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Quantification of telomere length in PCa tissues based on an automated 3D imaging-based workflow. (A) Shows an overview of the analyzed TMA. From this TMA, 34 tissue slides of 17 patient samples were imaged representing three different patient sample cohorts: one cohort included all patient samples with a PITX1 status high and high Gleason Score (≥4 + 4), one cohort with PITX1 status low and high Gleason Score (≥4 + 4), and one with PITX1 status low and low Gleason Score (3 + 4). (B) For each core, tiled images were acquired and stitched together for the analysis. (C) To focus on the tumors, the tumor regions were manually marked by a pathologist. Only tumor regions were considered. (D) shows the distribution of mean telomere intensities of cells in samples with high (blue) versus negative (red) PITX1 levels, violet: overlapping events.
Source publication
The current risk stratification in prostate cancer (PCa) is frequently insufficient to adequately predict disease development and outcome. One hallmark of cancer is telomere maintenance. For telomere maintenance, PCa cells exclusively employ telomerase, making it essential for this cancer entity. However, TERT, the catalytic protein component of th...
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Citations
... PITX1 has been reported to be a tumor suppressor whose expression is reduced in esophageal squamous cell carcinoma, rectal cancer, and melanoma [58][59][60]. However, the expression of PITX1 was upregulated in breast cancer and lung cancer, which was associated with poor prognosis [61,62]. This difference may be largely attributed to differences in the tumor microenvironment or cell lines. ...
Background:
Pulmonary hypertension (PH) is a highly fatal pathophysiological syndrome. The group 1 pulmonary arterial hypertension (PAH) is characterized by acute pulmonary vasoconstriction and chronic vascular remodeling caused by hyperplasia and hypertrophy of pulmonary artery smooth muscle cells (PASMCs) and chronic inflammation. Pyroptosis is an inflammatory mode of cell death that is regulated by super-enhancers (SEs) and occurs in the setting of tumors and cardiovascular diseases. However, whether SEs are involved in the pathological process of pyroptosis in PAH and the specific mechanism involved remain unclear.
Methods:
Here, we identified the SE target gene DUSP4 via ChIP-seq with an anti-H3K27ac antibody, and bioinformatics predictions revealed that the transcription factor PITX1 can bind to the promoter and SE sequences of DUSP4. The AAV5 vector was used to deliver shRNAs targeting PITX1 and DUSP4 to PASMCs.
Results:
PITX1 overexpression reversed the increase in right ventricular systolic pressure and pulmonary vascular remodeling, restored the PAAT/PAVTI ratio in hypoxic pulmonary hypertension (HPH, Group 3 PH) and SuHx PAH (Group 1 PAH) mice, and suppressed pyroptosis in pulmonary vascular cells. However, knockdown of DUSP4 counteracted the effects of PITX1 overexpression. Similar results were obtained in cultured PASMCs. In addition, treatment with the SE inhibitors JQ1 and iBET decreased the transcription of DUSP4 and increased the expression of hypoxia-induced pyroptosis proteins in PASMCs.
Conclusion:
We confirmed that PITX1 can promote DUSP4 expression by binding to the DUSP4 promoter and SE to reduce pyroptosis in hypoxic PASMCs, providing new insights into the role of SEs and pyroptosis in pulmonary vascular remodeling and a theoretical basis for the treatment of PAH and related diseases.
... Past research has indicated that TERT is typically not expressed in differentiated somatic cells but is reactivated in tumor cells, leading to the elongation of telomeric repeat sequences [55,56]. Additionally, low expression of TERT has been observed in PCa cells [57]. The OBFC1 gene plays a crucial role in telomere replication, capping, and protection by regulating telomere length [58]. ...
Purpose:
Evidence of an association between leukocyte telomere length (LTL) and prostate cancer (PCa) is accumulating; however, their shared genetic basis remains unclear.
Materials and methods:
Using summary statistics obtained from the genome-wide association study (GWAS), we quantified the global and local genetic correlations between two traits. Subsequently, we identified potential pleiotropic loci, common tissue-enriched regions, and risk gene loci while inferring assumed causal relationships.
