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Rhabdomyosarcoma (RMS) is an aggressive pediatric soft-tissue cancer with features of skeletal muscle. Because of poor survival of RMS patients and severe long-term side effects of RMS therapies, alternative RMS therapies are urgently needed. Here we show that the prospero-related homeobox 1 (PROX1) transcription factor is highly expressed in RMS tumors regardless of their cell type of origin. We demonstrate that PROX1 is needed for RMS cell clonogenicity, growth and tumor formation. PROX1 gene silencing repressed several myogenic and tumorigenic transcripts and transformed the RD cell transcriptome to resemble that of benign mesenchymal stem cells. Importantly, we found that fibroblast growth factor receptors (FGFR) mediated the growth effects of PROX1 in RMS. Because of receptor cross-compensation, paralog-specific FGFR inhibition did not mimic the effects of PROX1 silencing, whereas a pan-FGFR inhibitor ablated RMS cell proliferation and induced apoptosis. Our findings uncover the critical role of PROX1 in RMS and offer insights into the mechanisms that regulate RMS development and growth. As FGFR inhibitors have already been tested in clinical phase I/II trials in other cancer types, our findings provide an alternative option for RMS treatment.

The purpose of this study is to investigate the role of Prox1 in the progression of cutaneous melanoma (CMM) and its relationship with lymphatic metastasis. By analyzing the data from the Cancer Genome Atlas (TCGA), we found that the expression of Prox1 and LYVE1 was significantly upregulated in the metastatic melanoma group. Additionally, elevated levels of Prox1 were associated with shorter survival times. Correlation analysis demonstrated a significant relationship between Prox1 and markers associated with lymphangiogenesis, including LYVE1, FLT4, FOXC2, and ANGPT2. A clinical study involving 32 cases of CMM was conducted to analyze Prox1 expression and its relationship with lymphangiogenesis and clinicopathological characteristics. Research revealed that Prox1 was expressed significantly higher in patients with lymph node (LN) metastasis and in those classified as stage 3C-4. Additionally, the density of lymphatic vessels(LVD) in the LN metastasis group and the stage 3C-4 group was markedly higher than in the group without lymph node metastasis and in the stage 0-3B group. Furthermore, Breslow thickness was found to correlate with both Prox1 expression and LVD. Prox1-positive expression was associated with increased LVD. Further investigation was conducted on the role of Prox1 in the CMM cell line A375 and its derived exosomes. Exosomes were collected from CMM and CMM to verify the changes in Prox1 expression, respectively. It was observed that the proliferation, migration, and tube formation abilities of human lymphatic endothelial cells(HLECs) diminished with the downregulation of Prox1. Additionally, VEGFR3 activation was reduced in HLECs following the reduction of Prox1. Prox1 played an important role in promoting cell proliferation, migration, and lymphangiogenesis, which is related to tumor metastasis and poor prognosis. These results indicated the potential importance of Prox1 as a biomarker, which is expected to lead to the development of a new insight for anti-tumor therapy.

Abstract Background Esophageal squamous carcinoma (ESCC) is a common malignancy that originates in the digestive tract. Lymph node metastasis (LNM) is a complicated process, and tumor lymphangiogenesis has been reported to be associated with the spread of tumor cells to lymph nodes (LNs), including in ESCC. However, little is currently known about the mechanisms involved in lymphangiogenesis in ESCC tumors. According to previous literature, we know that hsa_(c)irc₀026611 expresses at a high level in serum exosomes of patients with ESCC and shows a close association with LNM and poor prognosis. However, details on the functions of circ₀026611 in ESCC remain unclear. We aim to explore the effects of circ₀026611 in ESCC cell-derived exosomes on lymphangiogenesis and its potential molecular mechanism. Methods We firstly examined how circ₀026611 may express in ESCC cells and exosomes by quantitative reverse transcription real-time polymerase chain reaction (RT-qPCR). The potential effects circ₀026611 may exert on lymphangiogenesis in ESCC cell-derived exosomes were assessed afterward via mechanism experiments. Results circ₀026611 high expression pattern was confirmed in ESCC cells and exosomes. ESCC cell-derived exosomes promoted lymphangiogenesis by transferring circ₀026611. Besides, circ₀026611 interacted with N-α-acetyltransferase 10 (NAA10) to inhibit NAA10-mediated prospero homeobox 1 (PROX1) acetylation with subsequent ubiquitination and degradation. Furthermore, circ₀026611 was verified to promote lymphangiogenesis in a PROX1-mediated manner. Conclusions Exosomal circ₀026611 inhibited PROX1 acetylation and ubiquitination to promote lymphangiogenesis in ESCC. Graphical Abstract

