LINC01320 facilitates cell proliferation and migration of ovarian cancer via regulating PURB/DDB2/NEDD4L/TGF-ß axis.

Ovarian cancer (OC) is one of the most prevalent and lethal malignancies affecting the female reproductive system, due to its tendency for metastasis and recurrence. This study identified the overexpression of LINC01320 (or long intergenic nonprotein coding RNA 1320) in tissues of ovarian cancer through the analysis of patient samples and online datasets. In vitro and in vivo experiments demonstrate that silencing of LINC01320 expression led to inhibition of proliferation and metastasis of OC cells. RNA pull-down followed by liquid chromatography tandem mass spectrometry (RNA pull-down-LC-MS/MS) revealed that LINC01320 interacted with purine-rich element binding protein B (PURB), a transcriptional repressor. Furthermore, the RNA-seq analysis identified damage-specific DNA binding protein 2 (DDB2) as a major common target of LINC01320 and PURB. Mechanistically, LINC01320 could recruit PURB to the promoter region of DDB2 to repress DDB2 transcription; thus, promoting the expression of NEDD4L and impeding the TGF-ß/SMAD signaling pathway, and ultimately facilitating the progression of OC. Finally, rescue experiments confirmed the involvement of the DDB2/NEDD4L/TGF-ß axis in LINC01320-mediated OC progression. In conclusion, this study unveils for the first time the pivotal function of the LINC01320/PURB/DDB2/NEDD4L/TGF-ß axis and explores its prospective clinical implications in OC.

TSPO deficiency promotes the progression of malignant peripheral sheath tumors by regulating the G2/M phase of the cell cycle via CDK1.

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell-derived sarcomas that are sporadic or associated with Neurofibromatosis 1 (NF1) gene mutations. Traditional therapies are usually ineffective for treating MPNSTs, so new targets need to be identified for the treatment of MPNSTs. In the present study, the role of the mitochondrial translocator protein (TSPO) in the regulation of cell proliferation and the cell cycle in MPNSTs was investigated. TSPO expression was lower in MPNSTs than in NFs. Loss-of-function experiments revealed that TSPO deficiency promoted MPNST cell growth, migration, and invasion and influenced the cell cycle in vitro and in vivo. In addition, TSPO depletion suppressed cell apoptosis by downregulating the expression of caspase-3, caspase-8, HSP60, p27, p53, and BCL-2 and suppressed the cell cycle by upregulating CDK1, CDK2, CCNB1 and CCNA2. Furthermore, CDK1 was determined to be an upstream target of TSPO-mediated regulation via RNA-seq, qPCR, and Western blotting. Specifically, depletion of CDK1 weakened the effect of TSPO deficiency on cell proliferation and migration. More importantly, CDK1 knockdown induced significant cell cycle arrest in the G2/M phase. In summary, TSPO deficiency regulates the cell cycle in MPNSTs by targeting CDK1, which may be an effective molecular target for prognosis evaluation and treatment.

Elevated expression levels of the protein kinase DYRK1B induce mesenchymal features in A549 lung cancer cells.

BACKGROUND: The protein kinase DYRK1B is a negative regulator of cell proliferation but has been found to be overexpressed in diverse human solid cancers. While DYRK1B is recognized to promote cell survival and adaption to stressful conditions, the consequences of elevated DYRK1B levels in cancer cells are largely uncharted. METHODS: To elucidate the role of DYRK1B in cancer cells, we established a A549 lung adenocarcinoma cell model featuring conditional overexpression of DYRK1B. This system was used to characterize the impact of heightened DYRK1B levels on gene expression and to monitor phenotypic and functional changes. RESULTS: A549 cells with induced overexpression of wild type DYRK1B acquired a mesenchymal cell morphology with diminished cell-cell contacts and a reorganization of the pericellular actin cytoskeleton into stress fibers. This transition was not observed in cells overexpressing a catalytically impaired DYRK1B variant. The phenotypic changes were associated with increased expression of the transcription factors SNAIL and SLUG, which are core regulators of epithelial mesenchymal transition (EMT). Further profiling of DYRK1B-overexpressing cells revealed transcriptional changes that are characteristic for the mesenchymal conversion of epithelial cells, including the upregulation of genes that are related to cancer cell invasion and metastasis. Functionally, DYRK1B overexpression enhanced the migratory capacity of A549 cells in a wound healing assay. CONCLUSIONS: The present data identify DYRK1B as a regulator of phenotypic plasticity in A549 cells. Increased expression of DYRK1B induces mesenchymal traits in A549 lung adenocarcinoma cells.

