Synaptotagmin-binding cytoplasmic RNA-interacting protein (SYNCRIP) is an RNA-binding protein (RBP) implicated in the pathogenesis of various cancers through involvement in regulating multiple cellular processes. Notably, this study identified that SYNCRIP expression is significantly elevated in glioblastoma (GBM) and is associated with poor prognosis and tumor progression. Mechanistically, SYNCRIP upregulates SIRT1 expression at both the transcriptional and post-transcriptional levels by stabilizing SIRT1 mRNA. Meanwhile, loss of SYNCRIP leads to reduced SIRT1 expression, accumulation of reactive oxygen species (ROS), and induction of ferroptosis. Notably, restoration of SIRT1 rescues cells from ferroptotic cell death, supporting the critical role of SIRT1 in SYNCRIP-mediated ferroptosis resistance. SYNCRIP also enhances hexokinase 2 (HK2) expression through transcriptional activation and internal ribosome entry site (IRES)-mediated translation, thereby promoting glycolytic activity in GBM. Furthermore, depletion of SYNCRIP results in mitochondrial dysfunction and impairs GBM cell migration and invasion by downregulating epithelial-mesenchymal transition (EMT)-associated factors. Collectively, these findings suggest that SYNCRIP is a key regulator of GBM progression by maintaining metabolic homeostasis and ferroptosis resistance, highlighting SYNCRIP as a potential therapeutic target in GBM.

Glioblastoma (GBM), the most common and aggressive primary brain tumor, exhibits profound metabolic reprograming that sustains its progression and therapy resistance. Our previously published work demonstrated that C3G expression is downregulated in GBM, which enhances migration and invasion. Here, we show that C3G silencing or knockout in GBM cells reprograms glucose metabolism favoring glycolysis and lactate production through upregulation of PKM2 and LDHA. Furthermore, Seahorse metabolic profiling further revealed increased respiratory capacity and glycolysis upon C3G downregulation or depletion. Mechanistically, C3G silencing increases the levels of the splicing factor PTBP1, which forces PKM splicing towards PKM2 expression as demonstrated by transient PTBP1 silencing, although other splicing factors such as SRSF3 could also contribute to PKM2 expression. Additionally, C3G downregulation or depletion enhances sphere formation, stemness and tumor initiating capacity in GBM cells, which is rescued by C3G re-expression in C3G knockout GBM cells. This enhanced stemness induced by C3G silencing in GBM cells is prevented by transient PTBP1 or PKM2 silencing or pharmacological inhibition of PKM2 with compound 3K, which also decreases cell viability within the spheres (3D-cell cultures) and the expression of stemness markers. However, in 2D-cell cultures compound 3K increases cell viability in C3G-silenced GBM cells, while decreasing that of C3G knockout cells. This supports a specific role for C3G/PKM2 axis in GBM cancer stem cells through mechanisms likely dependent on both PKM2-mediated metabolic reprogramming and nuclear effects on gene transcription. Altogether, our findings identify C3G as a novel regulator of GBM metabolism and stemness acting through PKM2, unveiling new potential diagnostic and therapeutic implications for C3G in a subset of GBM patients.

Tumor-immune cell interactions critically contribute to the progression of non-small cell lung cancer (NSCLC). In this study, we investigated the role of WNT1-inducible signaling pathway protein 3 (WISP-3) in regulating tumor cell adhesion and the underlying molecular mechanisms in lung adenocarcinoma cells. Treatment with recombinant WISP-3 significantly increased intercellular adhesion molecule-4 (ICAM-4) expression at both mRNA and protein levels in A549 and H1299 cells in a dose-dependent manner. Consistently, WISP-3 enhanced tumor-monocyte adhesion, indicating its involvement in tumor-immune cell interactions. Mechanistically, WISP-3 stimulated rapid activation of the MEK/ERK signaling cascade, as demonstrated by increased phosphorylation of MEK and ERK. Pharmacological inhibition of MEK using PD98059 or U0126, as well as direct inhibition of ERK with SCH772984, markedly attenuated WISP-3-induced ICAM-4 expression and THP-1 adhesion. These findings were further supported by siRNA-mediated knockdown of MEK or ERK, confirming the essential role of this pathway. In addition, WISP-3 suppressed the expression of hsa-miR-12131, which was identified as a negative regulator of ICAM-4. Restoration of hsa-miR-12131 significantly reduced ICAM-4 expression and impaired tumor-monocyte adhesion, indicating that miR-12131 functions downstream of MEK/ERK signaling. Collectively, these results demonstrate that WISP-3 promotes ICAM-4-dependent monocyte adhesion through activation of the MEK/ERK pathway and subsequent suppression of hsa-miR-12131. This WISP-3/MEK/ERK/miR-12131/ICAM-4 axis provides new insight into tumor-immune interactions in NSCLC and highlights potential therapeutic targets.

