Cancer Poor Prognosis Research Articles

CT-based radiomics model for predicting perineural invasion status in gastric cancer.

Perineural invasion (PNI) is an independent risk factor for poor prognosis in gastric cancer (GC) patients. This study aimed to develop and validate predictive models based on CT imaging and clinical features to predict PNI status in GC patients. This retrospective study included 291 GC patients (229 in the training cohort and 62 in the validation cohort) who underwent gastrectomy between January 2020 and August 2022. The clinical data and preoperative abdominal contrast-enhanced computed tomography (CECT) images were collected. Radiomics features were extracted from the venous phase of CECT images. The intraclass correlation coefficient (ICC), Pearson correlation coefficient, and t-test were applied for radiomics feature selection. The random forest algorithm was used to construct a radiomics signature and calculate the radiomics feature score (Rad-score). A hybrid model was built by aggregating the Rad-score and clinical predictors. The area under the receiver operating characteristic curve (ROC) and decision curve analysis (DCA) were used to evaluate the prediction performance of the radiomics, clinical, and hybrid models. A total of 994 radiomics features were extracted from the venous phase images of each patient. Finally, 5 radiomics features were selected and used to construct a radiomics signature. The hybrid model demonstrated strong predictive ability for PNI, with AUCs of 0.833 (95% CI: 0.779-0.887) and 0.806 (95% CI: 0.628-0.983) in the training and validation cohorts, respectively. The DCA showed that the hybrid model had good clinical utility. We established three models, and the hybrid model that combined the Rad-score and clinical predictors had a high potential for predicting PNI in GC patients.

HPRT1: a preliminary investigation on its involvement in nasopharyngeal carcinoma.

Accumulating evidences have stressed the association between hypoxanthine phosphoribosyl transferase 1 (HPRT1) overexpression and the poor prognosis of various cancers. Our study, herein, preliminarily investigates the involvement of HPRT1 in nasopharyngeal carcinoma (NPC). Data from TCGA were applied to read HPRT1 expression in diverse cancers including NPC and to predict the prognosis of NPC patients. The total RNA and protein from NPC cells and nasopharyngeal epithelial cells NP460 were extracted to quantify HPRT1 expression. Following the completion of transfection, the proliferation and migration of NPC cells were determined employing MTT, colony formation and western blot assay (the quantification on expressions of protein related to proliferation and migration). HPRT1 was differentially expressed in diverse cancers yet particularly highly expressed in NPC, and high HPRT1 expression was related to the poor prognosis of NPC patients. Also, HPRT1 expression was higher in NPC cells and its silencing diminished the viability and proliferation of NPC cells and reduced the expressions of CyclinD1, CyclinE, Multidrug Resistance Protein 1 (MDR1), matrix metalloproteinase (MMP)-2, and MMP-9. This study preliminarily explored the involvement of HPRT1 in NPC based on some cellular assays in vitro, which may provide evidence for investigating the specific mechanism underlying the effects of HPRT1 in cancers.

Over-expression of Transmembrane Protein 158 Predicts Aggressive Tumor Behavior and Poor Prognosis in Lung Cancer.

Transmembrane protein 158 (TMEM158) has emerged as a potential contributor to cancer progression. While TMEM158 has been studied in various cancer types, its role in lung cancer remains unclear. Kaplan-Meier curves were used to evaluate the association between TMEM158 expression and overall survival rates. Gene set enrichment analysis (GSEA) was performed to explore pathways related to TMEM158, and sequence analysis was conducted to identify putative hypoxia-responsive element (HRE) sites in the TMEM158 promoter region. Hypoxic conditions were induced, and TMEM158 expression levels were measured by qPCR. The effect of hypoxia-inducible factor-1α (HIF-1α) depletion on TMEM158 expression was also examined. Additionally, lung cancer cells with either over-expressed or reduced TMEM158 levels were analyzed for epithelial-mesenchymal transition (EMT) and cell migration. Analysis of clinical datasets revealed elevated TMEM158 expression in tumors, particularly in patients with advanced stages. High TMEM158 expression was correlated with lower overall survival. TMEM158 was associated with EMT, hypoxia, and other tumor-promoting pathways. Under hypoxic conditions, TMEM158 expression was at least partially induced in a HIF-1α-dependent manner. Functional studies showed that over-expression of TMEM158 promoted EMT and increased lung cancer cell migration, while depletion of TMEM158 reduced these effects, indicating its role in aggressive tumor behavior. TMEM158 is highly expressed in lung cancer, is associated with hypoxia, and promotes EMT and cell migration. These findings suggest TMEM158 as a potential target for lung cancer therapies.