Exosomal miR-199a-3p Secreted From Cancer-Associated Adipocytes Promotes Pancreatic Cancer Progression.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer. Recent studies indicated that cancer-associated adipocytes (CAAs) play crucial roles in tumor progression; however, the precise mechanism remains unknown. Here, we analyzed specific exosomal microRNAs (miRNA) signatures derived from pancreatic CAAs to investigate their role in cancer progression. METHODS: CAAs were generated by co-culturing human adipocytes with human pancreatic cancer cells, and exosomes were isolated from the CAA-conditioned medium (CAA-CM). Small RNA-seq analysis was used to identify differentially expressed miRNAs in these exosomes. The effects of miRNAs on cell proliferation, migration/invasion, and drug sensitivity were examined. Luciferase reporter assays, real-time polymerase chain reaction, and western blotting were performed to investigate the molecular mechanisms of the miRNAs. The clinical relevance of the miRNAs was investigated using publicly available data and our cohort of patients with PDAC. RESULTS: miR-199a-3p expression was significantly increased in CAA-CM-derived exosomes. CAA-derived exosomes transferred miR-199a-3p to pancreatic cancer cells. Transfection with miR-199a-3p increased the proliferation, invasion, migration, and drug resistance of pancreatic cancer cells by downregulating SOCS7, increasing STAT3 phosphorylation, and upregulating SAA1 expression. High tissue miR-199a-3p expression is correlated with poor prognosis in patients with PDAC. Liquid biopsies revealed that exosomal miR-199a-3p could accurately differentiate patients with PDAC from healthy controls. Multivariate survival analysis indicated that miR-199a is an independent prognostic factor for PDAC. CONCLUSION: miR-199a-3p in CAA-derived exosomes contributes to the malignant transformation of pancreatic cancer via the SOCS7/STAT3/SAA1 pathway, suggesting its potential as a biomarker and therapeutic target for PDAC.

The lncRNA TPTEP1 suppresses PI3K/AKT signalling and inhibits ovarian cancer progression by interacting with PTBP1.

The expression of the long noncoding RNA (lncRNA) TPTE pseudogene 1 (TPTEP1) is significantly downregulated in ovarian cancer (OC). However, the function and mechanism of the lncRNA TPTEP1 in OC have not been identified. To investigate the expression of the lncRNA TPTEP1, we analysed a publicly available dataset and 20 pairs of OC and normal ovarian samples tissue from the First Affiliated Hospital of Anhui Medical University. Functional assays were used to determine the role of the lncRNA TPTEP1 in OC progression. Furthermore, Western blot, FISH, RNA pull-down, mass spectrometry and RNA immunoprecipitation approaches were used to determine the mechanism by which the lncRNA TPTEP1 affects OC progression. Animal experiments were used to determine the role of the lncRNA TPTEP1 in ovarian tumorigenicity in vivo. The expression of the lncRNA TPTEP1 in OC tissues was significantly lower than that in normal tissues and low expression of the lncRNA TPTEP1 was significantly correlated with advanced FIGO stage and the presence of malignant ascites in OC patients. In vitro and in vivo, regulation of the expression of the lncRNA TPTEP1 caused changes in OC cell proliferation, migration, invasion and apoptosis. Mechanistically, we found that TPTEP1 directly binds to the polypyrimidine tract-binding protein 1 (PTBP1) protein and inhibits PI3K/AKT signalling. The lncRNA TPTEP1 inhibits PI3K/AKT signalling by directly binding PTBP1, possibly indicating the molecular mechanism underlying its biological function. With further research, these findings may aid in the development of clinically useful strategies for the treatment of OC.