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) selectively induces apoptosis in cancer cells. However, many cancer cells are resistant to TRAIL because of downregulation of death receptors (DRs) and overexpression of anti-apoptotic proteins. Ubiquitin-conjugating enzyme E2N (UBE2N), also known as Ubc13, plays a central role in ubiquitin-mediated cellular activities. In this study, we aimed to explore the sensitization effect of UBE2N inhibition in TRAIL-mediated apoptosis in cancer cells. NSC697923 (a potent inhibitor of UBE2N) alone and TRAIL alone did not induce apoptosis in renal carcinoma Caki cells. However, combined treatment with NSC697923 and TRAIL significantly enhanced apoptotic cell death in cancer cells, but not in normal cells. Mechanistically, NSC697923 induced upregulation of DR5 mRNA and protein levels through CHOP-mediated DR5 transcriptional activation and ubiquitin-mediated DR5 stabilization. NSC697923-mediated DR5 mRNA upregulation was regulated by upregulation of CHOP expression, a key transcriptional factor of DR5. CHOP siRNA treatment inhibited NSC697923-mediated DR5 protein expression. Moreover, NSC697923 generated ROS, and pretreatment with ROS scavengers inhibited DR5 upregulation and NSC697923 plus TRAIL-mediated cell death. These findings suggest that UBE2N inhibitor enhances TRAIL-induced apoptosis by DR5 upregulation and UBE2N inhibition may serve as a potential strategy to overcome TRAIL resistance in cancer therapy.

Oral squamous cell carcinoma (OSCC) frequently metastasizes, leading to poor patient outcomes. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) has been implicated in cancer progression; however, the downstream mechanism driving OSCC motility remains incompletely defined. Cyr61 expression was elevated in OSCC and associated with advanced clinicopathological features. In OSCC cell lines, recombinant Cyr61 enhanced wound closure and Transwell migration and increased intercellular adhesion molecule-1 (ICAM-1) expression at both the mRNA and protein levels. ICAM-1 silencing significantly attenuated Cyr61-induced cell motility, indicating that ICAM-1 is an important downstream effector. Mechanistically, Cyr61 signaling was initiated through integrin αvβ3 and αvβ5, as neutralizing antibodies and siRNAs targeting these integrins suppressed Cyr61-induced migration and ICAM-1 expression. Cyr61 also induced phosphorylation of PLC, PKC, and c-Src, and pharmacological or siRNA-mediated inhibition of these kinases attenuated ICAM-1 upregulation and cell migration. Moreover, Cyr61 enhanced AP-1 activity via c-Jun phosphorylation, increased c-Jun occupancy at the ICAM-1 promoter, and inhibition of AP-1 signaling diminished Cyr61-driven ICAM-1 expression and motility. Together, these data define an integrin αvβ3/αvβ5-PLC-PKC-c-Src-AP-1 axis that transcriptionally upregulates ICAM-1, promoting OSCC migration and providing a mechanistic basis for targeting Cyr61-driven migratory programs in OSCC.