Results:
Our study demonstrated a global genetic correlation between LTL and PCa (genetic correlation=0.066, p=0.017), which was further confirmed in local genomic regions. Cross-trait GWAS meta-analysis revealed 44 shared loci, including 10 novel pleiotropic single nucleotide polymorphisms appearing concurrently in significant local genetic correlation regions. Notably, two new loci (rs9419958; rs3730668) were additionally validated to co-localize. For the first time, we identified a significant shared genetic enrichment of both traits in the small intestine tissue at the terminal ileum, with functional genes in this region affecting both LTL and PCa. Concurrently, Mendelian randomization analysis indicated a positive causal relationship between LTL and PCa.
Conclusions:
In conclusion, our study makes a significant contribution to the ongoing debate concerning the potential association between longer LTL and a higher risk of PCa. Additionally, we provide new evidence for the development of therapeutic targets for PCa and propose new directions for future risk prediction in this regard.
... Baena et al. observed that increased TERC expression was associated with a poorer prognosis in patients with PRAD [16]. Furthermore, Poos et al. found that the expression levels of PITX1, a transcription factor that regulates TERC, increased with increasing levels of Ki67 in PRAD, indicating a poorer clinical outcome [17,18]. ...
Alterations in telomeres constitute some of the earliest occurrences in the tumourigenesis of prostate adenocarcinoma (PRAD) and persist throughout the progression of the tumour. While the activity of telomerase and the length of telomeres have been demonstrated to correlate with the prognosis of PRAD, the prognostic potential of telomere-related genes (TRGs) in this disease remains unexplored. Utilising mRNA expression data from the Cancer Genome Atlas (TCGA), we devised a risk model and a nomogram to predict the survival outcomes of patients with PRAD. Subsequently, our investigations extended to the relationship between the risk model and immune cell infiltration, sensitivity to chemotherapeutic drugs, and specific signalling pathways. The risk model we developed is predicated on seven key TRGs, and immunohistochemistry results revealed significant differential expression of three TRGs in tumours and paracancerous tissues. Based on the risk scores, PRAD patients were stratified into high-risk and low-risk cohorts. The Receiver operating characteristics (ROC) and Kaplan–Meier survival analyses corroborated the exceptional predictive performance of our novel risk model. Multivariate Cox regression analysis indicated that the risk score was an independent risk factor associated with Overall Survival (OS) and was significantly associated with T and N stages of PRAD patients. Notably, the high-risk group exhibited a greater response to chemotherapy and immunosuppression compared to the low-risk group, offering potential guidance for treatment strategies for high-risk patients. In conclusion, our new risk model, based on TRGs, serves as a reliable prognostic indicator for PRAD. The model holds significant value in guiding the selection of immunotherapy and chemotherapy in the clinical management of PRAD patients.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12672-024-00986-2.
... It is assumed that it functions as a tumor-suppressor gene in several human cancer types: decreased expression level of PITX1 is observed in various malignant tumors, e.g., HN-SCC [48,49], gastric cancer [50], lung cancer [51], and colorectal carcinoma [52]. However, there is contrary evidence that PITX1 expression is upregulated in breast cancer [53,54], prostate cancer [55], and lung cancer [56]. Thus, PITX1 expression is tumor-type-specific. ...
We studied the gene-expression patterns in specimens of tumor and peritumor tissue biopsies of 26 patients with head and neck carcinomas depending on smoking status. Histological and immunohistochemical examinations verified that all tumors belonged to the “classical” subgroup of head and neck carcinomas, and the HPV-negative tumor status was confirmed. The expression of 28 tumor-associated genes determined by RT-PCR was independent of patients’ sex or age, TNM status, degree of differentiation, or tissue localization. Moreover, in peritumor tissue, none of the 28 genes were differentially expressed between the groups of smoking and nonsmoking patients. During oncotransformation in both studied groups, there were similar processes typical for HNSCC progression: the expression levels of paired keratins 4 and 13 were reduced, while the expression levels of keratin 17 and CD44 were significantly increased. However, further investigation revealed some distinctive features: the expression of the genes EGFR and TP63 increased significantly only in the nonsmoking group, and the expression of IL6, CDKN2A, EGF, and PITX1 genes changed only in the smoking group. In addition, correlation analysis identified several clusters within which genes displayed correlations in their expression levels. The largest group included 10 genes: TIMP1, TIMP2, WEE1, YAP, HIF1A, PI3KCA, UTP14A, APIP, PTEN, and SLC26A6. The genetic signatures associated with smoking habits that we have found may serve as a prerequisite for the development of diagnostic panels/tests predicting responses to different therapeutic strategies for HNSCC.
