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RUN and FYVE domain containing 1 (RUFY1) knockdown attenuated podocalyxin‐like protein (PODXL)‐induced biological behaviors and inactivated the PI3K/AKT, NF‐κB and MAPK/ERK signaling pathways in vitro. A, B, RUFY1 knockdown significantly inhibited the wound healing and attenuated the PODXL‐induced changes in wound healing. C‐F, RUFY1 knockdown significantly inhibited migration and invasion and attenuated the PODXL‐induced changes in migration and invasion. G, H, RUFY1 knockdown significantly inhibited the phosphorylation of PI3K, AKT, MAPK, NF‐κB and ERK1 without significantly changing the basal level of protein expression and attenuated the PODXL‐induced changes in the activation of signaling pathways (*P < .05)
Source publication
Podocalyxin‐like protein (PODXL), a transmembrane glycoprotein with anti‐adhesive properties, has been proved to associate with an aggressive tumor phenotype and poor prognosis of several cancers. To elucidate the biological significance of PODXL and its molecular mechanism in gastric cancer (GC), we investigated the expression of PODXL in GC sampl...
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... In addition, the result that membrane-expressed PODXL was associated with poor survival, further supported the deduction that PODXL promoted tumor progression by enhancing the motility and invasiveness of tumor cells. PODXL also took part in the NF-kB, PI3K/AKT, Hippo and MAPK/ERK signaling pathway, and facilitated tumor progression by increasing cell proliferation, migration and invasion as well as suppressing apoptosis [21,45,46]. PODXL was expected to be a novel therapeutic and monitoring biomarker in certain cancers, because the high expressed PODXL might be a potential indicator of poor prognosis of cancers. ...
Absract:
BACKGROUND: Several studies have investigated the associations between the podocalyxin-like protein (PODXL) expression quantity or locations and cancers survival, but the results were far from conclusive. Therefore, we proceeded a meta-analysis on PODXL in various human cancers to find its prognostic value and followed confirmation using the TCGA datasets.
Methods:
We performed a systematic search, and 18 citations, including 5705 patients were pooled in meta-analysis. The results were verified with TCGA datasets.
Results:
Total eligible studies comprised 5705 patients with 10 types of cancer. And the result indicated that PODXL high-expression or membrane-expression were significantly related to poor overall survival (OS). However, subgroup analysis showed a significant association between high expressed PODXL and poor OS in the colorectal cancer, pancreatic cancer, urothelial bladder cancer, renal cell carcinoma and glioblastoma multiforme. Then, we validated the inference using TCGA datasets, and the consistent results were demonstrated in patients with pancreatic cancer, glioblastoma multiforme, gastric cancer, esophageal cancer and lung adenocarcinoma.
Conclusion:
The result of meta-analysis showed that high expressed PODXL was significantly linked with poor OS in pancreatic cancer and glioblastoma multiforme, but not in gastric cancer, esophageal cancer or lung adenocarcinoma. And the membrane expression of PODXL might also associate with poor OS. PODXL may act as tumor promotor and may serve as a potential target for antitumor therapy.
... Some latest studies showed that PODXL promoted the gelsolin-actin interaction in cell protrusions to enhance the motility and invasiveness [26], and some showed that the PODXL-ezrin signaling axis could rearrange the dynamic cytoskeleton for transendothelial migration [43]. PODXL also took part in the NF-kB, PI3K/AKT, Hippo and MAPK/ERK signaling pathway, and facilitated tumor progression by increasing cell proliferation, migration and invasion as well as suppressing apoptosis [21,44,45]. ...
Background Several studies have investigated the associations between the podocalyxin-like protein (PODXL) expression quantity or locations and cancers survival, but the results were far from conclusive. Therefore, we proceeded a meta-analysis on PODXL in various human cancers to find its prognostic value and followed confirmation using the TCGA datasets.
Methods We performed a systematic search, and 18 citations, including 5705 patients were pooled in meta-analysis. The results were verified with TCGA datasets.