CircRNA_SLC8A1 alleviates hypertrophic scar progression by mediating the Nrf2-ARE pathway.

BACKGROUND: Hypertrophic scar (HS) is associated with cosmetic defects, mobility, and functional impairments, pruritus, and pain. Previous circRNA microarray analysis identified reduced expression of circRNA_SLC8A1 in HS tissues. Therefore, this study aims to investigate the role of circRNA_SLC8A1 in modulating the abnormal behavior of HS-derived fibroblasts (HSFs) in vitro. METHODS: RT-qPCR and FISH assays were used to assess the differential expression and localization of circRNA_SLC8A1 in normal and HS tissues. Following modulation of circRNA_SLC8A1 expression, CCK-8, flow cytometry, Transwell, and wound healing assays were employed to evaluate the effects of circRNA_SLC8A1 on the biological behaviors of HSFs. The Starbase database, dual-luciferase reporter assays, and Ago2-RIP assays were utilized to predict and validate the interaction between circRNA_SLC8A1 and downstream miRNAs. RESULTS: CircRNA_SLC8A1 was found to be downregulated in HS tissues and was primarily localized in the cytoplasm. Overexpression of circRNA_SLC8A1 reduced cell viability, cell invasion, wound healing, and the expression of Vimentin, N-cadherin, Col I, and Col III, while enhancing apoptosis and E-cadherin expression in HSFs. CircRNA_SLC8A1 activates the Nrf2-ARE pathway by competitively binding to miRNA-27a-3p. miRNA-27a-3p and Nrf2 exhibited high and low expression, respectively in HS tissues, with an inverse correlation between their levels. Overexpression of miRNA-27a-3p counteracted the effects of circRNA_SLC8A1 in HSF proliferation, apoptosis, migration, EMT, collagen deposition, and Nrf2-ARE pathway activity. CONCLUSION: CircRNA_SLC8A1 inhibits the proliferation, migration, EMT, and collagen deposition of HSF through competitive binding with miRNA-27a-3p, thereby activating the Nrf2-ARE pathway. The circRNA_SLC8A1/miRNA-27a-3p/Nrf2-ARE axis may offer a promising molecular target for HS therapy.

METTL3 facilitates the progression of cervical cancer by m6A modification-mediated up-regulation of NEK2.

N6-methyladenosine (m6A) is the most prevalent modification found in eukaryotic RNA and played a significant role in various cancers. However, the mechanism by which m6A modification influences cervical cancer (CC) tumorigenesis remains unclear. Therefore, we aim to elucidate the role and mechanism of METTL3 in CC progression. In the present study, we observed a significant upregulation of METTL3 in CC tissues and cell lines. Knockdown of METTL3 resulted in reduced growth, migration, and invasion of CC cells, as well as affected apoptosis, while overexpression of METTL3 reversed these effects. Through a combined analysis of meRIP-seq and Ribo-seq data following METTL3 knockdown, NEK2 was identified as a key target of METTL3 in CC cells. Correlation analysis, MeRIP-qPCR, and luciferase reporter assay suggested that METTL3 regulates NEK2 expression through m6A modification. NEK2 synergized with METTL3 to mediate the malignant phenotype of CC cells. The METTL3-NEK2 axis promoted CC progression by activating the Wnt/ß-catenin pathway and inhibiting the apoptosis pathway. In conclusion, METTL3 facilitated the malignant progression of CC and contributed to the formation of the METTL3-NEK2 regulatory axis in an m6A-dependent manner, which represented a potential target for CC therapy.

