Migration Capabilities Research Articles

A telomere-related signature for predicting prognosis and assessing immune microenvironment in osteosarcoma

ObjectiveOsteosarcoma is the most common primary bone cancer with a high propensity for local invasion and metastasis. An increasing number of research studies show that telomeres play an important role in the occurrence and development of cancer. Thus, we established a telomere-related signature in osteosarcoma to comprehensively evaluate the pathogenic roles of telomeres in this disease.MethodsThe data on osteosarcoma were collected from the TARGET and Gene Expression Omnibus databases. First, we constructed a telomere-related signature using univariate and LASSO Cox regression analyses. Subsequently, we analyzed the prognostic value, functional annotation, immune microenvironment, and cell communication patterns of the telomere-related signature in osteosarcoma via comprehensive bioinformatics analyses. Cell proliferation was analyzed using the CCK-8 assay, and cell migration and invasion capabilities were evaluated using the Transwell assay.ResultsBased on the SP110, HHAT, TUBB, MORC4, TERT, PPARG, MAP3K5, PAGE5, MAP7, and CAMK1G, a telomere-related signature was built in osteosarcoma patients. The telomere-related signature could effectively predict the prognosis of osteosarcoma patients. The osteosarcoma patients in the high TELscore group exhibited poor prognosis. In addition, the telomere-related signature demonstrated predictive value for the immune microenvironment and drug sensitivity in osteosarcoma. Finally, we discovered significant reduction in MAP7 expression in osteosarcoma cells, and patients with low MAP7 expression had poor prognosis. Moreover, the overexpression of MAP7 significantly reduced cell proliferation, the ability of cell migration, and invasion in osteosarcoma cells.ConclusionA telomere-related signature was constructed in osteosarcoma patients, offering predictive values into prognosis, the immune microenvironment, and drug sensitivity. Moreover, MAP7 might serve as a prognostic marker for osteosarcoma patients.

Volatile MoS2 Memristors with Lateral Silver Ion Migration for Artificial Neuron Applications

Layered 2D semiconductors have shown enhanced ion migration capabilities along their van der Waals (vdW) gaps and on their surfaces. This effect can be employed for resistive switching (RS) in devices for emerging memories, selectors, and neuromorphic computing. To date, all lateral molybdenum disulfide (MoS2)‐based volatile RS devices with silver (Ag) ion migration have been demonstrated using exfoliated, single‐crystal MoS2 flakes requiring a forming step to enable RS. Herein, present volatile RS with multilayer MoS2 grown by metal‐organic chemical vapor deposition (MOCVD) with repeatable forming‐free operation is presented. The devices show highly reproducible volatile RS with low operating voltages of ≈2 V and fast‐switching times down to 130 ns considering their micrometer‐scale dimensions. The switching mechanism is investigated based on Ag ion surface migration through transmission electron microscopy, electronic transport modeling, and density functional theory. Finally, a physics‐based compact model is developed and the implementation of the volatile memristors as artificial neurons in neuromorphic systems is exploredd.

Decreased PD-L1 contributes to preeclampsia by suppressing GM-CSF via the JAK2/STAT5 signal pathway

Programmed cell death protein 1 (PD-1) and its ligand PD-L1 have been detected at the materno-embryonic interface in both human and murine pregnancy models. However, research regarding the PD-1/PD-L1 signal in preeclampsia (PE) is limited. In the present investigation, 30 normal pregnant females and 30 PE patients were enrolled. Cellular functional experiments were performed in two trophoblast cell lines by transfection with lentiviral vectors for overexpression and down-regulation of PD-L1. The placental expressions of PD-1, PD-L1, and granulocyte macrophage colony-stimulating factor (GM-CSF) exhibited a notable reduction in PE cases compared with healthy pregnancies. Cellular functional experiments indicated that excessive PD-L1 expression significantly enhanced trophoblast migratory, invasive, and proliferative capabilities while inhibiting cell apoptosis. Additionally, the administration of lentivirus-mediated PD-L1 overexpression could alleviate clinical symptoms (hypertension, proteinuria) of PE-like rats. Therefore, decreased PD-L1 may contribute to PE by inhibiting GM-CSF via activating the JAK2/STAT5 pathway. Our study provides a novel pathway that can be targeted for the therapy of this disease.

