BACKGROUND:Prostate cancer is one of the principal malignancies threatening human health, and the development of castration resistance often constitutes a major cause of treatment failure in its management. METHODS:To elucidate the potential association between programmed death-ligand 1 (PD-L1) and castration resistance in prostate cancer, we analyzed the expression levels of PD-L1 in both primary prostate cancer tissues and castration-resistant prostate cancer (CRPC) specimens as well as in corresponding cell lines by using western blots and immunohistochemistry. Then, we explored the specific mechanisms through transcriptomic sequencing technology. RESULTS:Our findings revealed that, compared to adjacent non-cancerous tissue, PD-L1 expression was unexpectedly lower in primary prostate cancer but notably elevated in CRPC tissues and cells. In CRPC cell lines where PD-L1 was knocked down, a significant suppression of proliferation, invasion, and migration capabilities was observed. By employing next-generation sequencing technology, we investigated the impact of PD-L1 knockdown on intracellular signaling pathways in castration-resistant cells. The results demonstrated that PD-L1 knockdown led to alterations in gene expression within several signaling pathways, including those involved in cell surface interactions, regulation of natural killer cell activity, and sodium channel regulatory activity. We further elucidated through experimentation that PD-L1 contributes to tumor progression in CRPC by modulating the expression of SCUBE1. More intriguingly, PD-L1 knockdown also appeared to induce changes at the level of alternative splicing in multiple genes. CONCLUSIONS:PD-L1 is upregulated in CRPC and can modulate the expression of multiple tumor-associated genes in CRPC cells. Finally, we found that PD-L1 contributes to tumor progression in CRPC by modulating the expression of SCUBE1. This study provides a theoretical basis for understanding the intracellular signaling mediated by PD-L1 and offers valuable insights into the mechanisms underlying castration resistance in prostate cancer.

MTHFD2 is highly overexpressed in breast cancer tissues, indicating that it might be used as a target in breast cancer treatment. This study aims to determine the role of MTHFD2 in breast cancer cell proliferation and the molecular pathways involved. In order to investigate MTHFD2 gene expression and its downstream pathways in breast cancer, we started our inquiry with a bioinformatics analysis. We then engineered breast cancer cell lines with either silenced or overexpressed MTHFD2 to study its effects on the cell cycle, proliferation, and the m6A methylation status of the gene IFRD1, predicted as a downstream target. Overexpression of MTHFD2 enhanced cellular proliferation, increased the proportion of EdU-positive cells, and accelerated progression into the S+G2/M phase. In contrast, MTHFD2 knockdown led to opposite effects. MTHFD2 and IFRD1 expression levels showed a strong positive association. Increased MTHFD2 activity boosted HDAC3 and mTOR phosphorylation, activating p70 S6K and 4EBP1-key regulators of cell proliferation. Moreover, overexpression of MTHFD2 was associated with reduced p53 acetylation and total protein levels. Silencing MTHFD2 decreased m6A methylation of IFRD1 RNA, whereas its overexpression increased methylation. Notably, IFRD1 siRNA transfection reversed the proliferative effects induced by MTHFD2 overexpression. Furthermore, MTHFD2 knockdown enhanced the sensitivity of breast cancer cells to several chemotherapeutic agents. In conclusion, MTHFD2 influences breast cancer cell proliferation by modulating the m6A methylation of IFRD1 RNA, which regulates the HDAC3/p53/mTOR pathway. These findings suggest that MTHFD2 inhibitors may synergistically enhance the efficacy of existing chemotherapies.

Endogenous noncoding RNAs with a covalently closed loop are known as circular RNAs (circRNAs). Recently, published works have revealed that circRNAs, which act as microRNA sponges, are critical for the biological behavior of several kinds of malignancies, including tumor cell proliferation, apoptosis, invasion, and metastasis. Additionally, there is a significant correlation between circRNAs and tumor resistance, stage, prognosis, and size. At present, colorectal cancer (CRC) is one of the most serious malignant tumors for human health. CircRNAs could represent potential targets to use in the prevention, diagnosis, and therapy of CRC, according to many studies. To fully comprehend the role of circRNAs in the incidence and progression of CRC, this review outlines the regulatory role and mechanisms of circRNAs in CRC and assesses their potential relevance as diagnostic and treatment possibilities for CRC. Our goal is to offer meaningful biological information for clinical evaluation and decision-making process for CRC treatment.

