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

Abstract

The testis‐specific protein, Y‐linked 1 ( TSPY 1), a newly recognized cancer/testis antigen, has been suggested to accelerate tumor progression. However, the mechanisms underlying TSPY 1 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 TSPY 1 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 TSPY 1 promotes cell proliferation, invasiveness, and cycle transition and inhibits apoptosis, whereas TSPY 1 knockdown has the opposite effects on these cancer cell phenotypes. Transcriptomic analysis revealed the involvement of TSPY 1 in PI 3K/ 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 PI 3K‐ AKT and RAS signaling pathways in TSPY 1‐overexpressing cancer cells, and by the suppression on the activity of these two pathways in TSPY 1‐knockdown cells. Further investigation identified that TSPY 1 could directly bind to the promoter of insulin growth factor binding protein 3 ( IGFBP 3) to inhibit IGFBP 3 expression and that downregulation of IGFBP 3 increased the activity of PI 3K/ AKT / mTOR / BCL 2 and RAS / RAF / MEK / ERK / JUN signaling in LUAD and LIHC cells. Taken together, the observations reveal a novel mechanism by which TSPY 1 could contribute to the progression of LUAD and LIHC . Our finding is of importance for evaluating the potential of TSPY 1 in immunotherapy of male tumor patients with TSPY 1 expression.

Targeted Delivery of PD‐L1‐Derived Phosphorylation‐Mimicking Peptides by Engineered Biomimetic Nanovesicles to Enhance Osteosarcoma Treatment

“…[ 26 ] However, IGFBP3 is also known to repress tumor progression and metastasis through the inactivation of PI3K/AKT and RAS signaling pathways. [ 27,28 ] We previously reported that the E3 ligase TRAIP promotes osteosarcoma tumor growth via KANK1‐IGFBP3‐AKT signaling. [ 19 ] In this study, we further show that PD‐L1 binds with IGFBP3 to activate mTOR signaling in osteosarcoma.…”

Expression of Cancer Testis Antigens in Tumor-Adjacent Normal Liver Is Associated with Post-Resection Recurrence of Hepatocellular Carcinoma

“…Several CTAs of our panel, such as the MAGE-family members, CTAG1B, TSPY1, and CAGE1, are functionally involved in tumorigeneses and cancer progression by modulating gene expression, regulating mitosis, and tumorigenic signaling [8,10,[36][37][38]. More specifically, MAGE-A9 and TSPY have been shown to be involved in HCC tumor cell proliferation [36,38].…”

Molecular characterization of the Yp11.2 region deletion in the Chinese Han population

“…Previous studies demonstrated that TSPY1 has physiological functions in the proliferation and differentiation of spermatogonia during spermatogenesis [ 15 ]. Remarkably, TSPY1 is also involved in the initiation and development of many tumors by activating the PI3K/AKT and RAS signaling pathways by suppressing IGFBP3 expression [ 16 ]. Amelogenins are useful for sex identification and are involved in biomineralization during tooth enamel development [ 17 ].…”