Accumulation of CD38 in Hybrid Epithelial/Mesenchymal Cells Promotes Immune Remodeling and Metastasis in Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly metastatic subtype of breast cancer. The epithelial-to-mesenchymal transition is a nonbinary process in the metastatic cascade that generates tumor cells with both epithelial and mesenchymal traits known as hybrid EM cells. Recent studies have elucidated the enhanced metastatic potential of cancers featuring the hybrid EM phenotype, highlighting the need to uncover molecular drivers and targetable vulnerabilities of the hybrid EM state. Here, we discovered that hybrid EM breast tumors are enriched in CD38, an immunosuppressive molecule associated with worse clinical outcomes in liquid malignancies. Altering CD38 expression in tumor cell impacted migratory, invasive, and metastatic capabilities of hybrid EM cells. Abrogation of CD38 expression stimulated an antitumor immune response, thereby preventing the generation of an immunosuppressive microenvironment in hybrid EM tumors. CD38 levels positively correlated with PD-L1 expression in samples from patients with TNBC. Moreover, targeting CD38 potentiated the activity of anti-PD-L1, eliciting strong antitumor immunity, with reduced tumor growth in hybrid EM models. Overall, this research exposes upregulation of CD38 as a specific survival strategy utilized by hybrid EM breast tumors to suppress immune cell activity and sustain metastasis, with strong implications in other carcinomas that have hybrid EM properties. Significance: Hybrid cells co-featuring epithelial and mesenchymal traits in triple-negative breast cancer express elevated levels of CD38 to induce immunosuppression and metastasis, indicating CD38 inhibition as potential strategy for treating breast cancer.

HDAC3 and Snail2 complex promotes melanoma metastasis by epigenetic repression of IGFBP3.

The treatment of metastatic melanoma has long posed a complex challenge within clinical practice. Previous studies have found that EMT transcription factors are essential in the development of various cancers through their induction of EMT. Here, we demonstrate that Snail2 expression is dramatically increased in melanoma and is associated with an adverse prognosis. Elevated Snail2 in melanoma cells enhanced migratory and invasive capabilities in vitro and in vivo. Furthermore, RNA-Seq analysis revealed a significant reduction of IGFBP3 expression in melanoma cells overexpressing Snail2. IGFBP3 might mitigate the Snail2's ability to promote melanoma metastasis via the PI3K-AKT pathway. Moreover, Snail2 and HDAC3 collaborate to suppress IGFBP3 transcription through H3K4 deacetylation and H4K5 delactylation. Additionally, the combination of HDAC3 and p-GSK-3β inhibitors significantly improved the treatment outcomes for lung metastasis in melanoma in vivo. The results of our study indicate that Snail2, HDAC3, and IGFBP3 play significant roles in melanoma progression and represent promising therapeutic targets.

Similarities in Mechanisms of Ovarian Cancer Metastasis and Brain Glioblastoma Multiforme Invasion Suggest Common Therapeutic Targets

Epithelial-to-mesenchymal transition (EMT) is a critical process in malignant ovarian cancer metastasis. EMT involves the conversion of epithelial cells to mesenchymal cells, conferring enhanced migratory and invasive capabilities. Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor and exhibits an aggressive invasive phenotype that mimics some steps of EMT but does not undergo true metastasis, i.e., the invasion of other organ systems. This study conducts a comparative genomic analysis of EMT in ovarian cancer and invasion in GBM—two malignancies characterized by poor prognosis and limited therapies. Investigating the molecular biology in ovarian cancer and GBM demonstrates shared mechanisms of tumor progression, such as similar genetic and molecular pathways influencing cell plasticity, invasion, and resistance to therapy. The comparative analysis reveals commonalities and differences in the regulatory networks and gene expression profiles associated with EMT and invasion in these cancers. Key findings include the identification of core EMT regulators, such as TWIST1, SNAIL, and ZEB1, which are upregulated in both ovarian cancer and GBM, promoting mesenchymal phenotypes and metastasis. Additionally, the analysis uncovers EMT-related pathways, such as the PI3K/AKT and TGF-β signaling, which are critical in both cancers but exhibit distinct regulatory dynamics. Understanding the intricacies of EMT in ovarian cancer and invasion in GBM provides valuable insights into their aggressive behavior and identifies potential common therapeutic targets. The findings stress the importance of targeting EMT/invasion transitions to develop effective treatments to halt progression and improve patient outcomes in these malignancies.