CH25H Promotes Autophagy and Regulates the Malignant Progression of Laryngeal Squamous Cell Carcinoma Through the PI3K-AKT Pathway.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is a type of cancer of the respiratory tract that often presents with subtle symptoms at the early stage and is susceptible to recurrence and metastasis. MATERIALS AND METHODS: To find out key regulatory genes involved in LSCC development, we downloaded LSCC-related sequencing datasets for bioinformatics analysis. WGCNA was performed on GSE142083 and differential analysis was conducted on GSE51985 and TCGA-HNSC. Intersection genes were taken from the above three datasets. To confirm the function of genes, we overexpressed and knocked down genes in cells and treated them with autophagy agonist Rapamycin and PI3K-AKT pathway inhibitor. At the cellular level, the expression of CH25H, autophagy-related proteins (LC3 I, LC3 II, p62, and Beclin 1), and PI3K-AKT pathway-related proteins (PI3K, AKT, and p-AKT) were assessed via Western blot; the mRNA level of CH25H was evaluated through qRT-PCR; the cell activity was examined by CCK8; the apoptosis was assessed through flow cytometry; and the cell migration and invasion were assessed through wound healing and Transwell assays. RESULTS: Through bioinformatics analysis, we screened 7 genes (CH25H, NELL2, STC2, TMEM158, ZIC2, HOXD11, and HOXD10). Ultimately, CH25H was selected for follow-up experiments. By detecting CH25H expression in human immortalized keratinocytes (HaCaT) and LSCC cells (Tu-686, SNU899, and AMC-HN-8), it was found out that CH25H expression was higher in HaCaT cells than in LSCC cells. To elucidate the role of CH25H in LSCC development, we overexpressed CH25H in Tu-686 cells and downregulated its expression in AMC-HN-8 cells. CH25H was revealed to reduce the proliferation, activity, invasion, and migration of LSCC cells while increasing their apoptosis levels. Significant changes were also observed in the expressions of autophagy- and PI3K-AKT pathway-related proteins. To further investigate the roles of autophagy and the PI3K-AKT pathway in LSCC development, we respectively employed autophagy agonists and inhibitors targeting the PI3K-AKT pathway to intervene the cells, and found that CH25H regulated the PI3K-AKT pathway to promote autophagy, thus enhancing the apoptosis of LSCC cells. We further investigated CH25H's impact on tumor growth, autophagy, and the PI3K-AKT pathway at the animal level and found that CH25H promoted autophagy of LSCC cells and inhibited the PI3K-AKT pathway, and ultimately inhibiting the progression of LSCC. CONCLUSIONS: In summary, CH25H promotes autophagy and affects the malignant progression of LSCC through the PI3K-AKT pathway.

Identification of miR-6794-3p as a suppressor in pancreatic cancer metastasis.

Metastasis is a major cause of treatment failure in patients with pancreatic cancer, highlighting the urgent need for effective therapeutic strategies. Here, we focused on identifying novel miRNAs with key roles in metastasis of pancreatic cancer. Microarray analysis of miRNA expression in metastatic and non-metastatic pancreatic cancer samples revealed significantly lower expression of miR-6794-3p in the metastatic tumor group. Gain- and loss-of-function approaches using the pancreatic cancer cell lines MIA-PaCa-2 and HPAF-II expressing low and high levels of miR-6794-3p, respectively, indicated a role of miR-6794-3p in suppression of cell invasion, migration, and EMT signaling. Importantly, our results showed that miR-6794-3p exerts its effects by inhibiting expression of the chromatin remodeling factor, RBBP4. The resulting suppression of RBBP4 induced an increase in the levels of GRHL2 involved in regulating invasion, migration, and EMT signaling in metastatic pancreatic cancer cells. Consistent with these findings, low miR-6794-3p expression levels correlate with poor pancreatic cancer patient survival. Additional preclinical experiments on nude mice clearly demonstrated inhibitory effects of miR-6794-3p on pancreatic cancer cell metastasis. The collective results highlight the functional significance of miR-6794-3p as a suppressor of metastasis and support its predictive utility as a prognostic biomarker and therapeutic target in pancreatic cancer.

GAS5 promotes glucose metabolism reprogramming and resistance to ferroptosis of endothelial progenitor cells through the miR-495-3p/SIX1 and IGF2BP2/NRF2 dual-regulatory pathways in coronary heart disease.