Results Total eligible studies comprised 5705 patients with 10 types of cancer. And the result indicated that PODXL high-expression or membrane-expression were significantly related to poor overall survival (OS). However, subgroup analysis showed a significant association between high expressed PODXL and poor OS in the colorectal cancer, pancreatic cancer, urothelial bladder cancer, renal cell carcinoma and glioblastoma multiforme. Then, we validated the inference using TCGA datasets, and the consistent results were demonstrated in patients with pancreatic cancer, glioblastoma multiforme, gastric cancer, esophageal cancer and lung adenocarcinoma.
Conclusion The result of meta-analysis showed that high expressed PODXL was significantly linked with poor OS in pancreatic cancer and glioblastoma multiforme, but not in gastric cancer, esophageal cancer or lung adenocarcinoma. And the membrane expression of PODXL might also associate with poor OS. PODXL may act as tumor promotor and may serve as a potential target for antitumor therapy.
The role of tumor interaction with stromal components during carcinogenesis is crucial for the design of efficient cancer treatment approaches. It is widely admitted that tumor hypoxic stress is associated with tumor aggressiveness and thus impacts susceptibility and resistance to different types of treatments. Notable biological processes that hypoxia functions in include its regulation of tumor heterogeneity and plasticity. While hypoxia has been reported as a major player in tumor survival and dissemination regulation, the significance of hypoxia inducible factors in cancer stem cell development remains poorly understood. Several reports indicate that the emergence of cancer stem cells in addition to their phenotype and function within a hypoxic tumor microenvironment impacts cancer progression. In this respect, evidence showed that cancer stem cells are key elements of intratumoral heterogeneity and more importantly are responsible for tumor relapse and escape to treatments. This paper briefly reviews our current knowledge of the interaction between tumor hypoxic stress and its role in stemness acquisition and maintenance. Our review extensively covers the influence of hypoxia on the formation and maintenance of cancer stem cells and discusses the potential of targeting hypoxia-induced alterations in the expression and function of the so far known stem cell markers in cancer therapy approaches. We believe that a better and integrated understanding of the effect of hypoxia on stemness during carcinogenesis might lead to new strategies for exploiting hypoxia-associated pathways and their targeting in the clinical setting in order to overcome resistance mechanisms. More importantly, at the present time, efforts are oriented towards the design of innovative therapeutical approaches that specifically target cancer stem cells.
Since gastric cancer is the second leading cause of cancer deaths worldwide, more understanding of its molecular basis is urgently needed. Gastric gland mucin secreted from pyloric gland cells, mucous neck cells, and cardiac gland cells of the gastric mucosa harbors unique O-glycans carrying terminal α1,4-linked N-acetylglucosamine residues (αGlcNAc). We previously reported that αGlcNAc loss correlated positively with poor outcomes for patients with differentiated-type gastric cancer. However, the molecular mechanisms underlying these outcomes remained poorly understood. Here, we examined the effects of upregulated αGlcNAc expression on malignant phenotypes of the differentiated-type gastric cancer cell lines, AGS and MKN7. αGlcNAc upregulation following ectopic expression of its biosynthetic enzyme attenuated cell proliferation, motility, and invasiveness of AGS and MKN7 cells in vitro. Moreover, AGS cell tumorigenicity was significantly suppressed by αGlcNAc overexpression in a xenograft model. To define molecular mechanism underlying these phenotypes, we investigated αGlcNAc binding proteins in AGS cells and identified Mucin-1 (MUC1) and podocalyxin. Both proteins were colocalized with αGlcNAc on human gastric cancer cells. We also found that αGlcNAc was bound to MUC1 in murine normal gastric mucosa. When we assessed effects of αGlcNAc binding to MUC1, we found that αGlcNAc blocked galectin-3 binding to MUC1, phosphorylation of the MUC1 C-terminus and recruitment of Src and β-catenin to that C-terminus. These results suggest that αGlcNAc regulates cancer cell phenotypes by dampening MUC1 signal transduction.
Background
Endothelial cell disturbance underpins a role in pathogenesis of atherosclerosis. Notably, accumulating studies indicate the substantial role of microRNAs (miRs) in atherosclerosis, and miR-199a-5p dysregulation has been associated with atherosclerosis and other cardiovascular disorders. However, the effect of miR-199a-5p on the phenotypes of endothelial cells and atherosclerosis remains largely unknown.