Relationship between transmembrane emp24 domain containing 2 expression and tumor stem cell characteristics in oral cancer

Objective: Transmembrane Emp24 Domain Containing 2 (TMED2) is a mediator of membrane protein trafficking involved in intracellular protein transport. Recent research suggests that TMED2 plays an important role in the development and metastasis of tumors; however, its exact mechanisms in oral cancer (OC) remain unclear. This study aims to elucidate the role and possible mechanisms of TMED2 in OC. Material and Methods: We investigated the impact of TMED2 knockdown on the invasion, migration, and proliferation capabilities of OC cells. Furthermore, we analyzed the in vitro and in vivo interactions between TMED2 and polypeptide-N-acetylgalactosaminyltransferase 7 (GALNT7) as well as explored the regulatory function of TMED2 on GALNT7. The alterations in stem cell markers were assessed using clone formation assays, western blot, and quantitative real-time polymerase chain reaction. Results: The upregulation of TMED2 promoted the proliferation and invasion abilities of OC cells. Further analysis revealed that TMED2 enhanced the stem-like properties and tumorigenicity of OC cells by directly regulating the expression of GALNT7. In vivo and in vitro results suggested that silencing TMED2 expression reduced the incidence of OC. Conclusion: Our data imply that TMED2 stimulates GALNT7 transcription, which in turn amplifies the stem-like characteristics and carcinogenic potential of OC cells. Moreover, the block of TMED2 prevents cancers from growing and spreading in vivo. This finding provides a new therapeutic target for the treatment of OC and highlights the critical role of TMED2 in the condition.

M1A-regulated DIAPH3 promotes the invasiveness of colorectal cancer via stabilization of KRT19

BackgroundIn recent years, the emphasis has shifted to understanding the role of N1-methyladenosine (m1A) in tumor progression as little is known about its regulatory effect on mRNA and its role in the metastasis of colorectal cancer (CRC).MethodsWe performed methylated RNA immunoprecipitation sequencing of tumor tissues and tumor-adjacent normal tissues from three patients with CRC to determine the m1A profile of mRNA in CRC. The expression of diaphanous-related formin 3 (DIAPH3) and its correlation with clinicopathological characteristics of CRC were evaluated using immunohistochemistry and online datasets. The role of DIAPH3 in the migration and invasion of CRC cells was evaluated using wound healing assay, Transwell assay and xenograft metastatic model. The downstream targets of DIAPH3 were screened using mass spectrometry. By co-transfecting DIAPH3 siRNA and a keratin 19 (KRT19) ectopic plasmid into CRC cells, the role of DIAPH3-KRT19 signaling axis was confirmed.ResultsThe mRNA level of DIAPH3 and its m1A modifications increased simultaneously in the CRC tissues. In addition, high DIAPH3 expression in CRC tissues is significantly associated with metastasis and progression to an advanced stage. After the knockdown of DIAPH3, the migration and invasion capabilities of CRC cells suffered a notable decline, which could be rescued by overexpressing KRT19. In addition, the proteasome inhibitor MG132 could block the degradation of KRT19 induced by DIAPH3 silencing.ConclusionsOur study reveals that DIAPH3 mRNA was modified in CRC cells by m1A methylation. Silencing DIAPH3 suppresses the migration and invasion of CRC cells, potentially through the proteasome-dependent degradation of downstream KRT19.