We aimed to explore the potential along with mechanism of lncRNA growth arrest-specific 5 (GAS5) in modulating glucose metabolism and ferroptosis of endothelial progenitor cells (EPCs) in coronary heart disease (CHD). CCK-8, flow cytometry, EdU, colony formation, scratch test as well as transwell assays were implemented to assess cell biological behaviors. Glucose uptake testing, lactic acid production assay, and detection of extracellular acidification rate (EACR) together with oxygen consumption rate (OCR) were used to assess glucose metabolism. Iron, GSH and MDA detection were used to measure ferroptosis. Besides, a series of mechanical experiments were implemented to clarify the modulatory relationship between GAS5 and nuclear factor erythroid 2-related factor 2 (NRF2) as well as sine oculis homeobox 1 (SIX1). We found that GAS5 was down-regulated in CHD patients relative to healthy controls. GAS5 depletion repressed EPCs proliferation, migration along with invasion while elevated cell apoptosis. GAS5 promoted the reprogramming of glucose metabolism and inhibited ferroptosis in EPCs. GAS5 affected glycometabolic reprogramming and ferroptosis resistance through regulating SIX1 and NRF2. On the one hand, GAS5 promoted NRF2 mRNA stability through IGF2BP2. On the other hand, GAS5 regulated the miR-495-3p/SIX1 axis in EPCs. To sum up, GAS5 promotes glucose metabolism reprogramming and resistance to ferroptosis of EPCs through the miR-495-3p/SIX1 and IGF2BP2/NRF2 dual-regulatory pathways in CHD.

Identification of a senescence-related transcriptional signature to uncover molecular subtypes and key genes in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a cancer caused by abnormal cell growth due to faulty signal transduction. Cells secrete tumor suppressor factors in response to potential carcinogenic signals, inducing cellular senescence (CS) as a countermeasure. However, accurately measuring CS levels in different types of tumors is challenging due to tumor heterogeneity and the lack of universal and specific CS markers. Machine learning has revealed unique molecular traits in HCC patients, leading to clinical advantages. More research is needed to understand senescence-related molecular features in these patients. In this study, the gene expression profile features of patients with HCC were analyzed by integrating single-cell RNA sequencing and bulk RNA-seq datasets from HCC samples. The analysis identified the senescence-related pathways exhibiting HCC specificity. Subsequently, genes from these pathways were used to identify senescence-related molecular subtypes in HCC, showing significant variations in biological and clinical attributes. An HCC-specific CS risk model developed in this study revealed substantial associations between the patients' CS scores and prognosis grouping, clinical staging, immune infiltration levels, immunotherapy response, and drug sensitivity levels. Within the constructed model, G6PD was identified as a key gene, potentially serving as a senescence-related target in liver cancer. Molecular biology experiments demonstrated that overexpression of G6PD effectively promotes the proliferative, invasive, and migration capacities of HepG2 and SK-HEP-1 cells. In conclusion, this analysis offers a valuable framework for understanding senescence in HCC and introduces a new biomarker. These findings improve our understanding of senescence in HCC and have potential for future research.

ETV4­mediated transcriptional activation of SLC12A5 exacerbates ferroptosis resistance and glucose metabolism reprogramming in breast cancer cells.

Solute carrier family 12 member 5 (SLC12A5) is an oncogene in numerous types of cancer, however its function in breast cancer (BC) remains elusive. ETS translocation variant 4 (ETV4) promotes BC. Therefore, the present study aimed to elucidate the role of SLC12A5 in ferroptosis and glucose metabolism in BC cells as well as to understand the underlying mechanism. Analysis of data from the UALCAN database demonstrated expression levels of SLC12A5 in BC and its association with prognosis. Reverse transcription­quantitative PCR and western blotting were conducted to evaluate the expression levels of SLC12A5 and ETV4 in BC cells. The abilities of BC cells to proliferate, migrate and invade were assessed using Cell Counting Kit­8, colony formation, wound healing and Transwell assays. Thiobarbituric acid reactive substances assay and a C11 BODIPY 581/591 probe were used to evaluate lipid peroxidation. Ferroptosis resistance was evaluated by the measurement of Fe2+ and ferroptosis­related solute carrier family 7a member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), acyl­CoA synthetase long­chain family member 4 (ACSL4) and transferrin receptor 1 (TFR1) protein levels. Glycolysis was assessed via evaluation of extracellular acidification rate, oxygen consumption rate, lactate production and glucose consumption. Finally, luciferase reporter and chromatin immunoprecipitation assay were used to verify the interaction between ETV4 and the SLC12A5 promoter. UALCAN database analysis indicated that SLC12A5 was upregulated in BC tissues and cells and that SLC12A5 elevation indicated a poor prognosis of patients with BC. SLC12A5 knockdown suppressed the BC cell proliferative, migratory and invasive capabilities. Moreover, SLC12A5 knockdown decreased BC cell ferroptosis resistance and glucose metabolism reprogramming. The transcription factor ETV4 was demonstrated to bind to the SLC12A5 promoter and upregulate its transcription. Furthermore, ETV4 overexpression counteracted the suppressive effect of SLC12A5 knockdown on the BC cell proliferative, migratory and invasive abilities, as well as on ferroptosis resistance and glucose metabolism reprogramming. Transcriptional activation of SLC12A5 by ETV4 modulated the migration, invasion, ferroptosis resistance and glucose metabolism reprogramming of BC cells.