Attenuated titin protein expression correlates with poor prognosis in ovarian cancer

Attenuated titin protein expression correlates with poor prognosis in ovarian cancer

Exploring treatment decision-making at diagnosis for children with advanced cancer in low- and middle-income countries

PurposeGlobal childhood cancer survival outcomes correlate with regional contextual factors, yet upfront treatment decision-making for children with advanced or poor prognosis cancer in low- and middle-income countries (LMICs) is not well understood. This study aimed to (1) characterize the landscape of contextual factors that shape physician decision-making at diagnosis for these children in LMICs and (2) describe physician rationales for if/when to offer treatment with non-curative intent, including how they define “poor prognosis” during treatment decision-making.MethodsAn international panel of pediatric oncologists practicing in LMICs participated in two focus groups structured for the collaborative generation of factors influencing treatment decision-making, including consideration of non-curative treatment pathways at diagnosis. Thematic analysis of qualitative data was conducted, followed by member checking.ResultsEleven pediatric oncologists participated, representing all global regions defined by the World Health Organization. Participants identified a broad range of factors influencing decision-making across multiple levels, including the individual, hospital, health system, community, and country levels. All participants agreed that treatment with non-curative intent could be offered at diagnosis in certain contexts, and diverse definitions for poor prognosis were described.ConclusionsUpfront treatment decision-making for children with advanced or poor prognosis cancer in LMICs is variable and challenging. Difficulties with decision-making in LMICs may be amplified by inconsistent definitions of poor prognosis and underrepresentation of the factors that influence treatment decision-making within existing decision-making frameworks or childhood cancer treatment guidelines. Future research should explore decision-making approaches, preferences, and challenges in depth from the perspectives of pediatric cancer patients, families, and multidisciplinary clinicians.

Forkhead box D subfamily genes in colorectal cancer: potential biomarkers and therapeutic targets.

The forkhead box (FOX) family members regulate gene transcription and expression. FOX family members regulate various biological processes, such as cell proliferation and tumorigenesis. FOXD, a FOX protein subfamily, is associated with poor prognosis for various cancers. However, the potential clinical value of FOXD subfamily members in colorectal cancer (CRC) has not yet been elucidated. Therefore, in this study, we aimed to determine the role of the FOXD subfamily members in CRC development. Using HTSeq-count data, clinical data, and single-nucleotide polymorphisms (obtained from The Cancer Genome Atlas Project), and bioinformatics analyses (using DESEQ2 software), we identified differentially expressed genes (DEGs) in CRC. Next, each DEG expression was validated in vitro using reverse transcription-quantitative polymerase chain reaction, western blotting, and immunohistochemistry (IHC). Among the FOXD subfamily members, the area under the receiver operating characteristic curve of FOXD3 was 0.949, indicating that FOXD3 has a high overall diagnostic accuracy for CRC. Gene Set Enrichment Analysis revealed that FOXD-DEGs were mainly related to pathways such as cytokine, cytokine, and extracellular matrix receptor interactions. Kaplan-Meier curves and nomograms showed that FOXD1, FOXD3, and FOXD4 were prognostically significant. In conclusion, FOXD subfamily members (especially FOXD3) could serve as diagnostic and prognostic biomarkers for CRC and an immunotherapy target in patients with CRC.