P1174 Engineering therapeutic Tregs to overexpress GPR15 improves functional fitness for in vivo gut homing

Abstract Background Inflammatory bowel diseases (IBD) like Crohn’s disease and ulcerative colitis, are marked by an imbalance of pro- and anti-inflammatory T cells in the lamina propria of the intestinal tract. Only subgroups of patients respond to current therapeutic approaches designed to restrain pro-inflammatory cells or signalling. Adoptive transfer of autologous ex vivo expanded regulatory T cells (Tregs) has previously been suggested as a promising future therapeutic approach to resolve chronic intestinal inflammation by promoting anti-inflammatory pathways. Methods Using a previously established protocol for the ex vivo expansion of Tregs (Investigational Medicinal Product-Tregs; IMP-Tregs), we characterized the migration and homing capabilities as well as the immunosuppressive function of non-expanded and IMP-Tregs using 3D-motility, in vivo gut homing and T cell suppression assays. Furthermore, via electroporation with GPR15 mRNA, IMP-Tregs were engineered to express the gut homing marker GPR15 and tested for their functional fitness in dynamic adhesion, T cell suppression assays as well as in vivo gut homing assays. Results Our data show that while the expansion protocol generates highly suppressive Tregs, only a fraction of them is equipped with surface molecules for gut homing. In order to overcome this limitation, we successfully engineered IMP-Tregs to express the gut homing marker GPR15. On a functional level, this led to improved adhesion to the cell adhesion molecules MAdCAM-1 and VCAM-1, which are expressed on the intestinal endothelium, as well as to increased gut homing in a humanized in vivo mouse model without affecting the immunosuppressive character of the engineered IMP-Tregs. Conclusion In conclusion, our data indicate superior functional fitness of GPR15-engineered IMP-Tregs for homing to the inflamed gut nominating them a promising further development of autologous Treg transfer therapy for IBD.

Electrolyte Engineering with Asymmetric Spatial Shielding Effect for Aqueous Zinc Batteries

AbstractThe electrochemical instability of electrode/electrolyte interface and aqueous electrolyte collectively brings technical barriers, such as side reactions like hydrogen evolution and corrosion, as well as zinc dendrites, which hinder the practical application of aqueous zinc batteries. Here, an electrolyte engineering strategy is proposed with asymmetric spatial shielding effect by employing the molecules with asymmetric spatial structure as a cosolvent. Such molecule contains small methyl group and large cyclopentyl group to balance migration capability and shielding volume, which can not only promote the solvation structure of Zn2+ containing more anions and solid electrolyte interface derived from abundant anions but also rapidly and effectively adsorb on the surface of Zn anode to remodel the electric double layer. This strategy alleviates hydrogen evolution and corrosion while achieving dendrite‐free Zn deposition. Consequently, the Zn/I2 cell can operate stably at 2 A g−1 for 30 000 cycles over 180 days, with a capacity retention of 79.8%. Despite featuring a cathode areal capacity of 4.74 mAh cm−2 and an N/P ratio of 2.5, the Zn/NH4V4O10 cell still achieves an impressive capacity retention of 88.8% at 0.5 A g−1 for 200 cycles, demonstrating a significant potential for practical application.

BRAF regulates circPSD3/miR-526b/RAP2A axis to hinder papillary thyroid carcinoma progression

BackgroundPapillary thyroid carcinoma (PTC) is a common malignant tumor. BRAFV600E mutation has become a common molecular event in PTC pathogenesis. Circular RNA PSD3 (circPSD3) is known to be highly expressed in PTC. However, the bio-functional role of circPSD3 and its possible relationship with the BRAF in PTC is not clear. This study aims to probe the biofunction and molecular mechanism of circPSD3 in PTC pathogenesis.MethodsRT-qPCR was utilized to measure the expression of circPSD3 and BRAF in PTC tissues and cells. The CCK-8 and EdU assays were employed to assess cell viability and proliferation. Cell apoptosis was quantified using flow cytometry. The migratory and invasive capabilities of the cells were evaluated via wound healing and transwell assays. The interaction between RNAs was investigated using luciferase reporter assay. Additionally, xenograft tumor experiments were conducted to validate our findings in vivo.ResultsData showed that circPSD3 was highly expressed in PTC patients and cell lines. CircPSD3 was found to promote cell growth and migration and inhibit apoptosis in PTC cells. Results also revealed that circPSD3 upregulated RAP2A expression by specifically sponging miR-526b. Interestingly, inhibiting miR-526b reversed the tumorigenic properties of circPSD3 in PTC. Additionally, BRAF expression was low in PTC patients, and overexpression of BRAF hampered PTC development by downregulating circPSD3 and RAP2A while upregulating miR-526b expressions.ConclusionsOur study reveals that circPSD3 is a key regulator promoting PTC progression via the circPSD3/miR-526b/RAP2A pathway. Furthermore, we found that overexpressing BRAF, which inhibits circPSD3, significantly hampers the progression of PTC.

