Placenta-Specific 8 Is Overexpressed and Regulates Cell Proliferation in Low-Grade Human Pancreatic Neuroendocrine Tumors

Abstract

Background/Aims: Many aspects of the biology of pancreatic neuroendocrine tumors (PanNETs), including determinants of proliferative, invasive, and metastatic potential, remain poorly understood. Placenta-specific 8 (PLAC8), a gene with unknown molecular function, has been reported to have tumor-promoting roles in different human malignancies, including exocrine pancreatic cancer. Since preliminary data suggested deregulation of PLAC8 expression in PanNET, we have performed detailed analyses of PLAC8 expression and function in human PanNET. Methods: Primary tissue from PanNET patients was immunohistochemically stained for PLAC8, and expression was correlated with clinicopathological data. In vitro, PLAC8 expression was inhibited by siRNA transfection in PanNET cell lines and effects were analyzed by qRT-PCR, Western blot, and proliferation assays. Results: We report that PLAC8 is expressed in the majority of well-differentiated human PanNETs, predominantly in early-stage and low-grade tumors. SiRNA-mediated knockdown of PLAC8 in PanNET cells resulted in decreased proliferation and viability, while apoptosis was not induced. Mechanistically, these effects were mediated by attenuation of cell cycle progression, as Western blot analyses demonstrated upregulation of the tumor suppressor p21/CDKN2A and downregulation of the cell cycle regulator Cyclin D1 as well as reduced levels of phosphorylated ribosomal protein s6 and retinoblastoma protein. Conclusion: Our findings establish PLAC8 as a central mediator of cell growth in a subset of human PanNET, providing evidence for the existence of distinct molecular subtypes within this class of tumors.

Placenta-specific 8 limits IFNγ production by CD4 T cells in vitro and promotes establishment of influenza-specific CD8 T cells in vivo

“…When Plac8 was depleted in CD8 T cells, we observed a decrease in effector CD8 T cell establishment relative to WT CD8 T cells which led us to hypothesize that Plac8 promotes proliferation within CD8 T cells. This hypothesis is supported by Plac8's documented role in promoting proliferation in multiple cancerous epithelial cell lines [12,26,27]. However, in our model we found that Plac8 does not regulate the proliferation of antigen-specific CD8 T cells as measured by similar surface expression of CD25 and BrdU incorporation 8 dpi (Fig 5E).…”

“…In other cell types, Plac8 is known to regulate cellular proliferation [ 12 , 26 , 27 ], and modified proliferation can impact CD8 T cells not only acutely during the effector phase of the anti-viral response, but also the development of subsequent memory CD8 T cells. Therefore, we next assessed whether Plac8 is important for the establishment of the immunodominant influenza nucleoprotein (NP)-specific CD8 T cells within WT and Plac8 -/- mice.…”

Ribosomal Protein S6: A Potential Therapeutic Target against Cancer?

“…FASN-KD induces apoptosis and downregulates both p-RPS6 (S240/244) and total (t)-RPS6 through AKT/mTOR/SK6 axis by stimulating protein ubiquitination in ovarian cancer cells [173] Gal-13/PLAC8 (galectin-13/placenta-specific 8) absent in healthy adult exocrine pancreas but ectopically expressed in pancreatic ductal adenocarcinoma [174][175][176] PLAC8-KD downregulates p-RPS6 (S235/236) and p-RB (S807/811) in human BON-1 pancreatic neuroendocrine tumor cells [177] GlnRS/QARS (glutaminyl-tRNA synthase)…”

Expression profiling of lncRNAs and mRNAs in placental site trophoblastic tumor (PSTT) by microarray

“…Our results showed that compared to normal villi MAPK14, MAPK13, MAPK7 and MAPK1 were significantly down-regulated in PSTT, but Köbel et al have reported that MAPK was highly expressed [38]. PLAC8, also named onzin, is a small protein (∼16 kDa) that was originally described to be highly expressed in mouse placenta [39] and its deficiency in mice may result in innate immunity deficiency [40]. We also found that PLAC8 is highly expressed in PSTT but not choriocarcinoma (Figure S2).…”