Autophagy has vasculoprotective roles, but whether and how it regulates lymphatic endothelial cells (LEC) homeostasis and lymphangiogenesis is unknown. Here, we show that genetic deficiency of autophagy in LEC impairs responses to VEGF-C and injury-driven corneal lymphangiogenesis. Autophagy loss in LEC compromises the expression of main effectors of LEC identity, like VEGFR3, affects mitochondrial dynamics and causes an accumulation of lipid droplets (LDs) in vitro and in vivo. When lipophagy is impaired, mitochondrial ATP production, fatty acid oxidation, acetyl-CoA/CoA ratio and expression of lymphangiogenic PROX1 target genes are dwindled. Enforcing mitochondria fusion by silencing dynamin-related-protein 1 (DRP1) in autophagy-deficient LEC fails to restore LDs turnover and lymphatic gene expression, whereas supplementing the fatty acid precursor acetate rescues VEGFR3 levels and signaling, and lymphangiogenesis in LEC-Atg5 −/− mice. Our findings reveal that lipophagy in LEC by supporting FAO, preserves a mitochondrial-PROX1 gene expression circuit that safeguards LEC responsiveness to lymphangiogenic mediators and lymphangiogenesis. Autophagy is essential to endothelial cell homeostasis. Here the authors show that lipophagy in LEC supports fatty acid oxidation to sustain a mitochondrial-Prox1 gene expression circuit and promote response of LEC to lymphangiogenic mediators.

The progressive, multifactorial and multistep dynamic process of metastasis is the primary cause of breast cancer (BC) lethality. PROX1 (Prospero-related homeobox 1), as a type of transcription factor that plays a key role in the formation of lymphatic vessels in animal embryonic development, has been proven to promote or suppress cancer in a variety of malignant tumors. However, molecular mechanisms behind PROX1 induced breast cancer metastases remain elusive. Changes of PROX1 expression and clinical significance of PROX1 in BC were evaluated by BC tissue, as well as public database. The functional role of PROX1 in metastases BC was analyzed by transwell assay , and by lung metastases model of nude mice via lentivirus mediated knockdown assays. Mechanism studies were performed by public database screening, western blot and PCR assay, immunoprecipitation, immunofluorescence staining and luciferase promoter assays. In this study, we found that PROX1 was upregulated in breast cancer tissues; increased PROX1 expression in breast cancer was associated with tumor size, lymph node metastasis, ER and PR status. Meanwhile, PROX1 can promote breast cancer invasion and metastasis and . Furthermore, PROX1 can interact with hnRNPK to activate WNT/β-catenin signaling in breast cancer cells. Moreover, the interaction of PROX1 and hnRNPK inhibits the ubiquitination of hnRNPK, and subsequently activates WNT pathway to promote the invasion and metastasis of breast cancer. In conclusion, our findings indicated PROX1 contributes to breast cancer EMT and metastasis and serves as a candidate diagnostic biomarker and promising therapeutic target for breast cancer.

The process of angiogenesis has been well documented, but little is known about the biology of lymphatic endothelial cells and the molecular mechanisms controlling lymphangiogenesis. The homeobox gene Prox1 is expressed in a subpopulation of endothelial cells that, after budding from veins, gives rise to the mammalian lymphatic system. In Prox1 −/− embryos, this budding becomes arrested at around embryonic day (E)11.5, resulting in embryos without lymphatic vasculature. Unlike the endothelial cells that bud off in E11.5 wild‐type embryos, those of Prox1‐ null embryos did not co‐express any lymphatic markers such as VEGFR‐3, LYVE‐1 or SLC. Instead, the mutant cells appeared to have a blood vascular phenotype, as determined by their expression of laminin and CD34. These results suggest that Prox1 activity is required for both maintenance of the budding of the venous endothelial cells and differentiation toward the lymphatic phenotype. On the basis of our findings, we propose that a blood vascular phenotype is the default fate of budding embryonic venous endothelial cells; upon expression of Prox1, these budding cells adopt a lymphatic vasculature phenotype.

During mammalian development, a subpopulation of endothelial cells in the cardinal vein (CV) expresses lymphatic‐specific genes and subsequently develops into the first lymphatic structures, collectively termed as lymph sacs. Budding, sprouting and ballooning of lymphatic endothelial cells (LECs) have been proposed to underlie the emergence of LECs from the CV, but the exact mechanisms of lymph vessel formation remain poorly understood. Applying selective plane illumination‐based ultramicroscopy to entire wholemount‐immunostained mouse embryos, we visualized the complete developing vascular system with cellular resolution. Here, we report emergence of the earliest detectable LECs as strings of loosely connected cells between the CV and superficial venous plexus. Subsequent aggregation of LECs resulted in formation of two distinct, previously unidentified lymphatic structures, the dorsal peripheral longitudinal lymphatic vessel (PLLV) and the ventral primordial thoracic duct (pTD), which at later stages formed a direct contact with the CV. Providing new insights into their function, we found vascular endothelial growth factor C (VEGF‐C) and the matrix component CCBE1 indispensable for LEC budding and migration. Altogether, we present a significantly more detailed view and novel model of early lymphatic development. Ultramicroscopy of wholemount mouse embryos uncovers the first, previously unknown lymphatic structures in mammals: the dorsal longitudinal lymphatic vessel and the ventral primordial thoracic duct, which eventually connect with the cardinal vein as previously described.