Modulation of DAPK1 expression by its alternative splice variant DAPK1-215 in cancer

BackgroundDeath-Associated Protein Kinase 1 (DAPK1) family members are calcium/calmodulin-regulated serine/threonine kinases implicated in cell death, normal development, and human diseases. However, the regulation of DAPK1 expression in cancer remains unclear.MethodsWe examined the expression and functional impact of a DAPK1 splice variant, DAPK1-215, in multiple cancer cell lines. DAPK1 and DAPK1-215 expression levels were quantified by qRT-PCR and Western blotting. Cell migration, invasion, and proliferation assays were conducted in vitro, and a zebrafish model was employed to evaluate metastatic potential. RNA pull-down and CLIP-seq analyses were performed to identify potential RNA-binding proteins. Finally, clinical liver cancer specimens were analyzed to assess the prognostic relevance of DAPK1-215 and DAPK1 mRNA levels.ResultsDAPK1-215 downregulated DAPK1 expression in liver, kidney, and gastric cancer cells by reducing DAPK1 mRNA stability. DAPK1-215 promoted migratory and invasive capabilities in liver and kidney cancer cells, but inhibited these processes in gastric cancer cells, without affecting cell proliferation. Mechanistically, DEAD-Box Helicase 3 X-Linked (DDX3X) stabilized both DAPK1-215 and DAPK1 mRNAs, suggesting that DAPK1-215 may act by competing for DDX3X binding to modulate DAPK1 mRNA stability. Importantly, high levels of DAPK1-215 correlated inversely with DAPK1 mRNA in liver cancer specimens and predicted poor prognosis, whereas high DAPK1 expression predicted improved patient outcomes.ConclusionsOur findings unveil DAPK1-215 as a molecular brake on DAPK1 expression, influencing cancer cell migration and invasion in a context-dependent manner. These results highlight the potential of DAPK1-215 as an important regulator of malignant progression and as a prognostic marker in liver cancer.

M6A-modified lncRNA GAS5 promotes M1-polarization of microglia in alcohol use disorder.

Long noncoding RNA (lncRNA) are essential for modulating the onset and progression of alcohol use disorder (AUD). In this study, we investigated the molecular pathways through which lncRNA may contribute to AUD development. We assessed the expression levels of long noncoding RNA GAS5 (lncRNA GAS5) and microRNA-136-5p (miR-136-5p) in AUD tissue samples and cell lines using reverse transcription-quantitative polymerase chain reaction. Detection of GAS5 N6-methyladenosine (m6A) modifications, facilitated by alkylation repair homolog 5 (ALKBH5), was performed using RNA immunoprecipitation and RNA pull-down assays. The effect of GAS5 on the functionality of SH-SY5Y cells was evaluated using CCK-8 and Transwell assays. Our findings showed high levels of GAS5 expression in both AUD tissues and cell lines. Overexpression of GAS5 decreased the migratory capability of SH-SY5Y cells, whereas silencing GAS5 increased this ability. Bioinformatics analyses predicted a relationship between expression levels of miR-136-5p and GAS5, which was subsequently confirmed using dual-luciferase reporter assays. Additionally, we discovered that GAS5 acts as a sponge for miR-136-5p, leading to the upregulation of ATF2. Elevated levels of ATF2 are associated with M1 microglial polarization. In summary, m6A-modified GAS5 may influence the M1 polarization of microglia via the miR-136-5p/ATF2 pathway. Statistical evaluations were performed using GraphPad Prism V8.0, employing the student's t-test for comparisons between two groups, assuming a normal distribution and equal variances. When variances were unequal, but normality was maintained, the corrected Student's t-test was applied. The non-parametric Wilcoxon rank-sum test was used to analyze non-normally distributed data, and one-way ANOVA was used to compare three or more groups. Independent replication was ensured in the studies, with each experiment repeated at least three times and statistical significance was set at P < 0.05.