CRISPR-edited human ES-derived oligodendrocyte progenitor cells improve remyelination in rodents.

In Multiple Sclerosis (MS), inflammatory demyelinated lesions in the brain and spinal cord lead to neurodegeneration and progressive disability. Remyelination can restore fast saltatory conduction and neuroprotection but is inefficient in MS especially with increasing age, and is not yet treatable with therapies. Intrinsic and extrinsic inhibition of oligodendrocyte progenitor cell (OPC) function contributes to remyelination failure, and we hypothesised that the transplantation of 'improved' OPCs, genetically edited to overcome these obstacles, could improve remyelination. Here, we edit human(h) embryonic stem cell-derived OPCs to be unresponsive to a chemorepellent released from chronic MS lesions, and transplant them into rodent models of chronic lesions. Edited hOPCs display enhanced migration and remyelination compared to controls, regardless of the host age and length of time post-transplant. We show that genetic manipulation and transplantation of hOPCs overcomes the negative environment inhibiting remyelination, with translational implications for therapeutic strategies for people with progressive MS.

Clinical significance and underlying mechanism of long non-coding RNA SNHG12 in lower extremity deep venous thrombosis.

D-dimer is widely used in the diagnosis of deep vein thrombosis (DVT), but the specificity is low. The study examined the diagnostic value of long non-coding RNA (lncRNA) SNHG12 in DVT, and preliminarily discussed its mechanism. SNHG12 levels were detected in 200 elderly fracture patients via RT-qPCR, including 38 DVTs. Logistic regression analysis and receiver operating characteristic (ROC) curve were applied for diagnostic value evaluation. HUVECs were used for function study. Cell proliferation, migration, apoptosis, release of inflammatory cytokines, and adhesion factors were detected. Student's t test and one-way ANOVA were applied for data comparison between two or among three or more groups. Correlation analysis of indicators was completed via Pearson's correlation analysis. Bioinformatics analysis predicted the target miRNAs and genes of SNHG12, with GO and KEGG for the function enrichment. It was found that SNHG12 was at low expression in DVT patients, and negatively correlated with D-dimer concentration (r = -0.535). SNHG12 and D-dimer were independent influence factors related to the development of DVT. SNHG12 and D-dimer combination had the best performance in DVT diagnosis. In HUVECs, SNHG12 promoted cell proliferation and migration and restricted the release of inflammatory cytokines and adhesion factors, but these influences were counteracted by miR-424-5p. A total of 208 overlapping target genes of miR-424-5p were identified, and their function was enriched in cellular cycle and senescence. PI3K-Akt signaling pathway was the most significant pathway based on KEGG results. In conclusion, SNHG12 had good diagnostic potential for DVT combined with D-dimer. SNHG12 maintains vascular endothelial cell function by acting as a competitive endogenous RNA (ceRNA) for miR-424-5p.

Potential cardiac-derived exosomal miRNAs involved in cardiac healing and remodeling after myocardial ischemia-reperfusion injury.

