recognized cancer/testis antigen, has been suggested to accelerate tumor progression. However, the mechanisms underlying TSPY1 cancer‐related function remain limited. By mining the RNA sequencing data of lung and liver tumors from The Cancer Genome Atlas, we found frequent ectopic expression of TSPY1 in lung adenocarcinoma (LUAD) and liver hepatocellular carcinoma (LIHC), and the male‐specific protein was associated with higher mortality rate and worse overall survival in patients with LUAD and LIHC. Overexpression of TSPY1 promotes cell proliferation, invasiveness, and cycle transition and inhibits apoptosis, whereas TSPY1 knockdown has the opposite effects on these cancer cell phenotypes. Transcriptomic analysis revealed the involvement of TSPY1 in PI3K/AKT and RAS signaling pathways in both LUAD and LIHC cells, which was further confirmed by the increase in the levels of phosphorylated proteins in the style="fixed-case">PI3K‐ style="fixed-case">AKT and style="fixed-case">RAS signaling pathways in style="fixed-case">TSPY1‐overexpressing cancer cells, and by the suppression on the activity of these two pathways in style="fixed-case">TSPY1‐knockdown cells. Further investigation identified that style="fixed-case">TSPY1 could directly bind to the promoter of insulin growth factor binding protein 3 ( style="fixed-case">IGFBP3) to inhibit style="fixed-case">IGFBP3 expression and that downregulation of style="fixed-case">IGFBP3 increased the activity of style="fixed-case">PI3K/ style="fixed-case">AKT/ style="fixed-case">mTOR/ style="fixed-case">BCL2 and style="fixed-case">RAS/ style="fixed-case">RAF/ style="fixed-case">MEK/ style="fixed-case">ERK/ style="fixed-case">JUN signaling in style="fixed-case">LUAD and style="fixed-case">LIHC cells. Taken together, the observations reveal a novel mechanism by which style="fixed-case">TSPY1 could contribute to the progression of style="fixed-case">LUAD and style="fixed-case">LIHC. Our finding is of importance for evaluating the potential of style="fixed-case">TSPY1 in immunotherapy of male tumor patients with style="fixed-case">TSPY1 expression.