Olaparib Combined with DDR Inhibitors Effectively Prevents EMT and Affects miRNA Regulation in TP53-Mutated Epithelial Ovarian Cancer Cell Lines.

Epithelial ovarian cancer (EOC) remains a leading cause of gynecologic cancer mortality. Despite advances in treatment, metastatic progression and resistance to standard therapies significantly worsen patient outcomes. Epithelial-mesenchymal transition (EMT) is a critical process in metastasis, enabling cancer cells to gain invasive and migratory capabilities, often driven by changing miRNA expression involved in the regulation of pathological processes like drug resistance. Targeted therapies like PARP inhibitors (PARPi) have improved outcomes, particularly in BRCA-mutated and DNA repair-deficient tumors; however, resistance and limited efficacy in advanced stages remain challenges. Recent studies highlight the potential synergy of PARPi with DNA damage response (DDR) inhibitors, such as ATR and CHK1 inhibitors, which disrupt cancer cell survival pathways under stress. This study investigated the combined effects of olaparib with ATR and CHK1 inhibitors (ATRi and CHK1i) on migration, invasion, and EMT-related protein expression and miRNA expression in ovarian cancer cell lines OV-90 and SKOV-3. The results demonstrated enhanced cytotoxicity, inhibition of migration and invasion, and modulation of miRNAs linked to metastasis. These findings suggest that combination therapies targeting DNA repair and cell cycle pathways may offer a novel, more effective approach to managing advanced EOC and reducing metastatic spread.

Mechanistic Insights into the Inhibition of Colorectal Cancer by BuShenFang through Adenomatous Polyposis Coli Expression and Wnt/β-catenin Pathway Regulation

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Despite advances in chemotherapy and radiotherapy, significant side effects persist, prompting the exploration of alternative therapies such as traditional Chinese medicine (TCM). BuShenFang (BSF), a TCM formulation, is believed to exhibit anti-CRC effects, although its exact mechanism is unclear. This study aims to investigate the effects of BSF on CRC cells through the modulation of the Wnt/β-catenin pathway. The study utilized HCT116 and SW620 CRC cell lines, employing in vitro experiments including cell viability assays, colony formation, flow cytometry, and Western blot to examine the influence of BSF on cellular proliferation, apoptosis, migration, and the Wnt/β-catenin signaling pathway. Results demonstrated that BSF significantly inhibited the proliferation of CRC cells in a dose-dependent manner. The apoptotic rate was markedly increased in the 20% BSF group, while colony formation, migration, and invasion capabilities of CRC cells were notably suppressed. Furthermore, Western blot results revealed that BSF enhanced adenomatous polyposis coli (APC) expression and inhibited β-catenin, c-Myc, and Cyclin D1, key proteins in the Wnt/β-catenin pathway. In conclusion, BSF exerts anti-CRC effects by modulating the Wnt/β-catenin pathway, suggesting its potential as a complementary therapeutic agent in CRC treatment. Future studies should focus on in vivo models to validate these findings.

