GeroScience

PCSK9 expression and cancer survival: a prognostic biomarker at the intersection of oncology and geroscience

Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily recognized for its role in cholesterol metabolism; however, emerging evidence suggests it plays a broader role in the regulation of cellular aging mechanisms and the pathogenesis of age-related diseases. Given that cancer is an age-related disease, PCSK9 has garnered attention for its potential impact on tumor progression and patient survival. In this study, we conducted a comprehensive analysis of PCSK9 expression across multiple tumor types, assessing its prognostic significance using RNA sequencing data from The Cancer Genome Atlas (TCGA) and gene expression microarray data from the Gene Expression Omnibus (GEO). Cox proportional hazards regression models and Kaplan–Meier survival analyses were employed to evaluate overall survival (OS) associations. Our findings reveal that elevated PCSK9 expression is associated with improved OS in breast and ovarian cancers, particularly in Luminal B breast cancer subtypes. Conversely, high PCSK9 expression correlates with worse OS in bladder cancer, renal clear cell carcinoma, melanoma, and pancreatic cancer. Notably, while PCSK9 expression is significantly upregulated in melanoma and bladder tumors, it is downregulated in renal clear cell carcinoma, yet relatively higher expression among renal tumors still predicts poorer survival. No significant associations between PCSK9 expression and OS were observed in colon, liver, gastric, lung, prostate, head and neck cancers, or low-grade gliomas in the available datasets.In conclusion, our study identifies PCSK9 as a prognostic biomarker with distinct, tumor-specific survival implications. Its dual role—associating with improved survival in some cancers while correlating with worse outcomes in others—suggests that PCSK9 may influence cancer progression through context-dependent mechanisms. Future research should focus on elucidating the mechanistic underpinnings of these associations and exploring the diagnostic and therapeutic potential of targeting PCSK9 in oncology.

Prognostic impact of glucagon-like peptide-1 receptor (GLP1R) expression on cancer survival and its implications for GLP-1R agonist therapy: an integrative analysis across multiple tumor types

Abstract Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as exenatide (Byetta, Bydureon), liraglutide (Victoza, Saxenda), albiglutide (Tanzeum), dulaglutide (Trulicity), lixisenatide (Lyxumia, Adlyxin), semaglutide (Ozempic, Rybelsus, Wegovy), and tirzepatide (Mounjaro, Zepbound), are widely used for the treatment of type 2 diabetes mellitus (T2DM) and obesity. While these agents are well known for their metabolic benefits, there is growing interest in their potential effects on cancer biology. However, the role of GLP-1R agonists in cancer remains complex and not fully understood, particularly across different tumor types. This study aimed to evaluate the prognostic significance of GLP1R expression on overall survival across various cancer types. Using a comprehensive analysis of gene expression data and survival outcomes a large cohorts of different tumor types, we employed Cox proportional hazards survival analyses, coupled with false discovery rate determinations, to explore correlations between GLP1R expression and survival. The integrated database included thousands of cancer specimens with available overall survival time and event data from numerous independent cohorts, providing a robust platform for survival analysis. Our findings reveal that increased GLP1R expression is associated with improved overall survival in cancers such as bladder cancer, breast cancer, esophageal adenocarcinoma, renal clear cell carcinoma, and thyroid carcinoma. Conversely, higher GLP1R expression is linked to poorer survival outcomes in cervical squamous cell carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. Additionally, GLP1R expression showed no significant impact on overall survival in cancers such as esophageal squamous cell carcinoma, colon cancer, head-neck squamous cell carcinoma, renal papillary cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, ovarian cancer, and pancreatic cancer. In conclusion, GLP1R expression levels serve as an important biomarker with potential prognostic significance across multiple cancers, demonstrating both protective and adverse associations depending on the tumor type. These findings highlight the complex role of GLP-1R agonists in cancer risk and survival, suggesting that the therapeutic use of these agents should be carefully tailored to the individual patient’s cancer risk profile.