CHAC1: a master regulator of oxidative stress and ferroptosis in human diseases and cancers

CHAC1, an essential regulator of oxidative stress and ferroptosis, is increasingly recognized for its significant roles in these cellular processes and its impact on various human diseases and cancers. This review aims to provide a comprehensive overview of CHAC1’s molecular functions, regulatory mechanisms, and effects in different pathological contexts. Specifically, the study objectives are to elucidate the biochemical pathways involving CHAC1, explore its regulatory network, and discuss its implications in disease progression and potential therapeutic strategies. As a γ-glutamyl cyclotransferase, CHAC1 degrades glutathione, affecting calcium signaling and mitochondrial function. Its regulation involves transcription factors like ATF4 and ATF3, which control CHAC1 mRNA expression. CHAC1 is crucial for maintaining redox balance and regulating cell death pathways in cancer. Its elevated levels are associated with poor prognosis in many cancers, indicating its potential as a biomarker and therapeutic target. Additionally, CHAC1 influences non-cancerous diseases such as neurodegenerative and cardiovascular disorders. Therapeutically, targeting CHAC1 could increase cancer cell sensitivity to ferroptosis, aiding in overcoming resistance to standard treatments. This review compiles current knowledge and recent discoveries, emphasizing CHAC1’s vital role in human diseases and its potential in diagnostic and therapeutic applications.

Fructose-bisphosphate Aldolase C Expression is Associated with Poor Prognosis and Stemness in Gastric Cancer

Fructose-bisphosphate Aldolase C Expression is Associated with Poor Prognosis and Stemness in Gastric Cancer

Human adipose-derived stem cells promote migration of papillary thyroid cancer cell via leptin pathway

Introduction Obesity is associated with the incidence and poor prognosis of thyroid cancer, but the mechanism is not fully understood. The aim of this study was to investigate the effects of human adipose-derived stem cells (ADSCs) on the invasion and migration of thyroid cancer cells. Methods ADSCs-conditioned medium (ADSC-CM) was collected to culture thyroid cancer cell lines TPC-1 cells and BCPAP cells. The effects of ADSCs on thyroid cancer cell proliferation were determined by CCK8 and EdU assays, and the effects on migration were determined by Transwell and wound closure assays. Leptin neutralizing antibodies (NAB) were added to ADSC-CM to block leptin. In animal experiments, TPC-1 cells and BCPAP cells were injected into the tail vein of nude mice, and the leptin receptor antagonist peptide allo-aca was injected subcutaneously to block the leptin pathway. The number and size of metastatic lung tumours were observed after 8 weeks. Results ADSC-CM significantly promoted the invasion and migration of thyroid cancer cells and upregulated their matrix metalloproteinase 2 (MMP-2) levels, while NAB with the addition of leptin reduced the invasion and migration of thyroid cancer cells and downregulated MMP-2 levels. Allo-aca treatment reduced the number of metastatic lung nodules formed by thyroid cancer cells in nude mice and reduced the diameter of metastatic lesions. Conclusion ADSCs upregulate MMP-2 levels of thyroid cancer cells through exocrine leptin, thereby promoting cancer cell migration, which may be one of the key mechanisms by which obesity increases the invasiveness of thyroid cancer.

LINC01518 predicts poor prognosis of prostate cancer and promotes its progression by regulating hsa-miR-320a/CNKSR2 axis

BackgroundProstate cancer (PCa) is the most common malignancy of the male genitourinary system. Understanding the molecular mechanism of PCa and its prognostic markers will assist in the selection of better treatment.AimTo explore the role of LINC01518 in the development of PCa and its prognostic value, and to understand its specific regulatory mechanism.MethodsThe levels of LINC01518, hsa-miR-320a, and CNKSR2 mRNA were detected by RT-qPCR. ROC curve was constructed to evaluate the prognostic value of LINC01518 in PCa. The effects of LINC01518 on the functions of PCa cells were demonstrated by CCK-8, Transwell test, and the detection of apoptotic markers, after LINC01518 knockdown. The interaction between hsa-miR-320a and LINC01518 or CNKSR2 mRNA was examined by constructing luciferase vectors.ResultsLINC01518 was abnormally expressed in PCa cells and tumor tissues, and knockdown of it inhibited the growth of PCa cells. LINC01518 predicted castration-resistant prostate cancer (CRPC) outcomes in PCa patients with AUC of 0.803, sensitivity and specificity of 75.4% and 74.6%, respectively. Hsa-miR-320a mimics reduced luciferase activity in PCa cells transfected with WT-LINC01518/CNKSR2 plasmids. Knocking down LINC01518 reduced CNKSR2 level, and this regulatory effect disappeared with the inhibition of hsa-miR-320a.ConclusionHigh levels of LINC01518 predicted poor prognosis in PCa patients and promoted CNKSR2 expression by competitively binding hsa-miR-320a, contributing to the progression of PCa.