Migratory cells exist in the heart, such as immune cells, fibroblasts, endothelial cells, etc. During myocardium injury, such as ischemia-reperfusion (MIRI), cells migrate to the site of injury to perform repair functions. However, excessive aggregation of these cells may exacerbate damage to the structure and function of the heart, such as acute myocarditis and myocardial fibrosis. Myocardial injury releases exosomes, which are a type of vesicle with signal transduction function and the miRNA carried by exosomes can control cell migration function. Therefore, regulating this migratory cell population through cardiac-derived exosomal miRNA is crucial for protecting and maintaining cardiac function. Through whole transcriptome RNA sequencing, exosomal miRNA sequencing and single-cell dataset analysis, we (1) determined the potential molecular regulatory role of the lncRNA‒miRNA‒mRNA axis in MIRI, (2) screened four important exosomal miRNAs that could be released by cardiac tissue, and (3) screened seven genes related to cell locomotion that are regulated by four miRNAs, among which Tradd and Ephb6 may be specific for promoting migration of different cells of myocardial tissue in myocardial infarct. We generated a core miRNA‒mRNA network based on the functions of the target genes, which may be not only a target for cardiac repair but also a potential diagnostic marker for interactions between the heart and other tissues or organs. In conclusion, we elucidated the potential mechanism of MIRI in cardiac remodeling from the perspective of cell migration, and inhibition of cellular overmigration based on this network may provide new therapeutic targets for MIRI and to prevent MIRI from developing into other diseases.

Differential effect of plakoglobin in restoring the tumor suppressor activities of p53-R273H vs. p53-R175H mutants.

The six most common missense mutations in the DNA binding domain of p53 are known as "hot spots" and include two of the most frequently occurring p53 mutations (p53-R175H and p53-R273H). p53 stability and function are regulated by various post-translational modifications such as phosphorylation, acetylation, sumoylation, methylation, and interactions with other proteins including plakoglobin. Previously, using various carcinoma cell lines we showed that plakoglobin interacted with wild-type and several endogenous p53 mutants (e.g., R280K, R273H, S241F, S215R, R175H) and restored their tumor suppressor activities in vitro. Since mutant p53 function is both mutant-specific and cell context-dependent, we sought herein, to determine if plakoglobin tumor suppressive effects on exogenously expressed p53-R273H and p53-R175H mutants are similarly maintained under the same genetic background using the p53-null and plakoglobin-deficient H1299 cell line. Functional assays were performed to assess colony formation, migration, and invasion while immunoblotting and qPCR were used to examine the subcellular distribution and expression of specific proteins and genes that are typically regulated by or regulate p53 function and are altered in mutant p53-expressing cell lines and tumors. We show that though, plakoglobin interacted with both p53-R273H and p53-R175H mutants, it had a differential effect on the transcription and subcellular distribution of their gene targets and their overall oncogenic properties in vitro. Notably, we found that plakoglobin's tumor suppressive effects were significantly stronger in p53-R175H expressing cells compared to p53-R273H cells. Together, our results indicate that exploring plakoglobin interactions with p53-R175H may be useful for the development of cancer therapeutics focused on the restoration of p53 function.

YBX1 promotes epithelial-mesenchymal transition in hepatocellular carcinoma via transcriptional regulation of PLRG1.

Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent cancer worldwide. The epithelial-mesenchymal transition (EMT) is a critical process in cancer progression, contributing to increased malignancy. While Pleiotropic Regulator 1 (PLRG1) is upregulated in HCC and is associated with enhanced cell proliferation, its oncogenic role in EMT remains unclear. In this study, we demonstrate that PLRG1 promotes EMT in HCC cells. Knockdown of PLRG1 in Huh7 cells resulted in decreased expression of the EMT markers N-cadherin and Snail, and impaired cell migration and invasion. Chromatin immunoprecipitation (ChIP) and luciferase assays identified Y-box binding protein 1 (YBX1) as a direct regulator of PLRG1 transcription, binding to its promoter region. Overexpression of YBX1 in SNU-449 cells led to increased PLRG1 expression and subsequent EMT activation, as well as enhanced migration, and invasion. These effects were attenuated by PLRG1 knockdown. Our findings indicate that YBX1 drives EMT in HCC by upregulating PLRG1, offering novel insights into the molecular mechanisms underlying HCC progression.