Methods
ApoE−/− male mice were fed with high-fat diet for detection of inflammation and aorta plaque area. Extracellular vesicles (EVs) were separated from THP-1-derived macrophage (THP-1-DM) that was treated by oxidized low-density lipoprotein, followed by co-culture with human aortic endothelial cells (HAECs). Ectopic expression and downregulation of miR-199a-5p were done in THP-1-DM-derived EVs to assess pyroptosis and lactate dehydrogenase (LDH) of HAECs. Binding relationship between miR-199a-5p and SMARCA4 was evaluated by luciferase activity assay.
Results
EVs derived from ox-LDL-induced THP-1-DM expedited inflammation and aorta plaque area in atherosclerotic mice. Besides, miR-199a-5p expression was reduced in EVs from ox-LDL-induced THP-1-DM, and miR-199a-5p inhibition facilitated HAEC pyroptosis and LDH activity. Moreover, miR-199a-5p targeted and restricted SMARCA4, and then SMARCA4 activated the NF-κB pathway by increasing PODXL expression in HAECs.
Conclusion
EV-packaged inhibited miR-199a-5p from macrophages expedites endothelial cell pyroptosis and further accelerates atherosclerosis through the SMARCA4/PODXL/NF-κB axis, providing promising targets and strategies for the prevention and treatment of atherosclerosis.
Graphical abstract
Simple Summary
Malignancies derived from epithelial cells account for over 90% of all human cancers. Several aspects of cancer progression such as metastasis, immune evasion, and resistance to chemotherapy are often associated with poor prognosis and unfavourable patient outcomes due to limited therapeutic options. Therefore, the discovery of new biomarkers and treatment targets is essential in improving patient prognosis. Podocalyxin, a membrane protein of the CD34 family, has recently gained recognition as a potential diagnostic and prognostic biomarker, as well as a potential target for chemoresistance. This review summarises the current knowledge of podocalyxin in normal tissues and epithelial cancers, highlighting its potential utility in cancer management.
Abstract
Podocalyxin (PODXL), a glycosylated cell surface sialomucin of the CD34 family, is normally expressed in kidney podocytes, vascular endothelial cells, hematopoietic progenitors, mesothelium, as well as a subset of neurons. In the kidney, PODXL functions primarily as an antiadhesive molecule in podocyte epithelial cells, regulating adhesion and cell morphology, and playing an essential role in the development and function of the organ. Outside the kidney, PODXL plays subtle roles in tissue remodelling and development. Furthermore, many cancers, especially those that originated from the epithelium, have been reported to overexpress PODXL. Collective evidence suggests that PODXL overexpression is linked to poor prognosis, more aggressive tumour progression, unfavourable treatment outcomes, and possibly chemoresistance. This review summarises our current knowledge of PODXL in normal tissue function and epithelial cancer, with a particular focus on its underlying roles in cancer metastasis, likely involvement in chemoresistance, and potential use as a diagnostic and prognostic biomarker.
Podocalyxin overexpression associates with poor survival in pancreatic cancer (PDAC). We investigated whether podocalyxin expression correlates with treatment response or survival in neoadjuvant-treated PDAC. Through immunohistochemistry, we evaluated podocalyxin expression in 88 neoadjuvant and 143 upfront surgery patients using two antibodies. We developed a six-tier grading scheme for neoadjuvant responses evaluating the remaining tumor cells in surgical specimens. Strong podocalyxin immunopositivity associated with poor survival in the patients responding poorly to the neoadjuvant treatment (HR 4.16, 95% CI 1.56–11.01, p = 0.004), although neoadjuvant patients exhibited generally low podocalyxin expression (p = 0.017). Strong podocalyxin expression associated with perineural invasion (p = 0.003) and lack of radiation (p = 0.036). Two patients exhibited a complete neoadjuvant response, while a strong neoadjuvant response (≤ 5% of residual tumor cells) significantly associated with lower stage, pT-class and grade, less spread to the regional lymph nodes, less perineural invasion, and podocalyxin negativity (p < 0.05, respectively). A strong response predicted better survival (HR 0.28, 95% CI 0.09–0.94, p = 0.039). In conclusion, strong podocalyxin expression associates with poor survival among poorly responding neoadjuvant patients. A good response associates with podocalyxin negativity. A strong response associates with better outcome.