Association between fish oil and glucosamine use and mortality in patients diagnosed with cancer: the role of the Life Essential 8 score and cancer prognosis

BackgroundThe effect of supplements on mortality risk in patients with cancer remains uncertain and has scarcely been investigated in subgroups of patients with varying characteristics. This study aimed to investigate the association between two popular supplements, fish oil and glucosamine, and mortality risk in a large population-based cohort and determine whether cardiovascular health and clinical prognosis influence these associations.MethodsThis prospective cohort study analyzed the data of UK Biobank participants who were diagnosed with cancer. The associations of fish oil and glucosamine consumption with mortality were analyzed using Cox proportional hazards models. Subgroup analyses were performed to assess the effects of Life Essential 8 [LE8] scores (a measure of cardiovascular health) and cancer prognosis (grouped according to the survival rates of specific cancer types) on the associations between supplement use and mortality.ResultsThis analysis included 14,920 participants (mean age = 59.9 years; 60.2% female). One third (34.1%) of the participants reported using fish oil, and one fifth (20.5%) reported using glucosamine. Over a median follow-up of 12.0 years, 2,708 all-cause deaths were registered. The use of fish oil was associated with reduced risks of all-cause mortality (adjusted hazard ratio [aHR] = 0.89, 95% Confidence Interval [CI] = 0.81–0.97) and cancer mortality (aHR = 0.89, 95% CI = 0.81–0.98). Similarly, glucosamine use was associated with reduced risks of all-cause mortality (aHR = 0.83, 95% CI = 0.74–0.92) and cancer mortality (aHR = 0.83, 95% CI = 0.74–0.93) in the fully adjusted model. Subgroup analyses revealed that the protective effects of fish oil and glucosamine against mortality risk were only observed in patients with LE8 scores lower than the mean score or a poor cancer prognosis. Additionally, the association between glucosamine use and a reduced risk of CVD-related mortality was only observed in patients with lower LE8 scores.ConclusionsThis large cohort study identified the potential differential impact of LE8 scores and cancer prognosis on the associations of fish oil and glucosamine supplementation with survival in patients with cancer. This suggests the importance of considering these factors in future research on supplements and in the provision of personalized integrative cancer care.

Prognostic value of miR-190a-5p in renal cell cancer and its regulatory effect on tumor progression.

As a usual malignant tumor in urinary system, renal cell cancer is regulated by microRNAs (miRNAs). This study revealed the prognostic value and regulatory effect of miR-190a-5p in renal cell cancer patients. A total of 253 renal cell cancer patients were included for prognostic value analysis. The target gene of miR-190a-5p was detected by luciferase reporter assay. Cell Counting Kit-8 analysis and Transwell analysis were performed to explore the proliferation, removal capability, and invasiveness of 786-0 and A498 cells. Prognostic value was calculated by Kaplan-Meier curve and Cox regression analysis. miR-190a-5p was more down-regulated in tumor tissues than in adjacent tissues. Renal cell cancer cases were differed as low and high groups ground on mean miR-190a-5p expression in tumor tissues. Overall survival probability was obviously high in patients with high miR-190a-5p level (log-rank test P = 0.011). Cox regression analysis revealed that miR-190a-5p expression (relative risk (RR) = 1.751, 95% confidence interval (CI) = 1.057-2.900, P = 0.030) and tumor node metastasis stage (RR = 1.719, 95% CI = 1.059-2.792, P = 0.028) were specialty indicators for poor renal cell cancer prognosis. GDF11 was directly targeting miR-190a-5p. Overexpressed miR-190a-5p could reduce the GDF11 expression, proliferation, removal capability, and invasiveness of renal cell cancer 786-0 and A498 cells. Elevated GDF11 could lead to a changeover of proliferation, removal capability, and invasiveness inhibition, which is induced by miR-190a-5p. miR-190a-5p was reduced in renal cell cancer tissues, and predicted worse outcomes of renal cell cancer cases. Overexpressed miR-190a-5p could restrain the proliferation, removal capability, and invasiveness of renal cell cancer cells via suppressing GDF11.

