Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell‐to‐cell crosstalk or phenotypic alterations including the acquisition of platinum‐resistance in OvCa cells. Herein, we report how OvCa‐associated mesothelial cells (OCAMs) induce platinum‐resistance in OvCa cells through direct cell‐to‐cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro coculturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF‐β1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum‐sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell‐to‐cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that are supposed to originate from MCs. Further, we also confirmed the activation of Akt signaling in OvCa cells in contact with TGF‐β1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell‐to‐cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum‐resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.
Proper bioriented attachment of microtubules and kinetochores is essential for the precise distribution of duplicated chromosomes to each daughter cell. An aberrant kinetochore-microtubule attachment results in chromosome instability, which leads to cellular transformation or apoptosis. In this article, we show that ubiquitin-associated protein 2-like (UBAP2L) is necessary for correct kinetochore-microtubule attachment. Depletion of UBAP2L inhibited chromosome alignment in metaphase and delayed progression to anaphase by activating spindle assembly checkpoint signaling. In addition, UBAP2L knockdown increased side-on attachment of kinetochores along the microtubules and suppressed stable kinetochore fiber formation. A proteomics analysis identified protein arginine methyltransferase (PRMT)1 as a direct interaction partner of UBAP2L. UBAP2L has an arginine- and glycine-rich motif called the RGG/RG or GAR motif in the N terminus. Biochemical analysis confirmed that arginine residues in the RGG/RG motif of UBAP2L were directly methylated by PRMT1. Finally, we demonstrated that the RGG/RG motif of UBAP2L is essential for the proper alignment of chromosomes in metaphase for the accurate distribution of chromosomes. Our results show a possible role for arginine methylation in UBAP2L for the progression of mitosis.
Ovarian cancer has one of the poorest prognoses among carcinomas. Advanced ovarian cancer often develops ascites and peritoneal dissemination, which is one of the poor prognostic factors. From the perspective of the “seed and soil” hypothesis, the intra-abdominal environment is like the soil for the growth of ovarian cancer (OvCa) and mesothelial cells (MCs) line the top layer of this soil. In recent years, various functions of MCs have been reported, including supporting cancer in the OvCa microenvironment. We refer to OvCa-associated MCs (OCAMs) as MCs that are stimulated by OvCa and contribute to its progression. OCAMs promote OvCa cell adhesion to the peritoneum, invasion, and metastasis. Elucidation of these functions may lead to the identification of novel therapeutic targets that can delay OvCa progression, which is difficult to cure.
Glioblastoma is a highly proliferative and invasive tumor. Despite extensive efforts to develop treatments for glioblastoma, the currently available therapies have only limited effects. To develop novel strategies for glioblastoma treatment, it is crucial to elucidate the molecular mechanisms that promote the invasive properties of glioblastoma. In the present study, we showed that the paired related homeobox 1 (PRRX1) is associated with glioblastoma cell invasion. The depletion of PRRX1 suppressed the invasion and neurosphere formation of glioblastoma cells. Conversely, the exogenous expression of PRRX1 promoted invasion. The Notch signaling pathway, which is an evolutionarily conserved pathway that is essential for developmental processes, plays an important role in the tumorigenesis of glioblastoma. The expression of PRRX1 induced the activation of Notch signaling, and the inhibition of Notch signaling suppressed PRRX1-mediated cell invasion. Our results indicate that activation of Notch signaling by PRRX1 is associated with the promotion of glioblastoma cell invasion.
RNA splicing is a fundamental process for protein synthesis. Recent studies have reported that drugs that inhibit splicing have cytotoxic effects on various tumor cell lines. In this report, we demonstrate that depletion of SNW1, a component of the spliceosome, induces apoptosis in breast cancer cells. Proteomics and biochemical analyses revealed that SNW1 directly associates with other spliceosome components, including EFTUD2 (Snu114) and SNRNP200 (Brr2). The SKIP region of SNW1 interacted with the N-terminus of EFTUD2 as well as two independent regions in the C-terminus of SNRNP200. Similar to SNW1 depletion, knockdown of EFTUD2 increased the numbers of apoptotic cells. Furthermore, we demonstrate that exogenous expression of either the SKIP region of SNW1 or the N-terminus region of EFTUD2 significantly promoted cellular apoptosis. Our results suggest that the inhibition of SNW1 or its associating proteins may be a novel therapeutic strategy for cancer treatment.
Adipocyte-rich omentum offers "good soil" for disseminating ovarian cancer (OvCa), contributing to therapeutic difficulty. However, little is understood about the association between adipocytes and tumor growth at peritoneal dissemination site. Herein, we report the induction of adipocyte dedifferentiation by OvCa cells and protumorigenic effects of resulted adipocyte-derived fibroblasts. We confirmed that malignant ascites promoted the dedifferentiation of the primary human adipocytes obtained from surgical omental specimen into omental adipocyte-derived fibroblast (O-ADF) that possess both mesenchymal stem cell and myofibroblast-like features. This promotion of dedifferentiation by malignant ascites was blocked by addition of Wnt signaling inhibitor. The effects of dedifferentiated adipocytes in proliferation and migration of OvCa cells were analyzed with in vitro coculturing experimental models and in vivo mice model, and we demonstrated that OvCa cell lines showed enhanced proliferative characteristics, as well as increased migratory abilities upon coculturing with O-ADF. Additionally, exogenous transforming growth factor-β1 augmented desmoplastic morphological change of O-ADF, leading to higher proliferative ability. Our results suggest that OvCa cells promote dedifferentiation of peritoneal adipocytes by activating Wnt/β-catenin signaling, and generated O-ADFs exhibit pro-tumoral hallmarks.
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