Cell-free ascites from ovarian cancer patients induces Warburg metabolism and cell proliferation through TGFβ-ERK signaling

AbstractAscites plays a key role in supporting the metastatic potential of ovarian cancer cells. Shear stress and carry-over of cancer cells by ascites flow support carcinogenesis and metastasis formation. In addition, soluble factors may participate in the procarcinogenic effects of ascites in ovarian cancer. This study aimed to determine the biological effects of cell-free ascites on carcinogenesis in ovarian cancer cells. Cell-free ascites from ovarian cancer patients (ASC) non-selectively induced cell proliferation in multiple models of ovarian cancer and untransformed primary human dermal fibroblasts. Furthermore, ASC induced a Warburg-type rearrangement of cellular metabolism in A2780 ovarian cancer cells characterized by increases in cellular oxygen consumption and glycolytic flux; increases in glycolytic flux were dominant. ASC induced mitochondrial uncoupling and fundamentally reduced fatty acid oxidation. Ascites-elicited effects were uniform among ascites specimens. ASC-elicited transcriptomic changes in A2780 ovarian cancer cells included induction of the TGFβ-ERK/MEK pathway, which plays a key role in inducing cell proliferation and oncometabolism. ASC-induced gene expression changes, as well as the overexpression of members of the TGFβ signaling system, were associated with poor survival in ovarian cancer patients. We provided evidence that the activation of the autocrine/paracrine of TGFβ signaling system may be present in bladder urothelial carcinoma and stomach adenocarcinoma. Database analysis suggests that the TGFβ system may feed forward bladder urothelial carcinoma and stomach adenocarcinoma. Soluble components of ASC support the progression of ovarian cancer. These results suggest that reducing ascites production may play an essential role in the treatment of ovarian cancer by inhibiting the progression and reducing the severity of the disease.

Discovery and ranking of the most robust prognostic biomarkers in serous ovarian cancer

AbstractProgress in ovarian cancer treatment lags behind other tumor types. With diagnosis usually at an advanced stage, there is a high demand for reliable prognostic biomarkers capable of the selection of effective chemo- and targeted therapies. Our goal was to establish a large-scale transcriptomic database and use it to uncover and rank survival-associated genes. Ovarian cancer cohorts with transcriptome-level gene expression data and clinical follow-up were identified from public repositories. All samples were normalized and entered into an integrated database. Cox univariate survival analysis was performed for all genes and was followed by multivariate analysis for selected genes involving clinical and pathological variables. False discovery rate was computed for multiple hypothesis testing and a 1% cutoff was used to determine statistical significance. The complete integrated database comprises 1816 samples from 17 datasets. Altogether, 2468 genes were correlated to progression-free survival (PFS), and 704 genes were correlated with overall survival (OS). The most significant genes were WBP1L, ASAP3, CNNM2, and NCAPH2 for progression-free survival and CSE1L, NUAK1, ALPK2, and SHKBP1 for overall survival. Genes significant for PFS were also preferentially significant for predicting OS as well. All data including HR andpvalues as well as the used cutoff values for all genes for both PFS and OS are provided to enable the ranking of future biomarker candidates across all genes. Our results help to prioritize genes and to neglect those which are most likely to fail in studies aiming to establish new clinically useful biomarkers and therapeutic targets in serous ovarian cancer.

Mitochondrial bioenergetics in resilience of older adults with gynecologic cancer: design and rationale of a pilot study

Abstract Resilience—the ability to recover and maintain function following stresses—is a critical factor influencing treatment tolerance and recovery in older adults with cancer. Despite the high incidence of gynecologic cancers in postmenopausal individuals, resilience in this population remains underexplored, even though patients commonly face compounded stress from both chemotherapy and surgery. The goal of our research is (1) to test the feasibility of cognitive and physical function assessments in older women with gynecologic cancers and (2) to discover reliable predictors that enhance clinical decision-making and guide personalized treatment strategies. Current clinical assessments focus on isolated physiological systems. As such, there is a need for a reliable predictor that captures systemic resilience more comprehensively. A reliable predictor of resilience following cancer treatment could improve clinical decision-making and identify potential targets for therapeutic intervention. Both mitochondrial bioenergetics and oxidative stress are presumably mechanistically linked to resilience of patients with gynecologic cancers because of widely known effects of chemotherapy and tumor burden on mitochondrial bioenergetics. Mitochondria generate more than 95% of cellular ATP through oxidative phosphorylation, a process essential for recovery following physiological stress. Oxidative stress disrupts excitation–contraction coupling and reduces metabolic efficiency in skeletal muscle, contributing to weakness and fatigue. In the brain, oxidative modifications have been associated with impaired neurotransmission and cognitive dysfunction. This protocol paper describes a longitudinal study design aimed at evaluating the feasibility of resilience assessment and testing mitochondria and oxidative stress as predictors of resilience in older adults diagnosed with advanced endometrial or ovarian cancer.