... Mechanistically, the upregulation of shelterin and CST genes probably promotes an environment that increases TL. Interestingly, this aligns with our results and the literature: we see several reports showing that increased telomerase associates with worst PC prognosis [52][53][54][55][56], we observed increased expression of POT1 and TPP1, main stimulators of telomerase activity [57], and the increased expression of shelterin and CST genes which will make telomeres more resistant to DNA damage (a critical factor in PC progression) [18,58]. ...
Introduction
Search for new clinical biomarkers targets in prostate cancer (PC) is urgent. Telomeres might be one of these targets. Telomeres are the extremities of linear chromosomes, essential for genome stability and control of cell divisions. Telomere homeostasis relies on the proper functioning of shelterin and CST complexes. Telomeric dysfunction and abnormal expression of its components are reported in most cancers and are associated with PC. Despite this, there are only a few studies about the expression of the main telomere complexes and their relationship with PC progression. We aimed to evaluate the role of shelterin (POT1, TRF2, TPP1, TIN2, and RAP1) and CST (CTC1, STN1, and TEN1) genes and telomere length in the progression of PC.
Methods
We evaluated genetic alterations of shelterin and CST by bioinformatics in samples of localized (n = 499) and metastatic castration-resistant PC (n = 444). We also analyzed the expression of the genes using TCGA (localized PC n = 497 and control n = 152) and experimental approaches, with surgical specimens (localized PC n = 81 and BPH n = 10) and metastatic cell lines (LNCaP, DU145, PC3 and PNT2 as control) by real-time PCR. Real-time PCR also determined the telomere length in the same experimental samples. All acquired data were associated with clinical parameters.
Results
Genetic alterations are uncommon in PC, but POT1, TIN2, and TEN1 showed significantly more amplifications in the metastatic cancer. Except for CTC1 and TEN1, which are differentially expressed in localized PC samples, we did not detect an expression pattern relative to control and cell lines. Nevertheless, except for TEN1, the upregulation of all genes is associated with a worse prognosis in localized PC. We also found that increased telomere length is associated with disease aggressiveness in localized PC.
Conclusion
The upregulation of shelterin and CST genes creates an environment that favors telomere elongation, giving selective advantages for localized PC cells to progress to more aggressive stages of the disease.
... Baena et al. observed that increased TERC expression was associated with a poorer prognosis in patients with PRAD [16]. Furthermore, Poos et al. found that the expression levels of PITX1, a transcription factor that regulates TERC, increased with increasing levels of Ki67 in PRAD, indicating a poorer clinical outcome [17, 18]. ...
Background
Telomere-related genes (TRGs) play an essential role in the carcinogenesis and progression of prostate adenocarcinoma(PRAD). However, the prognostic value of TRGs remains unclear in PRAD.
Methods
We conducted a study using The Cancer Genome Atlas-Prostate Adenocarcinoma (TCGA-PRAD) dataset as the training group and the Memorial Sloan-Kettering Cancer Center (MSKCC) and Gene Expression Omnibus (GEO) datasets as the validation group. We developed a risk model and a nomogram to predict survival rates in patients with PRAD. The expression of model genes and their possible regulatory mechanisms were then analyzed. Furthermore, we explored the relationship between the risk model and immune cell infiltration, chemotherapy drug sensitivity, and specific signaling pathways using the CIBERSORT algorithm, the Genomics of Drug Sensitivity in Cancer (GDSC) database, and motif enrichment.
Results
The developed risk model was based on seven key TRGs (HELLS, TOP3A, SRC, LARP7, BUB3, THRSP, and GTF2H4). Moreover, this model was an independent prognostic factor for patients with PRAD and was significantly associated with T and N stages. Among seven TRGs, TOP3A and BUB3 were not only significantly positively correlated with the clinical T and N phases of PRAD, but also expression was significantly increased in PRAD tissues compared to adjacent normal tissues. The model was a good predictor of 1-, 3-, and 5-year survival, and patients in the high-risk group had significantly shorter overall survival than those in the low-risk group. The integrated nomogram can be a good predictor of 3- and 5-year survival in patients with PRAD. Finally, compared to the low-risk group, the high-risk group had a higher response to chemotherapy and immunosuppression, which provided potential guidance to treatment options for patients in the high-risk group.