Within the vascular system, the mucin‐type transmembrane glycoprotein T1α/podoplanin is predominantly expressed by lymphatic endothelium, and recent studies have shown that it is regulated by the lymphatic‐specific homeobox gene Prox1 . In this study, we examined the role of T1α/podoplanin in vascular development and the effects of gene disruption in mice. T1α/podoplanin is first expressed at around E11.0 in Prox1‐positive lymphatic progenitor cells, with predominant localization in the luminal plasma membrane of lymphatic endothelial cells during later development. T1 α/ podoplanin −/− mice die at birth due to respiratory failure and have defects in lymphatic, but not blood vessel pattern formation. These defects are associated with diminished lymphatic transport, congenital lymphedema and dilation of lymphatic vessels. T1α/podoplanin is also expressed in the basal epidermis of newborn wild‐type mice, but gene disruption did not alter epidermal differentiation. Studies in cultured endothelial cells indicate that T1α/podoplanin promotes cell adhesion, migration and tube formation, whereas small interfering RNA‐mediated inhibition of T1α/podoplanin expression decreased lymphatic endothelial cell adhesion. These data identify T1α/podoplanin as a novel critical player that regulates different key aspects of lymphatic vasculature formation.

The balance of osteoblasts and marrow adipocytes from bone marrow mesenchymal stem cells (BM-MSCs) maintains bone health. Under aging or other pathological stimuli, BM-MSCs will preferentially differentiate into marrow adipocytes and reduce osteoblasts, leading to osteoporosis. Long non-coding RNA differentiation antagonizing non-protein coding RNA (DANCR) participates in the osteogenic differentiation of human BM-MSCs, but the mechanism by which DANCR regulates the osteogenic differentiation of human BM-MSCs has not been fully explained. We observed that DANCR and prospero homeobox 1 (PROX1) were downregulated during osteogenic differentiation of human BM-MSCs, while miR-1301-3p had an opposite trend. DANCR overexpression decreased the levels of alkaline phosphatase, RUNX2, osteocalcin, Osterix in BM-MSCs after osteogenic induction, but DANCR silencing had the opposite result. Moreover, DANCR sponged miR-1301-3p to regulate PROX1 expression. miR-1301-3p overexpression reversed the suppressive role of DANCR elevation on the osteogenic differentiation of human BM-MSCs. Also, PROX1 elevation abolished the promoting role of miR-1301-3p overexpression on the osteogenic differentiation of human BM-MSCs. In conclusion, DANCR suppressed the osteogenic differentiation of human BM-MSCs through the miR-1301-3p/PROX1 axis, offering a novel mechanism by which DANCR is responsible for the osteogenic differentiation of human BM-MSCs.

Increasing evidence suggests that Kaposi’s sarcoma (KS) arises from Kaposi’s sarcoma-associated herpesvirus (KSHV)-infected mesenchymal stem cells (MSCs) through mesenchymal-to-endothelial transition (MEndT). KSHV infection promotes MSC differentiation of endothelial lineage and acquisition of tumorigeneic phenotypes. To understand how KSHV induces MEndT and transforms MSCs to KS cells, we investigated the mechanism underlying KSHV-mediated MSC endothelial lineage differentiation. Like embryonic stem cells, MSC differentiation and fate determination are under epigenetic control. Prospero homeobox 1 (PROX1) is a master regulator that controls lymphatic vessel development and endothelial differentiation. We found that the PROX1 gene in MSCs harbors a distinctive bivalent epigenetic signature consisting of both active marker H3K4me3 and repressive marker H3K27me3, which poises expression of the genes, allowing timely activation upon differentiation signals or environmental stimuli. KSHV infection effectively resolves the bivalent chromatin by decreasing H3K27me3 and increasing H3K4me3 to activate the PROX1 gene. vIL-6 signaling leads to the recruitment of MLL2 and SET1 complexes to the PROX1 promoter to increase H3K4me3, and the vGPCR-VEGF-A axis is responsible for removing PRC2 from the promoter to reduce H3K27me3. Therefore, through a dual signaling process, KSHV activates PROX1 gene expression and initiates MEndT, which renders MSC tumorigenic features including angiogenesis, invasion and migration.