Spindle cell rhabdomyosarcomas: With TFCP2 rearrangements, and novel EWSR1::ZBTB41 and PLOD2::RBM6 gene fusions. A study of five cases and review of the literature.

AIMS: Spindle-cell/sclerosing rhabdomyosarcomas (SS-RMS) are clinically and genetically heterogeneous. They include three well-defined molecular subtypes, of which those with EWSR1/FUS::TFCP2 rearrangements were described only recently. This study aimed to evaluate five new cases of SS-RMS and to perform a clinicopathological and statistical analysis of all TFCP2-rearranged SS-RMS described in the English literature to more comprehensively characterize this rare tumour type. METHODS AND RESULTS: Cases were retrospectively selected and studied by immunohistochemistry, fluorescence in situ hybridization with EWSR1/FUS and TFCP2 break-apart probes, next-generation sequencing (Archer FusionPlex Sarcoma kit and TruSight RNA Pan-Cancer Panel). The PubMed database was searched for relevant peer-reviewed English reports. Five cases of SS-RMS were found. Three cases were TFCP2 rearranged SS-RMS, having FUSex6::TFCP2ex2 gene fusion in two cases and triple gene fusion EWSR1ex5::TFCP2ex2, VAX2ex2::ALKex2 and VAX2intron2::ALKex2 in one case. Two cases showed rhabdomyoblastic differentiation and spindle-round cell/sclerosing morphology, but were characterized by novel genetic fusions including EWSR1ex8::ZBTB41ex7 and PLOD2ex8::RBM6ex7, respectively. In the statistical analysis of all published cases, CDKN2A or ALK alterations, the use of standard chemotherapy and age at presentation in the range of 18-24 years were negatively correlated to overall survival. CONCLUSION: EWSR1/FUS::TFCP2-rearranged SS-RMS is a rare rhabdomyosarcoma subtype, affecting predominantly young adults with average age at presentation 34 years (median 29.5 years; age range 7-86 years), with a predilection for craniofacial bones, rapid clinical course with frequent bone and lung metastases, and poor prognosis (3-year overall survival rate 28%).

Integrative analysis regarding the correlation between collagen-related genes and prostate cancer.

PURPOSE: Prostate cancer (PCa) is a common malignancy in men, with an escalating mortality rate attributed to Recurrence and metastasis. Recent studies have illuminated collagen's critical regulatory role within the tumor microenvironment, significantly influencing tumor progression. Accordingly, this investigation is dedicated to examining the relationship between genes linked to collagen and the prognosis of PCa, with the objective of uncovering any possible associations between them. METHODS: Gene expression data for individuals with prostate cancer were obtained from the TCGA repository. Collagen-related genes were identified, leading to the development of a risk score model associated with biochemical recurrence-free survival (BRFS). A prognostic nomogram integrating the risk score with essential clinical factors was crafted and evaluated for efficacy. The influence of key collagen-related genes on cellular behavior was confirmed through various assays, including CCK8, invasion, migration, cell cloning, and wound healing. Immunohistochemical detection was used to evaluate PLOD3 expression in prostate cancer tissue samples. RESULTS: Our study identified four key collagen-associated genes (PLOD3, COL1A1, MMP11, FMOD) as significant. Survival analysis revealed that low-risk groups, based on the risk scoring model, had significantly improved prognoses. The risk score was strongly associated with prostate cancer prognosis. Researchers then created a nomogram, which demonstrated robust predictive efficacy and substantial clinical applicability.Remarkably, the suppression of PLOD3 expression notably impeded the proliferation, invasion, migration, and colony formation capabilities of PCa cells. CONCLUSION: The risk score, derived from four collagen-associated genes, could potentially act as a precise prognostic indicator for BRFS of patients. Simultaneously, our research has identified potential therapeutic targets related to collagen. Notably, PLOD3 was differentially expressed in cancer and para-cancer tissues in clinical specimens and it also was validated through in vitro studies and shown to suppress PCa tumorigenesis following its silencing.

PLOD2, a key factor for MRL MSC metabolism and chondroprotective properties.

BACKGROUND: Initially discovered for its ability to regenerate ear holes, the Murphy Roth Large (MRL) mouse has been the subject of multiple research studies aimed at evaluating its ability to regenerate other body tissues and at deciphering the mechanisms underlying it. These enhanced abilities to regenerate, retained during adulthood, protect the MRL mouse from degenerative diseases such as osteoarthritis (OA). Here, we hypothesized that mesenchymal stromal/stem cells (MSC) derived from the regenerative MRL mouse could be involved in their regenerative potential through the release of pro-regenerative mediators. METHOD: To address this hypothesis, we compared the secretome of MRL and BL6 MSC and identified several candidate molecules expressed at significantly higher levels by MRL MSC than by BL6 MSC. We selected one candidate, Plod2, and performed functional in vitro assays to evaluate its role on MRL MSC properties including metabolic profile, migration, and chondroprotective effects. To assess its contribution to MRL protection against OA, we used an experimental model for osteoarthritis induced by collagenase (CiOA). RESULTS: Among the candidate molecules highly expressed by MRL MSC, we focused our attention on procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2). Plod2 silencing induced a decrease in the glycolytic function of MRL MSC, resulting in the alteration of their migratory and chondroprotective abilities in vitro. In vivo, we showed that Plod2 silencing in MRL MSC significantly impaired their capacity to protect mouse from developing OA. CONCLUSION: Our results demonstrate that the chondroprotective and therapeutic properties of MRL MSC in the CiOA experimental model are in part mediated by PLOD2.

Procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 promotes collagen cross-linking and ECM stiffening to induce liver fibrosis.

Procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (Plod2) is a key collagen lysyl hydroxylase mediating the formation of collagen fiber and stabilized collagen cross-links, and has been identified in several forms of fibrosis. However, the potential role and regulatory mechanism of Plod2 in liver fibrosis remain unclear yet. Mouse liver fibrosis models were induced by injecting carbon tetrachloride (CCl4) intraperitoneally. The morphology and alignment of collagen was observed under transmission and scanning electron microscopy, and extracellular matrix (ECM) stiffness was measured by atomic force microscopy. Large amounts of densely packed fibrillar collagen fibers produced by myofibroblasts (MFs) were deposited in fibrotic liver of mice reaching very large diameters in the cross section, accompanied with ECM stiffening, which was positively correlated with collagen-crosslinking. The expression of Plod2 was dynamically up-regulated in fibrotic liver of mouse and human. In MFs transfection of Plod2 siRNA made collagen fibers more orderly and linear aligned which can be easily degraded and protected from ECM stiffness. Administration of Plod2 siRNA preventatively or therapeutically in CCl4 mice reduced the average size of collagen bundles in transverse section, increased collagen solubility, decreases the levels of crosslinking products hydroxylysylpyridinoline and lysylpyridinoline, prevented ECM stiffening and alleviated liver fibrosis. Altogether, Plod2 mediates the formation of stabilized profibrotic collagen cross-links in MFs, leading to the alteration of collagen solubility and ECM stiffness, and eventually aggravates liver fibrosis, which provide potential target for the treatment of liver disease.

Systematic characterization of the expression, prognosis and immune characteristics of PLOD family genes in breast cancer.

BACKGROUND: The expression patterns and prognostic value of Procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) family genes in breast cancer remain to be elucidated. METHODS: The expression levels, prognostic value, and biological function of PLODs were determined using Oncomine, cBioPortal, GEPIA, Timer, UALCAN, PrognoScan, GeneMANIA, Metascape, and breast cancer tissue microarrays. RESULTS: The expressions of PLOD1 and PLOD3 were upregulated in breast cancer tissues, indicating worse clinical stages. High expression levels of PLOD family genes were associated with worse disease-free survival and distant metastasis-free survival, while high expression levels of PLOD1 and PLOD3 were related to worse overall survival in all breast cancer patients. The levels of PLOD family genes were all significantly higher in the age ≤51 y group, HR-negative patients, and triple negative breast cancer (TNBC) patients. They are associated with tumor-infiltrating immune cells (TIICs), including CD4+ T cells, CD8+ T cells, B cells, macrophages, neutrophils, and dendritic cells. According to co-expression gene analysis and functional enrichment, they are associated with protein hydroxylation, collagen biosynthesis and modifying enzymes, collagen metabolism, RNA splicing, extracellular matrix organization, VEGFA-VEGFR2 signaling pathway, and skeletal system development. Immunohistochemistry showed that the expressions of all PLOD family genes were significantly elevated in breast cancer tissues. PLOD1 expression was positively correlated with ER, TNBC status, and tumor grade. PLOD2 expression was positively connected with Ki-67 status. PLOD3 expression was positively related with age and tumor grade. CONCLUSIONS: PLOD family genes are novel potential prognostic biomarkers for breast cancer, and targeting PLOD inhibitors might be an effective strategy for breast cancer therapy.

LncRNA FOXD2-AS1 promotes the growth, invasion and migration of OSCC cells by regulating the MiR-185-5p/PLOD1/Akt/mTOR pathway.

