Lack of Relationship Between PROX1 Expression and Clinicopathological Parameters and Prognosis in Gastric Cancer Patients: A Meta-analysis and TCGA Analysis

Background:The relationship between PROX1 expression and clinicopathological characteristics and prognosis in patients with gastric cancer (GC) is hotly contested and continues to be so. The aim of this study is to determine the clinicopathological and prognostic significance of PROX1 expression in patients with GC.Methods:PROX1 expression in GC patients was evaluated clinicopathologically and in terms of overall survival (OS) using a systematic literature search and meta-analysis. Additionally, the Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) datasets were utilized to examine the relationship between PROX1 expression and clinicopathological significance and overall survival (OS) in GC patients.Results:A total of 8 studies pooling 1289 GC patients were included in the assessment. PROX1 expression, in GC patients, was shown to be unrelated to gender (odds ratio (OR) : 1.234, 95%CI: 0.958-1.590, P = 0.104), depth of tumor invasion (OR: 0.742, 95%CI:0.428-1.287, P = 0.289), lymph node metastasis (OR: 2.161, 95%CI: 0.808-5.779, P = 0.125), TNM stage (OR: 1.324, 95%CI: 0.572-3.066, P = 0.513), tumor size (OR: 0.889, 95%CI: 0.502-1.576, P = 0.687), metastasis (OR: 1.096, 95%CI: 0.470-2.555, P= 0.763), 1-year OS (OR: 0.908, 95%CI: 0.631-1.306, P = 0.602), 3-years OS (OR: 1.234, 95%CI: 0.482-3.160, P = 0.661) and 5-years OS (OR: 0.853, 95%CI: 0.266-2.736, P = 0.790). Patients with high PROX1 expression had a worse OS than those with low PROX1 expression, according to TCGA analyses, however the difference was not statistically significant (p=0.119).Conclusion:The expression of PROX1 was shown to be unrelated to gender, TNM stage, depth of invasion, tumor size, stage, tumor cell metastasis, or lymph node metastasis. The expression of PROX1 was also unrelated to OS and it failed to be a meaningful biomarker to prevent and diagnose GC.

The association of transcription factor Prox1 with the proliferation, migration, and invasion of lung cancer

Background The current study investigates the effect of transcription factor Prox1 on the proliferation, migration, and invasion ability of lung cancer. Methods Lung cancer cell lines (A549 and H446 cells) were transfected with Prox1NAD and siRNA, respectively. Thus, the A549 and H446 cells overexpressed Prox1 after transfection of Prox1NAD plasmids, and A549 and H446 cells have low expression of Prox1 after transfection with siRNA. Reverse transcriptase quantitative PCR and western blot analyses were used to detect Prox1 mRNA and protein expression in cells. Plate clone formation experiments and MTT experiments were used to detect cell proliferation. Western blot was used to detect the expression of Rho family-related proteins in cells. Results Compared to untransfected wild-type A549 and H446 that served as blank controls, the expression level of Prox1mRNA and protein in A549 and H446 cells overexpressing Prox1 after plasmid transfection was high, while the expression level of Prox1mRNA and protein in A549 and H446 cells with low expression of Prox1 after siRNA transfection was low. With the increase of Prox1 expression, the expression of RhoA and RhoC increased, while the expression of RhoB decreased. Conclusion The finding of this study may provide a new approach for the treatment of lung cancer using targeted gene therapy.

YAP and TAZ maintain PROX1 expression in the developing lymphatic and lymphovenous valves in response to VEGF-C signaling

ABSTRACTLymphatic vasculature is an integral part of digestive, immune and circulatory systems. The homeobox transcription factor PROX1 is necessary for the development of lymphatic vessels, lymphatic valves (LVs) and lymphovenous valves (LVVs). We and others previously reported a feedback loop between PROX1 and vascular endothelial growth factor-C (VEGF-C) signaling. PROX1 promotes the expression of the VEGF-C receptor VEGFR3 in lymphatic endothelial cells (LECs). In turn, VEGF-C signaling maintains PROX1 expression in LECs. However, the mechanisms of PROX1/VEGF-C feedback loop remain poorly understood. Whether VEGF-C signaling is necessary for LV and LVV development is also unknown. Here, we report for the first time that VEGF-C signaling is necessary for valve morphogenesis. We have also discovered that the transcriptional co-activators YAP and TAZ are required to maintain PROX1 expression in LVs and LVVs in response to VEGF-C signaling. Deletion of Yap and Taz in the lymphatic vasculature of mouse embryos did not affect the formation of LVs or LVVs, but resulted in the degeneration of these structures. Our results have identified VEGF-C, YAP and TAZ as a crucial molecular pathway in valve development.

Post-mitotic Prox1 expression controls the final specification of cortical VIP interneuron subtypes

SummaryNeuronal identity is controlled in multiple developmental steps by key transcription factors that determine the unique properties of a cell. During embryogenesis, the transcription factor Prox1 has been shown to regulate VIP interneuron migration, survival, and as a result, circuit integration. Here, we explore the role of Prox1 as a regulator of genetic programs that guide the final specification of VIP interneuron subtypes in early post-natal life. Using in-vitro electrophysiology we find that post-natal removal of Prox1 differentially affects the synaptic integration of VIP bipolar and multipolar subtypes.RNA sequencing reveals that one of the downstream targets of Prox1 is the postsynaptic protein Elfn1, a constitutive regulator of presynaptic release probability. Genetic, pharmacological and electrophysiological experiments demonstrate that knocking out Prox1 reduces Elfn1 function in VIP multipolar but not in bipolar cells. Thus, in addition to the activity-dependent and contextual processes that finalize developmental trajectories, genetic programs engaged by Prox1 control the differentiation and connectivity of VIP interneuron subtypes.