Understanding the Dosage-Dependent Role of Dicer1 in Thyroid Tumorigenesis.

Tumors originating from thyroid follicular cells are the most common endocrine tumors, with rising incidence. Despite a generally good prognosis, up to 20% of patients experience recurrence and persistence, highlighting the need to identify the underlying molecular mechanisms. Dicer1 has been found to be altered in papillary thyroid cancer (PTC). Studies suggest that Dicer1 functions as a haploinsufficient tumor suppressor gene: partial loss promotes tumorigenesis, while complete loss prevents it. To investigate the effects of partial or total Dicer1 loss in PTC in vitro, we generated stable Dicer1 (+/-) cell lines from TPC1 using CRISPR-Cas9, though no Dicer1 (-/-) lines could be produced. Therefore, siRNA against Dicer1 was transfected into Dicer1 (+/-) cell lines to further decrease its expression. Transcriptomic analysis revealed changes in proliferation and cell locomotion. BrdU staining indicated a slow-down of the cell cycle, with fewer cells in S phase and more in G0-G1-phase. Additionally, transwell assays showed decreased invasion and migration after Dicer1 knockdown by siRNA. Moreover, Dicer1 overexpression led to decreased proliferation, invasion, and increased apoptosis. Our findings deepen the understanding of Dicer1's role in thyroid cancer, demonstrating that both complete elimination and overexpression of Dicer1 inhibit thyroid oncogenesis, highlighting Dicer1 as a promising target for novel therapeutic strategies.

The Double-Edged Sword Property of Mesenchymal Stem Cell-Derived Exosomal microRNAs in Colorectal Cancer.

Mesenchymal stem cells (MSCs)-based therapies are promising therapeutic strategies for cancer treatment, because of their strong immunomodulatory and tissue regeneration abilities. In case of colorectal cancer (CRC), MSCs indicate a double-edged sword activity. Some reports declared the inhibitory effects of MSCs on the proliferation, migration, and infiltration of cancer cells to suppress the CRC initiation and development, whereas others showed the tumor-promoter impacts of MSCs on the progression of CRC. Recent investigations have revealed that exosomal microRNAs (Exo-miRs) derived from MSCs (MSCs-Exo-miRs) are attributed to such paradoxical effect. Thus, the current review aimed to seek the role of MSCs-Exo-miRs in CRC progression and their therapeutic potential for the CRC treatment.

Circ_0008035 Promotes Gastric Cancer Development via the miR-429/SMAD2 Cascade.

The vital roles of circular RNAs (circRNAs) in human tumorigenesis have attracted more attention. Circ_0008035 is one of the most up-regulated circRNAs in gastric cancer (GC). Herein, we explored the associated mechanism of circ_0008035 in GC. EdU incorporation experiments were performed to monitor cell proliferation ability. Cell cycle progression, apoptosis, angiogenesis, migration, and invasion were analyzed using flow cytometry, Tube formation, and Transwell assays respectively. Protein expression was detected by Western blot. Dual-luciferase reporter experiments were applied to demonstrate the relationship between circ_0008035 or SMAD family member 2 (SMAD2) and microRNA-429 (miR-429). Mouse xenograft assays were conducted for evaluation of the role of circ_0008035 in vivo. Circ_0008035 content was elevated in GC tissues (P < .0001) and cell lines (P < .001), and its deficiency hindered GC cell proliferation (P < .01), HUVEC angiogenesis (P < .05), and GC cell metastasis (P < .01) and triggered apoptosis (P < .01). Circ_0008035 could sponge miR-429 to up-regulate SMAD2 expression (P < .0001). Circ_0008035 absence restrained tumor growth in vivo (P < .01). MiR429 was a mediator of circ_0008035 function, and miR-429 hindered GC cell malignant phenotypes by SMAD2. Circ_0008035 aggravates GC cell malignant progression partially by targeting the miR-429/SMAD2 axis. Considering the inhibitory effect of circ_0008035 deficiency on GC progression, targeting circ_0008035 may be a potential approach to prevent or treat GC.