Although lncRNAs are recognized to contribute to the development of oral squamous-cell carcinoma (OSCC), their exact function in invasion and cell migration is not clear. In this research, we explored the molecular and cellular mechanisms of FOXD2-AS1 in OSCC. Prognostic and bioinformatics analyses were used to test for the differential expression of FOXD2-AS1-PLOD1. Following FOXD2-AS1 suppression or overexpression, changes in cell viability were measured using the CCK-8 test; changes in cell migration and invasion abilities were measured using the migration and the Transwell assay. The expression of associated genes and proteins was found using Western blot and RT-qPCR. Analysis of luciferase reporter genes was done to look for regulatory connections between various molecules. The FOXD2-AS1-PLOD1 pair, which was highly expressed in OSCC, was analyzed and experimentally verified to be closely related to the prognosis of OSCC, and a nomogram model and correction curve were constructed. The inhibition of FOXD2-AS1 resulted in the reduction of cell activity, migration, invasion ability and changes in genes related to invasion and migration. In vivo validation showed that inhibition of FOXD2-AS1 expression slowed tumor growth, and related proteins changed accordingly. The experiments verified that FOXD2-AS1 negatively regulated miR-185-5 p and that miR-185-5 p negatively regulated PLOD1. In addition, it was found that the expression of PLOD1, p-Akt and p-mTOR proteins in OSCC cells was reduced by the inhibition of FOXD2-AS1, and FOXD2-AS1 and PLOD1 were closely related to the Akt/mTOR pathway. Increased expression of FOXD2-AS1 promotes OSCC growth, invasion and migration, which is important in part by targeting miR-185-5 p/PLOD1/Akt/mTOR pathway activity.

P3H4 and PLOD1 expression associates with poor prognosis in bladder cancer

PurposeThe prolyl 3-hydroxylase family member 4 gene (P3H4) is involved in the development of human cancers. The association of P3H4 with bladder cancer (BC) prognosis is unclear. This study aimed to analyze the association of P3H4 with BC prognosis.MethodsRNA-Seq data were downloaded from The Cancer Genome Atlas project and BC microarray datasets (GSE13507, GSE31684, and GSE32548) were downloaded from the Gene Expression Omnibus database. We analyzed the differences in P3H4 expression levels between BC tumors and non-tumor tissues and between samples with different clinical information. The association of P3H4 and P3H4-related genes with BC prognosis and the possibility of using P3H4 expression as a prognostic biomarker in BC patients were also analyzed. RevMan was used to perform the meta-analysis.ResultsP3H4 was upregulated in BC tissues compared with the adjacent non-tumor tissues (p = 4.06e−08). Univariate Cox regression analysis and meta-analysis showed that high P3H4 expression level contributed to a poor BC prognosis (Hazard ratio, HR = 1.348, 95% CI 1.140–1.594, p = 4.89e−04; meta-analysis: HR = 1.45, 95% CI 1.10–1.91; p = 9.00e−03). Among the genes related to P3H4, the PLOD1 gene was closely associated with P3H4 expression (r = 0.620, p = 2.49e−44). Also, a meta-analysis showed that PLOD1 expression was associated with a poor prognosis in BC patients (HR = 1.77, 95% CI 1.31–2.38; p = 2.00e−04). (AU)

Diagnóstico prenatal de síndrome de Bruck en una paciente con tres gestaciones consecutivas afectas / Prenatal diagnosis of Bruck syndrome in a patient with three consecutive pregnancies affected

La osteogénesis imperfecta es una enfermedad genética autosómica dominante, en la que existe un defecto en la formación de colágeno. Esto se traduce en distintos grados de debilidad y fragilidad ósea. Existen una serie de síndromes que durante años fueron clasificados como tipos de osteogénesis imperfecta, pero que más tarde se ha comprobado que a pesar de causar un fenotipo similar, no son causados por mutaciones en los genes del procolágeno tipo I. El síndrome de Bruck es un trastorno recesivo con contracturas congénitas y fragilidad ósea que fenotípicamente se parece a la osteogénesis imperfecta pero que el defecto se encuentra en ciertas regiones del cromosoma 3 y 17. Presentamos el caso de una paciente que realizó 3 interrupciones voluntarias del embarazo por fetos afectos de un síndrome caracterizado por fracturas patológicas intraútero. La necropsia del feto del tercer embarazo y los estudios genéticos realizados en tejido fetal y sangre de los padres, condujeron al diagnóstico de un síndrome de Bruck, lo que permitirá a la pareja la posibilidad de una futura gestación libre de enfermedad (AU)

Imperfect osteogenesis is a dominant autosomal genetic disease, which produce a defect in collagen formation, that results in degrees of weakness and bone fragility. For years, a number of syndromes were classified as types of imperfect osteogenesis, but it was found that despite it had a similar phenotype, they are caused by mutations in the genes of procollagen type I. Bruck syndrome is a recessive disorder with congenital contractures and bone fragility that phenotypically resembles imperfect osteogenesis, but that defect is found in certain regions of chromosome 3 and 17. We report a case of a patient who performed three abortions for fetuses suffering from a syndrome characterized by pathological fractures in utero. The autopsy of the fetus from the third pregnancy and genetic studies performed in fetal tissue and blood of parents, led to the diagnosis of Bruck syndrome, which allow the couple the possibility of future free disease gestation (AU)