The Impact of Transcription Factor Prospero Homeobox 1 on the Regulation of Thyroid Cancer Malignancy

Transcription factor Prospero homeobox 1 (PROX1) is continuously expressed in the lymphatic endothelial cells, playing an essential role in their differentiation. Many reports have shown that PROX1 is implicated in cancer development and acts as an oncoprotein or suppressor in a tissue-dependent manner. Additionally, the PROX1 expression in many types of tumors has prognostic significance and is associated with patient outcomes. In our previous experimental studies, we showed that PROX1 is present in the thyroid cancer (THC) cells of different origins and has a high impact on follicular thyroid cancer (FTC) phenotypes, regulating migration, invasion, focal adhesion, cytoskeleton reorganization, and angiogenesis. Herein, we discuss the PROX1 transcript and protein structures, the expression pattern of PROX1 in THC specimens, and its epigenetic regulation. Next, we emphasize the biological processes and genes regulated by PROX1 in CGTH-W-1 cells, derived from squamous cell carcinoma of the thyroid gland. Finally, we discuss the interaction of PROX1 with other lymphatic factors. In our review, we aimed to highlight the importance of vascular molecules in cancer development and provide an update on the functionality of PROX1 in THC biology regulation.

CyclinD1 controls development of cerebellar granule cell progenitors through phosphorylation and stabilization of ATOH1

Here we report that CyclinD1 (CCND1) directly regulates both the proliferative and immature states of cerebellar granule cell progenitors (GCPs). CCND1 not only accelerates cell cycle but also upregulates ATOH1 protein, an essential transcription factor that maintains GCPs in an immature state. In cooperation with CDK4, CCND1 directly phosphorylates Ser309 of ATOH1, which inhibits additional phosphorylation at S328, consequently preventing Ser328 phosphorylation-dependent ATOH1 degradation. PROX1 downregulates Ccnd1 expression by histone-deacetylation of Ccnd1 promoter in GCPs, leading to cell cycle exit and differentiation. WNT signaling upregulates PROX1 expression in GCPs. These findings suggest that WNT-PROX1-CCND1-ATOH1 signaling cascade cooperatively controls proliferation and immaturity of GCPs. We revealed that the expression and phosphorylation levels of these molecules dynamically change during cerebellar development, which was suggested to determine appropriate differentiation rates from GCPs to GCs at distinct developmental stages. This study contributes to understanding the regulatory mechanism of GCPs as well as neural progenitors.

Comprehensive Analysis of Porcine Prox1 Gene and Its Relationship with Meat Quality Traits

Prox1 is involved in muscle fiber conversion, adult-onset obesity, and type 2 diabetes. However, information regarding porcine Prox1 and its relationship with meat quality traits is still unknown. In this study, we characterized the full-length cDNA and proximal promoter of two transcript variants of porcine Prox1. Moreover, Prox1 was expressed abundantly in the skeletal muscle and its expression was higher in the soleus muscle than that in the biceps femoris muscle. Its expression pattern in the high and low meat color (redness) value a* groups was similar to that of myoglobin and MyHC I, but opposed to that of MyHC IIB. Importantly, there was a significant positive correlation between Prox1 expression and meat color (redness) value a* (r = 0.3845, p = 0.0394), and a significant negative correlation between Prox1 expression and drip loss (r = −0.4204, p = 0.0232), as well as the ratio of MyHC IIB to MyHC I expression (r = −0.3871, p = 0.0380). In addition, we found that the polymorphisms of three closely linked SNPs in Prox1 promoter 1 were significantly associated with pH24h in a pig population. Taken together, our data provide valuable insights into the characteristics of porcine Prox1 and indicate that Prox1 is a promising candidate gene affecting meat quality traits.

MSCs inhibits the angiogenesis of HUVECs through the miR-211/Prox1 pathway

The aim of this study was to investigate the effect of mesenchymal stem cells (MSCs) on the angiogenesis of human umbilical vein endothelial cells (HUVECs). MSCs were subconjunctival injected into rat corneal alkali burn models. Their impacts on the degree of corneal neovascularization (CNV) and corneal opacity were evaluated at 3, 6, 9 and 12 days after injection. An in vitro experiment of MSCs affecting HUVECs angiogenesis was performed and evaluated using the tube formation assay. The results showed that both CNV and corneal opacity were decreased in rats after MSCs injection. In HUVECs, angiogenesis of cells was inhibited by miR-211 overexpression. miR-211 negatively regulated Prox1 expression. Knockdown of miR-211 blocked the decrease of Prox1 expression induced by MSCs and the inhibitory effect of MSCs on the angiogenesis of HUVECs. The critical role of miR-211 in MSCs inhibition of corneal angiogenesis was confirmed in rat experiments. We concluded that MSCs inhibited the angiogenesis of HUVEC through miR-211 mediating the down-regulation of Prox1.