Altered metabolism of glucose, lipid and glutamine is a prominent hallmark of cancer cells. Currently, cell heterogeneity is believed to be the main cause of poor prognosis of glioblastoma (GBM) and is closely related to relapse caused by therapy resistance. However, the comprehensive model of genes related to glucose-, lipid- and glutamine-metabolism associated with the prognosis of GBM remains unclear, and the metabolic heterogeneity of GBM still needs to be further explored. Based on the expression profiles of 1,395 metabolism-related genes in three datasets of TCGA/CGGA/GSE, consistent cluster analysis revealed that GBM had three different metabolic status and prognostic clusters. Combining univariate Cox regression analysis and LASSO-penalized Cox regression machine learning methods, we identified a 17-metabolism-related genes risk signature associated with GBM prognosis. Kaplan-Meier analysis found that obtained signature could differentiate the prognosis of high- and low-risk patients in three datasets. Moreover, the multivariate Cox regression analysis and receiver operating characteristic curves indicated that the signature was an independent prognostic factor for GBM and had a strong predictive power. The above results were further validated in the CGGA and GSE13041 datasets, and consistent results were obtained. Gene set enrichment analysis (GSEA) suggested glycolysis gluconeogenesis and oxidative phosphorylation were significantly enriched in high- and low-risk GBM. Lastly Connectivity Map screened 54 potential compounds specific to different subgroups of GBM patients. Our study identified a novel metabolism-related gene signature, in addition the existence of three different metabolic status and two opposite biological processes in GBM were recognized, which revealed the metabolic heterogeneity of GBM. Robust metabolic subtypes and powerful risk prognostic models contributed a new perspective to the metabolic exploration of GBM.
Background
The methylation of the CpG islands of the LINE-1 promoter is a tight control mechanism on the function of mobile elements. However, simultaneous quantification of promoter methylation and transcription of LINE-1 has not been performed in progressive stages of colorectal cancer. In addition, the insertion of mobile elements in the genome of advanced adenoma stage, a precancerous stage before colorectal carcinoma has not been emphasized. In this study, we quantify promoter methylation and transcripts of LINE-1 in three stages of colorectal non-advanced adenoma, advanced adenoma, and adenocarcinoma. In addition, we analyze the insertion of LINE-1, Alu, and SVA elements in the genome of patient tumors with colorectal advanced adenomas.
Methods
LINE-1 hypomethylation status was evaluated by absolute quantitative analysis of methylated alleles (AQAMA) assay. To quantify the level of transcripts for LINE-1, quantitative RT-PCR was performed. To find mobile element insertions, the advanced adenoma tissue samples were subjected to whole genome sequencing and MELT analysis.
Results
We found that the LINE-1 promoter methylation in advanced adenoma and adenocarcinoma was significantly lower than that in non-advanced adenomas. Accordingly, the copy number of LINE-1 transcripts in advanced adenoma was significantly higher than that in non-advanced adenomas, and in adenocarcinomas was significantly higher than that in the advanced adenomas. Whole-genome sequencing analysis of colorectal advanced adenomas revealed that at this stage polymorphic insertions of LINE-1, Alu, and SVA comprise approximately 16%, 51%, and 74% of total insertions, respectively.
Conclusions
Our correlative analysis showing a decreased methylation of LINE-1 promoter accompanied by the higher level of LINE-1 transcription, and polymorphic genomic insertions in advanced adenoma, suggests that the early and advanced polyp stages may host very important pathogenic processes concluding to cancer.
Intracellular trafficking is essential for cell structure and function. In order to perform key tasks such as phagocytosis, secretion or migration, cells must coordinate their intracellular trafficking, and cytoskeleton dynamics. This relies on certain classes of proteins endowed with specialized and conserved domains that bridge membranes with effector proteins. Of particular interest are proteins capable of interacting with membrane subdomains enriched in specific phosphatidylinositol lipids, tightly regulated by various kinases and phosphatases. Here, we focus on the poorly studied RUFY family of adaptor proteins, characterized by a RUN domain, which interacts with small GTP-binding proteins, and a FYVE domain, involved in the recognition of phosphatidylinositol 3-phosphate. We report recent findings on this protein family that regulates endosomal trafficking, cell migration and upon dysfunction, can lead to severe pathology at the organismal level.