Regulatory role of lnc-MAP3K13-3:1 on miR-6894-3p and SHROOM2 in modulating cellular dynamics in hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is a prevalent primary liver malignancy and a leading cause of cancer-related mortality worldwide. Despite advancements in therapeutic strategies, the 5-year survival rate for individuals undergoing curative resection remains between 10% and 15%. Consequently, identifying molecular targets that specifically inhibit the proliferation and metastasis of HCC cells is critical for improving treatment outcomes. Database analysis using Targetscan identified complementary binding sites for the human-specific miRNA hsa-miR-6894-3p (hereafter referred to as miR-6894-3p) on SHROOM2, and Starbase data suggested a potential regulatory interaction between lnc-MAP3K13-3:1 and miR-6894-3p in liver cancer.ObjectiveThis study aimed to investigate the role of lnc-MAP3K13-3:1 in regulating miR-6894-3p, with a focus on its impact on proliferation, apoptosis, migration, and related cellular processes in liver cancer cells via SHROOM2 regulation.MethodsQuantitative PCR (qPCR) was initially employed to measure the expression levels of lnc-MAP3K13-3:1 and miR-6894-3p in three HCC cell lines: HepG2, HuH-7, and Li-7. Based on these initial assessments, two cell lines were selected for further experimentation. Stable cell lines overexpressing lnc-MAP3K13-3:1 were developed, and cells were transfected with miR-6894-3p mimics or a mimic negative control (NC). After 24 h, qPCR was utilized to quantify the relative expression of lnc-MAP3K13-3:1, miR-6894-3p, SHROOM2, and Caspase9 mRNA in each group. Cell proliferation was analyzed using the cell counting Kit-8 assay, while flow cytometry was used to assess cell cycle distribution and apoptosis. Migration capabilities were evaluated through cell scratch assays, and dual-luciferase assays were utilized to verify interactions between miR-6894-3p, lnc-MAP3K13-3:1, and SHROOM2.ResultsOverexpression of lnc-MAP3K13-3:1 and miR-6894-3p mimic transfection resulted in increased expression of SHROOM2 and Caspase9 mRNA, as demonstrated by qPCR. The miR-6894-3p mimic regulated the activity of lnc-MAP3K13-3:1. Functional assays showed that lnc-MAP3K13-3:1 overexpression inhibited proliferation in HuH-7 and Li-7 cells, promoted apoptosis, reduced migration in Li-7 cells, but enhanced migration in HuH-7 cells. Additionally, lnc-MAP3K13-3:1 overexpression significantly increased the proportion of HuH-7 cells in the G2/M phase and Li-7 cells in the S phase. The miR-6894-3p mimic modulated the effects of lnc-MAP3K13-3:1 on cell proliferation, apoptosis, and migration. Dual-luciferase assays confirmed direct binding between lnc-MAP3K13-3:1 and miR-6894-3p, as well as between miR-6894-3p and SHROOM2.ConclusionThese findings indicate that overexpression of lnc-MAP3K13-3:1 regulates SHROOM2 expression through targeting miR-6894-3p, thereby influencing cell proliferation, apoptosis, migration, and other cellular processes associated with HCC.

Dynamic Multilevel Regulation of EGFR, KRAS, and MYC Oncogenes: Driving Cancer Cell Proliferation Through (Epi)Genetic and Post-Transcriptional/Translational Pathways.

The epidermal growth factor receptor (EGFR) regulates gene expression through two primary mechanisms: as a growth factor in the nucleus, where it translocates upon binding its ligand, or via its intrinsic tyrosine kinase activity in the cytosol, where it modulates key signaling pathways such as RAS/MYC, PI3K, PLCγ, and STAT3. During tumorigenesis, these pathways become deregulated, leading to uncontrolled proliferation, enhanced migratory and metastatic capabilities, evasion of programmed cell death, and resistance to chemotherapy or radiotherapy. The RAS and MYC oncogenes are pivotal in tumorigenesis, driving processes such as resistance to apoptosis, replicative immortality, cellular invasion and metastasis, and metabolic reprogramming. These oncogenes are subject to regulation by a range of epigenetic and post-transcriptional modifications. This review focuses on the deregulation of EGFR, RAS, and MYC expression caused by (epi)genetic alterations and post-translational modifications. It also explores the therapeutic potential of targeting these regulatory proteins, emphasizing the importance of phenotyping neoplastic tissues to inform the treatment of cancer.

Exercise-Intervened Circulating Extracellular Vesicles Alleviate Oxidative Stress in Cerebral Microvascular Endothelial Cells Under Hypertensive Plus Hypoxic Conditions.