BACKGROUND:Long non-coding RNA PTENP1, the pseudogene of PTEN tumor suppressor, has been reported to exert its tumor suppressive function via modulation of PTEN expression in many malignancies, including breast cancer (BC). However, whether the PTENP1/miR-20a/PTEN axis exists and how it functions in BC progression remains elusive.METHODS:The levels of PTENP1, PTEN and miR-20a were measured by qRT-PCR. Furthermore, the breast cancer cells proliferation was further measured by CCK8 assay, colony formation assays, EDU and Ki67 staining. The migratory and invasive ability was determined by transwell assay. Flow cytometry, JC-1 and TUNEL assays were conducted to show the occurrence of apoptosis. Xenograft model was used to show the tumorigenesis of breast cancer cells.RESULTS:We analyzed PTENP1 and PTEN levels in clinical BC samples and cell lines, and found that PTENP1 and PTEN were confirmed and closely correlated with the malignancy of BC cell lines and poor clinical prognosis. Moreover, alteration of PTENP1 affects BC cell proliferation, invasion, tumorigenesis and chemoresistance to adriamycin (ADR). Bioinformatic analysis and dual-luciferase reporter gene assay predicted that PTENP1 was a direct target of miR-20a, which was clarified an alternative effect on BC aggressiveness phenotype. In addition, PTENP1 functioned as an endogenous sponge of miR-20a to regulate PTEN expression, which mediated BC cells proliferation, invasion and drug resistance via activation the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. PI3K inhibitor LY294002 or siAkt also prevented BC cells progression.CONCLUSION:Collectively, these data indicated that PTENP1/miR-20a/PTEN axis involved in the malignant behaviors of BC cells, illuminating the possible mechanism mediated by PTEN via PI3K/Akt pathway. Targeting PTENP1/miR-20a/PTEN may provide a potential diagnosis and treatment strategy for BC.

Myocardial infarction(MI) causes prolonged ischemia of infarcted myocardial tissue, which triggers a wide range of hypoxia cellular responses in cardiomyocytes. Emerging evidence has indicated the critical roles of long non-coding RNAs(lncRNAs) in cardiovascular diseases, including MI. The purpose of this study was to investigate the roles of lncRNA H19 and H19/HIF-1α pathway during MI. Results showed that cell injury and mitochondrial dysfunction were induced in hypoxia-treated H9c2 cells, accompanied by an increase in the expression of H19. H19 silencing remarkably diminishes cell injury, inhibits the dysfunctional degree of mitochondria, and decreases the injury of MI rats. Bioinformatics analysis and dual-luciferase assays revealed that H19 was the hypoxia-responsive lncRNA, and HIF-1α induced H19 transcription through direct binding to the H19 promoter. Moreover, H19 participates in the HIF-1α pathway by stabilizing the HIF-1α protein. These results indicated that H19 might be a potential biomarker and therapeutic target for myocardial infarction.

Cancer-associated fibroblasts (CAFs) contribute to tumour epithelial-mesenchymal transition (EMT) via interaction with cancer cells. However, the molecular mechanisms underlying tumour-promoting EMT of CAFs in lung adenocarcinoma (ADC) remain unclear. Here, we observed that CAFs isolated from lung ADC promoted EMT via production of stromal cell-derived factor-1 (SDF-1) in conditioned medium (CM). CAF-derived SDF-1 enhanced invasiveness and EMT by upregulating CXCR4, β-catenin, and PPARδ, while downregulating these proteins reversed the effect. Furthermore, RNAi-mediated CXCR4 knockdown suppressed β-catenin and PPARδ expression, while β-catenin inhibition effectively downregulated PPARδ without affecting CXCR4; however, treatment with a PPARδ inhibitor did not inhibit CXCR4 or β-catenin expression. Additionally, pairwise analysis revealed that high expression of CXCR4, β-catenin, and PPARδ correlated positively with 75 human lung adenocarcinoma tissues, which was predictive of poor prognosis. Thus, targeting the CAF-derived, SDF-1-mediated CXCR4 β-catenin/ PPARδ cascade may serve as an effective targeted approach for lung cancer treatment.

An amendment to this paper has been published and can be accessed via the original article.