Conclusion
In summary, a new risk model based on TRGs was successfully developed in PRAD. This risk model is valuable for guiding the selection of immunotherapy and chemotherapy in the clinical treatment of patients with PRAD.
... Previous research on PITX1 in cancer has revealed cancer-type-specific effects. While upregulation of PITX1 has been shown to be associated with tumor progression in lung adenocarcinoma 31 , kidney renal clear cell carcinoma 32 , breast 33 , epithelial ovarian 34 , and prostate 35 cancer, interestingly, in other cancer types, such as melanoma 36 , ESCC 37 , osteosarcoma 38 and head and neck squamous cell carcinoma 39 , down-regulation of PITX1 has been found to enhance tumor progression. Other EMT-related genes exclusively present in our signature included two long-non-coding RNA genes: ABHD11-AS1 and BCYRN1. ...
In the field of single-cell RNA sequencing (scRNA-seq), gene signature scoring is integral for pinpointing and characterizing distinct cell populations. However, challenges arise in ensuring the robustness and comparability of scores across various gene signatures and across different batches and conditions. Addressing these challenges, we evaluated the stability of established methods such as Scanpy, UCell, and JASMINE in the context of scoring cells of different types and states. Additionally, we introduced a new scoring method, the Adjusted Neighbourhood Scoring (ANS), that builds on the traditional Scanpy method and improves the handling of the control gene sets. We further exemplified the usability of ANS scoring in differentiating between cancer-associated fibroblasts and malignant cells undergoing epithelial-mesenchymal transition (EMT) in four cancer types and evidenced excellent classification performance (AUCPR train: 0.95-0.99, AUCPR test: 0.91-0.99). In summary, our research introduces the ANS as a robust and deterministic scoring approach that enables the comparison of diverse gene signatures. The results of our study contribute to the development of more accurate and reliable methods for analyzing scRNA-seq data.
... Recently, the PITX genes were shown to be involved in tumorigenesis. The expression of PITX activators is deregulated in some human malignancies, including hepatocellular carcinoma (Tai et al., 2016), lung cancer (Chen et al., 2007), prostate cancer (Poos et al., 2022), and cutaneous malignant melanoma (Osaki et al., 2013). PITX1 has been reported as a candidate tumor suppressor gene and a possible biomarker for predicting the chemical sensitivity of HNSC in humans (Takenobu et al., 2016). ...
Background: The PITX gene family, comprising PITX1, PITX2, and PITX3, is critical in organogenesis and has been evolutionary conserved in animals. PITX genes are associated with the advanced progression and poor prognosis of multiple cancers. However, the relationship between the PITX genes and head and neck squamous cell carcinoma (HNSC) has not been reported.
Methods: We used data from The Cancer Genome Atlas (TCGA) to analyze the association between PITX mRNA expression and clinicopathological parameters of patients with HNSC. The prognostic value of PITX genes was evaluated using the Kaplan-Meier plotter. Multivariate Cox analysis was used to screen out prognosis-associated genes to identify better prognostic indicators. The potential roles of PITX1 and PITX2 in HNSC prognosis were investigated using the protein-protein interaction (PPI) network, Gene Ontology (GO) analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The correlation between PITX1 and PITX2 expression or methylation and immune cell infiltration was evaluated using the tumor-immune system interaction database (TISIDB). MethSurv was used to identify DNA methylation and its effect on HNSC prognosis.
Results: PITX genes expression was correlated with different cancers. PITX1 and PITX2 expression was lower in the patients with HNSC. In HNSC, PITX1 expression was significantly related to the clinical stage, histologic grade, and N stage, while PITX2 expression was only significantly related to the histologic grade. The high expression of PITX3 was significantly related to the histologic grade, T stage, and N stage. Survival analysis revealed that PITX genes had prognostic value in HNSC, which was supported by multivariate Cox analysis. PPI network and enrichment analysis showed that the genes interacting with PITX1 and PITX2 belonged predominantly to signaling pathways associated with DNA binding and transcription. Of the CpG DNA methylation sites in PITX1 and PITX2, 28 and 22 were related to the prognosis of HNSC, respectively. Additionally, PITX1 and PITX2 expression and methylation was associated with tumor-infiltrating lymphocytes (TILs).