Pre-treatment of hyponatremia as a biomarker for poor immune prognosis in advanced or metastatic gastric cancer: A retrospective case analysis

ABSTRACT Hyponatremia, a prevalent electrolyte imbalance among tumor patients, has often been overlooked regarding its prognostic significance for immunotherapy. In this study, we delved into the prognostic ramifications of hyponatremia in advanced gastric cancer (AGC) patients undergoing immunotherapy. Enrolling AGC patients diagnosed between December 2014 and May 2021, we extracted pertinent data from electronic medical records, with a median follow-up of 35.8 months. Kaplan–Meier curves illuminated patients’ progression-free survival (PFS) and overall survival (OS), while survival disparities were tested using the Mantel–Haenszel log rank test. COX and logistic regressions were employed to scrutinize the correlation between serum sodium levels and prognosis in 268 AGC patients, both at baseline and during treatment. Notably, patients with hyponatremia exhibited shorter PFS (4.7 vs 2.1 months, p = .001*) and OS (12.5 vs 3.9 months, p < .001*). Serum sodium emerged as an independent prognostic factor for both PFS (HR = 1.773; 95% CI 1.067–2.945; p = .001*) and OS (HR = 1.773; 95% CI 1.067–2.945; p = .003*). Subgroup analysis revealed that AGC patients with hyponatremia derived no benefit from immunotherapy in terms of PFS and OS. Strikingly, a decrease in serum sodium during immunotherapy was associated with early relapse and mortality. Based on these findings, we hypothesize that hyponatremia portends poor prognostic outcomes in AGC patients treated with immunotherapy and may serve as a valuable prognostic biomarker. However, further large-scale prospective studies are warranted to validate these observations.

ROR1 MRNA EXPRESSION IN GLIOMA - A NOVEL PROGNOSTIC BIOMARKER

Abstract AIMS Glioblastoma is the most common and aggressive primary brain tumour in adults. Despite maximal surgical resection followed by concomitant chemo-/radiotherapy, the three-year survival remains less than 5%. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) overexpression is associated with poor prognosis in several cancers. ROR1 therapeutics are in Phase I/II clinical trials making it an exciting novel target with translational potential to explore for glioblastoma treatment. The aim of this study was to examine the association between ROR1 mRNA expression and overall survival (OS), by applying the WHO 2021 classification of transcriptomic glioma datasets. METHOD Clinical, histological, and molecular data were extracted from four independent glioma datasets (TCGA, CGGA, Rembrandt, and Gravendeel) via the GlioVis portal and analysed using the WHO 2021 classification. Only confirmed cases of astrocytoma, oligodendroglioma, or glioblastoma, and ROR1 mRNA expression data were included (2,216 cases). Kaplan-Meier survival curves were produced for OS with low/high grade glioma versus ROR1 mRNA expression. Log-rank (Mantel-Cox) multivariate regression was applied to analyse the effect of selected covariates on OS and ROR1 mRNA expression. RESULTS We observed a significant decrease in median OS in patients with high-ROR1 mRNA expression when compared to the low-ROR1 mRNA expression cohort (20 and 70 months, respectively). High-grade gliomas represented the highest ROR1 mRNA expression across the consortium, resulting in a poor median OS of 16 months. CONCLUSION This study represents the first report of an association between OS and the oncogenic role of ROR1 in glioma, a targetable cell surface marker for novel putative treatment in glioblastoma.

Lateral node metastasis in low rectal cancer as a hallmark to predict recurrence patterns.

Lateral node metastasis confers a poor prognosis in rectal cancer. Several multidisciplinary treatments have been proposed with favorable outcomes. However, appropriate neoadjuvant/adjuvant treatments or follow-up plans based on information about the probable recurrence site have not been specified. We aimed to clarify the distinctive features of recurrence patterns for lateral node-positive low rectal cancer according to the lateral and mesorectal lymph node status. We retrospectively analyzed 508 patients with stage III low rectal cancer who underwent lateral node dissection. We investigated the impact of lateral and mesorectal lymph node status on site-specific recurrence rates and patient survival. Analyses for relapse-free survival revealed the prognostic impact of lateral node positivity in stage III low rectal cancer (p < 0.0001). Lateral node-positive patients exhibited higher risk of overall recurrence, local recurrence, and recurrence in extra-regional nodes than lateral node-negative patients (p < 0.0001, p = 0.001, and p < 0.0001, respectively). However, lateral node positivity was not statistically associated with a hematogenous recurrence rate. In lateral node-positive patients, both tumor-node-metastasis (TNM)-N status and number of lateral nodes involved were revealed as significant prognostic factors (p < 0.0001, both). In addition, the number of lateral nodes involved could be a discriminatory indicator of probabilities of local recurrence and recurrence in extra-regional nodes (p = 0.02, and p < 0.0001, respectively). Lateral node-positive low rectal cancer exhibits higher local recurrence and extra-regional node recurrence rates that correlate with the number of lateral nodes involved.