ObjectiveTo investigate whether naringin enhances the chemosensitivity of nasopharyngeal carcinoma-derived CNE2 cells to paclitaxel and identify potential molecular mediators.MethodsCNE2 cells were treated with naringin alone or in combination with paclitaxel, cisplatin, or 5-fluorouracil. Cell viability, proliferation, and migration were assessed using cell counting kit-8 and Transwell assays. Transcriptomic profiling followed by bioinformatic analysis of Gene Expression Omnibus datasets (GSE53819, GSE12452, and GSE102349) was performed to identify nasopharyngeal carcinoma prognosis-related genes. AKR1C3 overexpression was established via lentiviral transduction, and pharmacological inhibition was performed using ASP9521. mRNA and protein expression were validated using reverse transcription quantitative polymerase chain reaction and Western blot analysis.ResultsNaringin (160 μM) demonstrated a trend toward reducing the half-maximal inhibitory concentration of paclitaxel from 10.52 to 8.04 nM; however, it did not significantly alter sensitivity to cisplatin or 5-fluorouracil. Combined treatment with 2 nM paclitaxel and 160 μM naringin synergistically suppressed CNE2 proliferation and migration compared with that using either agent alone (p < 0.05). Bioinformatic analysis revealed that high AKR1C3 expression was correlated with improved survival in patients with nasopharyngeal carcinoma (p < 0.05), whereas high PAIP1, PRKDC, PTPRR, and COL12A1 expressions were correlated with poorer outcomes. Reverse transcription quantitative polymerase chain reaction confirmed that both naringin and paclitaxel upregulated AKR1C3 mRNA, with the combination producing the strongest effect. Gain-of-function studies demonstrated that AKR1C3 overexpression significantly enhanced paclitaxel sensitivity, with half-maximal inhibitory concentration values decreasing from 13.63 to 6.994 nM in CNE2 cells and from 8.534 to 4.668 nM in CNE1 cells. Furthermore, the specific AKR1C3 inhibitor, ASP9521, significantly attenuated the synergistic anti-proliferative and anti-migratory effects of paclitaxel + naringin in CNE2 cells, confirming that naringin enhances chemosensitivity to paclitaxel by upregulating AKR1C3 expression.ConclusionsNaringin sensitizes CNE2 cells to paclitaxel, potentially via AKR1C3 upregulation. This flavonoid may represent a low-toxicity adjunct to enhance the efficacy of paclitaxel in nasopharyngeal carcinoma.

The objective of this study was to investigate the inhibitory effects and underlying molecular mechanisms of Isorhamnetin-3-O-neohesperidoside (IHN), a naturally occurring O-methylated flavonol, against human hepatocellular carcinoma (HepG2) cells, with a particular focus on its impact on cell proliferation, apoptosis, metabolic regulation, and oxidative stress.

Human liver cancer HepG2 cells were treated with varying concentrations of IHN for 24 and 48 hours. The cytotoxic and anti-proliferative effects were assessed using standard cytotoxicity assays. Flow cytometry was performed to analyze cell cycle distribution and apoptosis induction. Metabolic assays evaluated glucose uptake and lactate dehydrogenase A (LDH-A) activity to assess the Warburg effect. Oxidative stress markers were analyzed by measuring reactive oxygen species (ROS), lipid peroxidation, and the glutathione (GSH/GSSG) ratio. Quantitative real-time PCR (qRT-PCR) was used to determine the expression of key regulatory genes.

IHN exhibited potent, dose- and time-dependent cytotoxicity against HepG2 cells, with Half-maximal inhibitory concentration (IC₅₀) values decreasing from 161.22 μM (24 h) to 95.87 μM (48 h). IHN- induced G0/G1 cell cycle arrest accompanied by the upregulation of Cyclin-dependent kinase inhibitor 1A (CDKN1A/p21) and promoted apoptosis through the intrinsic pathway, as shown by increased expression of BCL2-associated X Protein (BAX), Caspase-3 (CASP-3), and Caspase-9 (CASP-9). Metabolically, IHN suppressed the Warburg effect, leading to reduced glucose uptake and decreased LDH-A activity. This was associated with a marked increase in ROS levels and lipid peroxidation, along with depletion of GSH/GSSG and downregulation of antioxidant genes, indicating severe oxidative stress.