Our group has recently demonstrated that exercise intervention affects the release and function of bone marrow endothelial progenitor cell-derived extracellular vesicles (EVs) in transgenic hypertensive mice. Whether such an exercise regimen can impact circulating EVs (cEVs) remains unknown. In this study, we investigated the influence of exercise on cEV level and function. Transgenic hypertensive mice (Alb1-Ren) underwent 8-week treadmill exercise (10 m/min for 1 h, 5 days per week). Age- and sex-matched sedentary Alb1-Ren mice served as controls. cEVs were isolated from the blood of exercised and sedentary mice and are denoted as ET-cEV and nET-cEV, respectively. cEVs were labeled to determine their uptake efficiency and pathways. The functions of cEVs were assessed in an Angiotensin II (Ang II) plus hypoxia-injured cerebral microvascular endothelial cell (mBMEC) injury model. Cellular migration ability and oxidative stress were evaluated. We found that treadmill exercise stimulated cEV release, and ET-cEVs were more prone to be internalized by mBMECs. The ET-cEV internalization was mediated by macropinocytosis and endocytosis pathways. Functional studies showed that ET-cEVs can improve the compromised migration capability of mBMECs challenged by Ang II plus hypoxia. Additionally, ET-cEV treatment upregulated the expression of p-Akt/Akt in mBMECs. Compared to nET-cEVs, ET-cEVs significantly reduced ROS overproduction in Ang II plus hypoxia-injured mBMECs, associated with decreased Nox2 expression. All these findings suggest that exercise-intervened cEVs can protect cerebral microvascular endothelial cells against hypertensive and hypoxic injury.

SEPT5 overexpression predicts poor prognosis and promotes progression through feedback regulation of HIF-1α in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC), a predominant subtype of renal cell carcinoma, significantly contributes to the heightened morbidity and mortality in individuals diagnosed with urologic tumors. The challenges posed by high malignancy at the initial diagnosis of ccRCC, therapeutic resistance, and unfavorable patient prognosis remain largely unresolved. Our findings indicate that SEPT5 is upregulated in ccRCC and this upregulation is associated with an adverse prognosis for ccRCC patients. Furthermore, we demonstrate that overexpression of SEPT5 promotes proliferation of ccRCC cells, alters their cell cycle distribution, and enhances their migratory and invasive capabilities. Additionally, we observe a positive correlation between SEPT5 overexpression and resistance to sorafenib and sunitinib in ccRCC cells. Further mechanistic investigations have revealed that SEPT5 serves as a novel direct transcriptional target of HIF-1α, leading to subsequent reduction in protein expression and nuclear translocation of HIF-1α. This establishes a feedback loop in ccRCC tumorigenesis. Ultimately, knockdown of SEPT5 significantly inhibits xenografted tumor growth in vivo. Overall, this study provides compelling evidence that directly targeting the HIF-1α-SEPT5 feedback axis may be an effective approach for suppressing the proliferation and progression of ccRCC, offering new insights into the diagnosis and treatment of ccRCC patients.

Prognostic Significance of S100A4 in Ovarian Clear Cell Carcinoma: Its Relation to Tumor Progression and Chemoresistance.

S100A4, a small calcium-binding protein, promotes metastasis in a variety of human malignancies, but little is known about its involvement in ovarian clear cell carcinoma (OCCC). Herein, we characterized the functional role of S100A4 in this tumor type. We analyzed immunohistochemical sections from 120 OCCC patients. OCCC cell lines in which S100A4 was knocked out (KO) or overexpressed were also used to study the protein's effects. Stable overexpression of S100A4 decreased the proliferation of OCCC cell lines (concomitant with more cells in G1 and fewer in the G2/M phase of the cell cycle). S100A4 overexpression also reduced susceptibility to cisplatin-induced apoptosis (probably due to an increased BCL2: BAX ratio), accelerated epithelial-mesenchymal transition (EMT)-related cell mobility, and enhanced cancer stem cell (CSC) properties (including increases in both spheroid formation and in the aldehyde dehydrogenase 1 (ALDH1)high population). In contrast, S100A4 KO generally induced the opposite phenotypes, although it did not affect migration capability. In clinical OCCC samples, high S100A4 expression was associated with a low frequency of cleaved poly-(ADP-ribose) polymerase 1-positive apoptotic cells, a reduced proliferative rate, and expression of high ALDH1 and vimentin levels. In addition, a high S100A4 score was a significant (but not independent) prognostic factor in OCCC. Our findings suggest that S100A4 may be an unfavorable prognostic factor in OCCC, as it accelerates tumor progression and promotes chemoresistance through the modulation of proliferation, susceptibility to apoptosis, and EMT/CSC properties.