The clinicopathological and prognostic significance of PSMD14 in cancers based on bioinformatics and meta-analysis.

Aim: To evaluate the clinic-pathological features and prognostic value regarding PSMD14 in cancers.Materials & methods: Literature was gathered from public databases until 22June2023 to analyze data on survival rates and clinicopathological characteristics associated with PSMD14. TCGA and GEO data were also utilized for validation.Results: Eight reports on seven types of tumors showed that high PSMD14 expression was linked to poorer overall survival and disease-free survival. PSMD14 expression also correlated with larger tumor size, differentiationand metastasis, as well as the effectiveness of various chemotherapy drugs.Conclusion: PSMD14 could serve as a potential biomarker of poor prognosis in cancers, including lung cancer, head and neck squamous cell carcinoma, ovarian cancer, breast cancer and hepatocellular carcinoma.

Tumor-associated macrophages/C-X-C motif chemokine ligand 1 promotes breast cancer autophagy-mediated chemoresistance via IGF1R/STAT3/HMGB1 signaling

Autophagy-mediated chemoresistance is the core mechanism for therapeutic failure and poor prognosis in breast cancer. Breast cancer chemotherapy resistance is believed to be influenced by tumor-associated macrophages (TAMs), by which C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant cytokine secreted. Yet, its role in mediating autophagy-related chemoresistance is still unknown. This study aimed to explore the molecular mechanisms by which TAMs/CXCL1 induced autophagy-mediated chemoresistance in breast cancer. It was found that TAMs/CXCL1 promoted chemoresistance of breast cancer cells through autophagy activation in vitro, and CXCL1 silence could enhance the chemosensitivity of paclitaxel-resistant breast cancer cells via autophagy inhibition. A high-throughput quantitative PCR chip and subsequent target validation showed that CXCL1 induced autophagy-mediated chemoresistance by inhibiting VHL-mediated IGF1R ubiquitination. The elevated IGF1R then promoted STAT3/HMGB1 signaling to facilitate autophagy. Additionally, TAMs/CXCL1 silence improved paclitaxel chemosensitivity by suppressing autophagy in breast cancer mice xenografts, and clinical studies further linked CXCL1 to IGF1R/HMGB1 signaling, as well as shorter free survival of recurrence. Taken together, these results not only uncover the crucial role of TAMs/CXCL1 signaling in mediating breast cancer chemoresistance through enhancing autophagy, but also shed novel light on the molecular mechanism of IGF1R/STAT3/HMGB1 pathway in regulating autophagy and its impact on cancer prognosis.

C-Reactive Protein Induces Immunosuppression by Activating FcγR2B in Pulmonary Macrophages to Promote Lung Metastasis.

C-reactive protein (CRP) is a liver-derived acute phase reactant that is a clinical marker of inflammation associated with poor cancer prognosis. Elevated CRP levels are observed in many types of cancer and are associated with significantly increased risk of metastasis, suggesting that CRP could have pro-metastatic actions. Here, we reported that CRP promotes lung metastasis by dampening the anti-cancer capacity of pulmonary macrophages in breast cancer and melanoma. Deletion of CRP in mice inhibited lung metastasis of breast cancer and melanoma cells without significantly impacting tumor growth compared to wildtype mice. In addition, the lungs of CRP deficient mice were enriched for activated pulmonary macrophages, which could be reduced to the level of wildtype mice by systemic administration of human CRP. Mechanistically, CRP blocked the activation of pulmonary macrophages induced by commensal bacteria in a FcγR2B-dependent manner, thereby impairing macrophage-mediated immune surveillance to promote the formation of a pre-metastatic niche in the lungs of tumor-bearing mice. Accordingly, treatment with specific CRP inhibitors activated pulmonary macrophages and attenuated lung metastasis in vivo. These findings highlight the importance of CRP in lung metastasis, which may represent an effective therapeutic target for patients with advanced solid cancers in clinics.

