Corrigendum to “Prostaglandin F2a-induced prostate transmembrane protein, androgen induced 1 mediates ovarian cancer progression increasing epithelial plasticity” [Neoplasia 21 (2019) 1073–1084]

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Prostaglandin F 2α-induced prostate transmembrane protein, androgen induced 1 mediates ovarian cancer progression increasing epithelial plasticity

The role of prostaglandin (PG) F2a has been scarcely studied in cancer. We have identified a new function for PGF2a in ovarian cancer, stimulating the production of Prostate Transmembrane Protein, Androgen Induced 1 (PMEPA1). We show that this induction increases cell plasticity and proliferation, enhancing tumor growth through PMEPA1. Thus, PMEPA1 overexpression in ovarian carcinoma cells, significantly increased cell proliferation rates, whereas PMEPA1 silencing decreased proliferation. In addition, PMEPA1 overexpression buffered TGF signaling, via reduction of SMADdependent signaling. PMEPA1 overexpressing cells acquired an epithelial morphology, associated with higher Ecadherin expression levels while catenin nuclear translocation was inhibited. Notwithstanding, high PMEPA1 levels also correlated with epithelial to mesenchymal transition markers, such as vimentin and ZEB1, allowing the cells to take advantage of both epithelial and mesenchymal characteristics, gaining in cell plasticity and adaptability. Interestingly, in mouse xenografts, PMEPA1 overexpressing ovarian cells had a clear survival and proliferative advantage, resulting in higher metastatic capacity, while PMEPA1 silencing had the opposite effect. Furthermore, high PMEPA1 expression in a cohort of advanced ovarian cancer patients was observed, correlating with Ecadherin expression. Most importantly, high PMEPA1 mRNA levels were associated with lower patient survivalThis work was supported by grants from Ministerio de Ciencia e Innovación (SAF201342850R and SAF201675988R) Comunidad de Madrid (S2017/BMD3671. INFLAMUNECM), Fondo de Investigaciones Sanitarias (BIOIMID) to M.F. and grants from the AECC (Grupos Estables de Investigacion 2011AECC GCB 110333 REVE) and the Instituto de Salud Carlos III (ISCIII: PI16/00134 and CIBEONC: CB16/12/00295) to G.M.B. K.S. was recipient of a Spanish Association Against Cancer oncology investigator grant (AECC AIO). A.J.S. and AM were recipients of FPU predoctoral fellowships from the Spanish Ministry of Education, Culture and Sports (FPU20122084 and 5338, respectively)

Quantitative Proteomic Analysis of Macrophages Infected with <i>Trypanosoma cruzi</i> Reveals Different Responses Dependent on the SLAMF1 Receptor and the Parasite Strain

Chagas disease is caused by the intracellular protozoan parasite Trypanosoma cruzi. This disease affects mainly rural areas in Central and South America, where the insect vector is endemic. However, this disease has become a world health problem since migration has spread it to other continents. It is a complex disease with many reservoirs and vectors and high genetic variability. One of the host proteins involved in the pathogenesis is SLAMF1. This immune receptor acts during the infection of macrophages controlling parasite replication and thus affecting survival in mice but in a parasite strain-dependent manner. Therefore, we studied the role of SLAMF1 by quantitative proteomics in a macrophage in vitro infection and the different responses between Y and VFRA strains of Trypanosoma cruzi. We detected different significant up- or downregulated proteins involved in immune regulation processes, which are SLAMF1 and/or strain-dependent. Furthermore, independently of SLAMF1, this parasite induces different responses in macrophages to counteract the infection and kill the parasite, such as type I and II IFN responses, NLRP3 inflammasome activation, IL-18 production, TLR7 and TLR9 activation specifically with the Y strain, and IL-11 signaling specifically with the VFRA strain. These results have opened new research fields to elucidate the concrete role of SLAMF1 and discover new potential therapeutic approaches for Chagas disease

Opposing Actions of TLR2 and TLR4 in Adipocyte Differentiation and Mature-Onset Obesity

Understanding the signaling cascades that govern adipocyte metabolism and differentiation is necessary for the development of therapies for obesity. Toll-like receptors (TLRs) are key mediators in adipogenesis, but their specific role is not completely understood. In this study, siRNA knockdown of Tlr2 in 3T3-L1 cells allowed them to differentiate more efficiently into adipocytes, whereas the opposite was observed for the knockdown of Tlr4. At the same time, we show that TLR2 knock-out mice spontaneously developed mature-onset obesity and insulin resistance. Besides a higher incidence of hyperplasia and hypertrophy in white adipose tissue (WAT), we found a significantly increased number of adipocyte precursor cells in TLR2-/- mice compared to TLR4-/- mice. Interestingly, genetic inactivation of Tlr4 in TLR2-/- mice reverted their increased adiposity, insulin resistance, and restored normal levels of adipocyte precursor cells. These findings provide evidence that TLR2 and TLR4 play opposing roles in WAT homeostasis and point to the existence of cross-regulation among TLR2 and TLR4 during adipocyte differentiation both in vitro and in vivo

Prostaglandin F2α-induced Prostate Transmembrane Protein, Androgen Induced 1 mediates ovarian cancer progression increasing epithelial plasticity

The role of prostaglandin (PG) F has been scarcely studied in cancer. We have identified a new function for PGF in ovarian cancer, stimulating the production of Prostate Transmembrane Protein, Androgen Induced 1 (PMEPA1). We show that this induction increases cell plasticity and proliferation, enhancing tumor growth through PMEPA1. Thus, PMEPA1 overexpression in ovarian carcinoma cells, significantly increased cell proliferation rates, whereas PMEPA1 silencing decreased proliferation. In addition, PMEPA1 overexpression buffered TGFβ signaling, via reduction of SMAD-dependent signaling. PMEPA1 overexpressing cells acquired an epithelial morphology, associated with higher E-cadherin expression levels while β-catenin nuclear translocation was inhibited. Notwithstanding, high PMEPA1 levels also correlated with epithelial to mesenchymal transition markers, such as vimentin and ZEB1, allowing the cells to take advantage of both epithelial and mesenchymal characteristics, gaining in cell plasticity and adaptability. Interestingly, in mouse xenografts, PMEPA1 overexpressing ovarian cells had a clear survival and proliferative advantage, resulting in higher metastatic capacity, while PMEPA1 silencing had the opposite effect. Furthermore, high PMEPA1 expression in a cohort of advanced ovarian cancer patients was observed, correlating with E-cadherin expression. Most importantly, high PMEPA1 mRNA levels were associated with lower patient survival.Ministerio de Ciencia e Innovacin (SAF201342850R and SAF201675988R) Comunidad de Madrid (S2017/BMD3671. INFLAMUNECM), Fondo de Investigaciones Sanitarias (BIOIMID) to M.F. and grants from the AECC (Grupos Estables de Investigacion 2011AECC GCB 110333 REVE) and the Instituto de Salud Carlos II