IHN exerts significant anti-hepatocellular carcinoma activity by targeting multiple oncogenic pathways. Its mechanism involves cell cycle arrest, intrinsic apoptosis induction, metabolic suppression, and redox imbalance. These findings suggest that IHN is a promising multi-target natural compound that exploits the metabolic and oxidative vulnerabilities of HepG2 cells, highlighting its potential as a novel therapeutic candidate for hepatocellular carcinoma.

Cholangiocarcinoma (CCA) has been noted to have increasing mortality globally. This study aims to evaluate the demographic, racial and geographic trends in CCA mortality across the United States.

Data was extracted through Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research by using ICD-10 codes C22.1, C24.0, C24.8 and C24.9 for people over 65 years of age, for the years 1999-2023. Age-adjusted mortality rates (AAMR) per 1,000,000 individuals and annual percentage changes (APC), with 95% confidence intervals, were analyzed across various demographic groups and geographical regions through Joinpoint regression. Negative Binomial Regression was utilized to compute adjusted Incidence Rate Ratios (IRRs), with South Dakota (SD) as the reference.

Our analysis revealed a total of 131,125 deaths in the United States from 1999 to 2023 due to CCA. Overall, there was a consistent increasing trend in the AAMR from 90.8 to 163.1 per 1,000,000 (AAPC: 2.40, 95% CI: 2.15 to 2.65). Males had a consistently higher AAMR than females across all years. African American population showed the highest increase in AAMR over the study years (AAPC: 3.36). Highest CCA-related mortality was seen in Rhode Island, followed by Massachusetts. Highest increase in mortality over the period was seen in Louisiana (AAPC 3.38, 95% CI: 1.70-5.10). Based on negative binomial regression, each one-year increase was associated with approximately 1% increase in AAMR (IRR=1.021, 95% CI: 1.020-1.022). Alaska had a 66% higher (IRR 1.66) and Rhode Island had a 23% higher incidence of mortality (IRR 1.23) when compared to SD. Mississippi had the lowest incidence of mortality, 51% less when compared to SD (IRR 0.49).

The upward trajectory of CCA mortality is disproportionately higher in some states and underscores the need for additional research aimed at understanding risk factors driving this increase.

Biliary cystadenomas are rare hepatobiliary tumors in cats and are usually characterized by cystic proliferation of the bile duct epithelium. A ten-year-old castrated male British Shorthair cat was brought to the clinic with complaints of abdominal distension and intermittent vomiting. Ultrasound, computed tomography, and magnetic resonance imaging revealed a large, multilocular cystic mass involving multiple hepatic lobes. Hematological and biochemical examinations revealed mild preoperative changes. Postoperative biochemical abnormalities consistent with hepatic dysfunction were observed. Under general anesthesia, resection of the gallbladder, including multiple liver lobes, was performed. Histopathological examination confirmed the diagnosis of biliary cystadenoma. Despite surgical resection and postoperative supportive care, the patient's general condition deteriorated, and the patient died one week after the operation. This case highlights the diagnostic challenges of distinguishing biliary cystadenomas from malignant hepatic neoplasms and the importance of histopathological evaluation for definitive diagnosis. Furthermore, while surgical resection is the gold standard of treatment, the extent of the lesion and postoperative complications significantly influence prognosis.

In the ever-evolving landscape of global health, Health and Demographic Surveillance Systems (HDSS) generate rare and valuable longitudinal data for understanding health and population dynamics and their determinants in low- and middle-income countries, where vital registration systems are often weak. However, the utility of HDSS centres relies heavily on the capabilities of those responsible for cleaning, describing and analysing the wealth of data they generate. This paper describes our targeted strategy for strengthening the capacity of personnel in HDSS research settings, particularly focusing on data managers and analysts. Additionally, we explore the unique challenges created by the COVID-19 pandemic for HDSS research centres, emphasizing the need for a skilled workforce to navigate complex data dynamics. Our approach involved three in-person workshops dedicated to data preparation, analysis, and scientific writing, supplemented by weekly online check-ins and a 25-week writing program. Each workshop included two representatives from participating sites with skills aligned to the workshops. Following two years of intensive capacity building, this project has yielded 15 original research manuscripts currently under review, forming part of a journal special issue on the impact of COVID-19 on mortality in African and South Asian populations. Open-access aggregated data will complement these papers.