Conclusion: The PITX genes were differentially expressed in patients with HNSC, highlighting their essential role in DNA methylation and tumor-infiltrating immune cell regulation, as well as overall prognostic value in HNSC.
Background
Chondrosarcoma (CHS) is a rare bone cancer originating from chondrocytes, with high-grade cases associated with high mortality rates. However, the prognostic factors and therapeutic targets for CHS have not been studied.
Methods
Graded gene differential analysis was conducted on 97 CHS tissues to identify genes associated with CHS grading. Additionally, we performed GO and KEGG enrichment analyses of the differentially-expressed genes (DEGs), as well as GSEA analysis, differential expression analysis, survival analysis, and univariable and multifactorial COX analysis of paired-like homology structural domain transcription factor 1 (PITX1). Furthermore, our findings investigated the relationship between tumor-infiltrating immune cells (TICs) in CHS tumors using CIBERSORT to calculate proportions and differences. Our findings also explored the associations among gene expression patterns, survival prognosis, TICs, and immune checkpoints across various cancer types. Finally, immunohistochemical staining was carried out on self-collected clinical samples to assess PITX1 expression levels and correlate them with clinical information.
Results
Gene differential expression analysis revealed a strong correlation between PITX1 expression and tumor grade. GO, KEGG enrichment, and GSEA analysis demonstrated the association of PITX1 with cell proliferation-related processes, such as cell cycle regulation and mitosis, and differentiation-related processes, such as RNA processing. PITX1 expression was associated with tumor stage and survival outcomes. Immunoassay indicated a positive correlation between PITX1 levels and TICs, immune checkpoints, and graded TICs. Pan-cancer analysis confirmed the differential expression of the PITX1 gene across multiple cancers, impacting survival prognosis, TIC patterns, and immune checkpoint regulation. Lastly, our 75 collection of clinical patient tissue samples exhibited varying levels of PITX1 expression across different cancer grades while also demonstrating a significant association with tumor differentiation and metastasis.
Conclusion
PITX1 is a novel biomarker for distinguishing between high-grade and low-grade CHS, serving as a prognostic indicator for patients with this condition and presenting a promising target for immunotherapy. These findings offer innovative insights into the treatment of CHS.
The microenvironment within lymph nodes plays a pivotal role in the pathogenesis of follicular lymphoma (FL), a malignancy characterized by the accumulation of neoplastic B cells. Here, we report that human FL lymph node mesenchymal stromal cells (FLSCs) display surface protein expression profiles consistent with the standard phenotypic criteria for human mesenchymal stromal/stem cells (MSCs), yet exhibit reduced mesenchymal differentiation capability. FLSCs did not show the typical immunomodulatory protein expression patterns observed in fibroblastic reticular cells, marginal reticular cells, or follicular dendritic cells, as they expressed chemokine (C-X-C motif) ligand 13 and podoplanin but lacked chemokine (C-C motif) ligand 19 and complement receptor 1/2. Functionally, FLSCs exhibited superior FL cell survival-supportive capability in cocultures compared with bone marrow MSCs. This supportive effect was reduced when the cell culture inserts were used. In addition, this supportive capability was accompanied by reduced levels of B-cell-supportive soluble factors such as interleukin-6, regardless of the presence of cell culture inserts. Thus, both cell-cell contact-dependent and -independent mechanisms are involved in this process. Comprehensive transcriptomic analysis revealed that transcription factor paired-like homeodomain 1 (PITX1) is downregulated in FLSCs. Given that PITX1 regulates human telomerase reverse transcriptase (hTERT) transcription, FLSCs exhibited longer telomeres and a higher population-doubling capacity than MSCs. Furthermore, FLSCs expressed elevated podoplanin, whereas MSCs did not. Notably, hTERT-transfected MSCs also showed increased podoplanin expression, suggesting a positive association between hTERT and podoplanin. In summary, our findings indicate that FLSCs deviate from classical MSCs in their differentiation potential and instead exhibit a protumorigenic phenotype. This phenotype supports FL cell survival and is potentially mediated by an aberrant PITX1-hTERT-podoplanin signaling axis. These results highlight the critical role of FLSCs in the FL lymph node microenvironment, with implications for understanding tumor-supportive niches in FL pathogenesis.