MCL1 inhibitor S63845 delivered by follicle-stimulating hormone modified liposome potentiates carboplatin efficacy in ovarian cancer

Platinum resistance cause therapeutic failure and poor prognosis in ovarian cancer, and evasion of apoptosis is a critical factor in chemoresistance. A limited number of FDA-approved anticancer drugs directly target apoptotic pathways. Here, we discovered that MCL1, a critical anti-apoptotic protein, is amplified and associated with platinum resistance and survival in ovarian cancer, assisting in personalized treatment. We further identified S63845 through drug-based screening, the most potent MCL1 inhibitor, which efficiently enhanced carboplatin (CBP) sensitivity in various ovarian cancer models, including primary ovarian cancer cells, orthotopic ovarian cancer, peritoneal metastasis, and human patient-derived xenograft (PDX) models. Mechanistically, S63845 competitively binds to MCL1, disrupts the binding of apoptosis effector (BAK and BAX) or pro-apoptotic BH3 protein (BIM) to MCL1 respectively, and eventually enhances CBP-induced apoptosis.To promote the clinical transformation of S63845, we developed follicle-stimulating hormone-modified liposome nanoparticles (S63845@Lipo-FSH) to enhance stability, membrane penetration, and tumor-targeting capabilities. S63845@Lipo-FSH exhibits a superior therapeutic efficacy and tumor targeting compared to free S63845, even when the dose of S63845 is reduced to one-fifth. Overall, targeting MCL1 by S63845@Lipo-FSH enhances CBP efficiency in ovarian cancer, with safety and efficacy, suggesting that this strategy is effective and promising for clinical application.

Berberine modulates ovarian cancer autophagy and glycolysis through the LINC01123/P65/MAPK10 signaling axis

BackgroundBerberine, a readily accessible natural compound known for its ease of synthesis and low toxicity, exhibits anti-tumor properties by modulating inflammatory responses. Recent studies have revealed that berberine can also treat malignant tumors by influencing tumor metabolic reprogramming, making it a potential candidate for metabolic therapy in ovarian cancer. MethodsThe anti-proliferative and anti-metastatic effects of berberine on ovarian cancer cells were investigated using CCK-8 assays, scratch assays, EDU proliferation assays, and assays related to glycolysis and autophagy. Differentially expressed lncRNAs in ovarian cancer were identified using data from the TCGA database. A specific lncRNA's role was delineated through RNA pulldown assays, silver staining, mass spectrometry analysis, CHIP assays, and immunoprecipitation experiments, focusing on its involvement in glycolysis and autophagy regulation in ovarian cancer. Additionally, the inhibitory mechanism of berberine on ovarian cancer cells was validated through cell thermal shift assays and cycloheximide protein degradation experiments to confirm its interaction with key targets. ResultsIn vitro experiments revealed that berberine reduces glycolysis and autophagy levels, leading to the inhibition of ovarian cancer cell proliferation and metastasis. Bioinformatics analysis of TCGA data identified LINC00123 as associated with poor prognosis in ovarian cancer. Experimental validation, including RNA pulldown assays, confirmed that the LINC00123/P65/MAPK10 signaling axis regulates glycolysis and autophagy in ovarian cancer. Furthermore, at the molecular level, berberine inhibits the interaction between LINC00123 and P65, thereby reducing P65 protein stability and impeding its transcriptional regulation of downstream MAPK10. These findings were further validated in animal models. ConclusionOur study highlights berberine's dual benefits of anti-inflammatory effects and inhibition of ovarian cancer proliferation and metastasis by modulating autophagy and glycolysis levels. Mechanistically, berberine targets the LINC00123/P65/MAPK10 signaling pathway to regulate glycolysis and autophagy in ovarian cancer. These insights not only expand the potential of berberine in ovarian cancer therapy but also provide new targets and therapeutic strategies for metabolic therapy in this cancer type.