In recent years, long non-coding RNAs (lncRNAs) have been demonstrated to be associated with many physiological and pathological processes in cardiac. Recent studies have shown that lncRNAs are expressed dynamically in cardiovascular diseases and participate in regulation through a variety of molecular mechanisms, which have become a critical part of the epigenetic and transcriptional regulatory pathways in heart development, as well as the initiation and progress of myocardial infarction. In this review, we summarized some current research about the roles of lncRNAs in heart development and myocardial infarction, with the emphasis on molecular mechanisms of pathological responses, and highlighted their functions in the secondary changes of myocardial infarction. We also discussed the possibility of lncRNAs as novel diagnostic biomarkers and potential therapeutic targets for myocardial infarction.

Background: The incidence of colorectal cancer (CRC) has been increasing worldwide in recent years. Targeting cancer stem cells (CSCs) in CRC remains a difficult challenge. KDM2B and EZH2 play important role in the maintenance of CSCs' self-renewal capacity and tumorigenic ability; however, the biological functions of those genes in CRC remain unclear. In this study, we aimed to define the contribution of the expression of KDM2B in the features of CRC and establish the relationship between KDM2B and EZH2 in colorectal CSCs. Methods: The expression of KDM2B and EZH2 in the specimens of CRC and CRC cell lines were analyzed by immunohistochemistry, Western blot, and immunofluorescence. The underlying mechanisms of altered expressions of KDM2B and EZH2 and their impact on the biologic features of CRC and stemness in CRC were investigated. Results: The KDM2B gene was highly expressed in CRC tissues, and its overexpression positively correlated with tumor stages and tumor/node/metastasis (TNM) classification. The downregulation of KDM2B retarded cell proliferation, induced DNA damage, reduced spheroid formation, and decreased CRC stem cell markers: CD44, CD133, and ALDH-1. Moreover, the downregulation of KDM2B decreased the expression of EZH2 and both regulated cell migration, invasion, and stemness in the CRC cell line. Additionally, the interaction between KDM2B and EZH2 significantly increased the components of the PI3K/AKT pathway including AKT and PI3K. The high expression of KDM2B positively correlated with EZH2 in CRC tissues. Conclusion: This study shows that the downregulation of KDM2B and EZH2 can regulate CRC cell stemness, and their interaction may serve as a novel prognostic marker and therapeutic target for patients with CRC.

BACKGROUND:Recent studies have indicated that deubiquitinating enzymes (DUBs) are related to the stem-cell pathway network and chemo-resistance in cancer. Ubiquitin-specific peptidase 37 (USP37), a novel DUB, was identified to be a potential factor associated with tumor progression. However, the biological functions of USP37 in breast cancer remain unclear.METHODS:The distribution of USP37 expression in breast cancer and the correlation between USP37 expression and the overall survival rate were detected by The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was utilized to evaluate potential mechanism of USP37 in breast cancer. The USP37 expression in breast cancer tissues and breast cancer cell lines were detected by immunohistochemistry and western blotting. Sorting of breast cancer stem cells (BCSCs) were by using MACS assay. In vitro and in vivo assays were performed to examine the biological functions of USP37 in breast cancer cells. MG132, CHX chase, immunofluorescence staining and co-immunoprecipitation assays were used to test the interaction between USP37 and Gli-1.RESULTS:Bioinformatics analysis demonstrated that USP37 gene was elevated in breast cancer tissues and its overexpression was strongly correlated with the increased mortality rate. GSEA analysis showed that USP37 expression was positively associated with cell growth and metastasis while negatively related to cell apoptosis in the TCGA breast cancer samples. USP37 expression was elevated in breast cancer tissues and breast cancer cell lines. Moreover, we also detected that USP37 was overexpressed in BCSCs. USP37 regulated the ability of cell invasion, epithelial-mesenchymal transition (EMT), stemness and cisplatin sensitivity in breast cancer cell lines. Additionally, USP37 knockdown inhibited tumorigenicity and increased anticancer effect of cisplatin in vivo. Knockdown of USP37 significantly decreased hedgehog (Hh) pathway components Smo and Gli-1. Gli-1 was stabilized by USP37 and they interacted with each other. Further studies indicated that USP37 knockdown could inhibit the stemness, cell invasion and EMT in breast cancer via downregulation of Hh pathway.CONCLUSIONS:These findings reveal that USP37 is highly expressed in BCSCs and is correlated with poor prognosis in breast cancer patients. USP37 can regulate the stemness, cell invasion and EMT via Hh pathway, and decreased USP37 confers sensitivity to cisplatin in breast cancer cells. USP37 is required for the regulation of breast cancer progression, as well as a critical target for clinical treatment of breast cancer.