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The Oncogenic Role of Prostate Stem Cell Antigen (PSCA) in Colorectal Cancer: Implications for Targeted Therapy

ABSTRACT: Prostate stem cell antigen (PSCA), a pivotal member of the lymphocyte antigen-6 (Ly6) protein family, has been implicated in the tumorigenesis and neoplastic progression of diverse cancer types. In this study, we conducted a thorough investigation into the role of PSCA in the development of colorectal cancer (CRC). Survival analysis based on The Cancer Genome Atlas (TCGA) dataset demonstrated that elevated expression of PSCA was tightly correlated with unfavorable overall survival, inferior relapse-free survival and worse post-progression survival among CRC patients.Additionally, PSCA exhibited significantly higher expression levels in colorectal cancer stem cell (CRC-SCs) rel-ative to CRC cell lines.Loss-of-function assaysusing small interfering RNA (siRNA)-mediated silencing were performed to evaluate the effects of PSCA downregula-tion on the stemness properties of CRC-SCs, including proliferative capacity, invasive potential and apoptotic rate, which were assessed by MTS assay, transwell invasion assay and flow cytometry analysis, respectively. The results showed that silencing PSCA markedly suppressed the proliferation and invasion of CRC-SCs, while significantly promoting cellular apoptosis. RNA sequencing was performed to identify differentially expressed genes (DEGs) in the PSCA knockdown group compared to the negative control group.

ORGANISM(S): Homo sapiens

PROVIDER: GSE337374 | GEO | 2026/08/05

REPOSITORIES: GEO

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Project description:Claret2009 - Predicting phase III overall survival in colorectal cancer This model is described in the article: Model-based prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor dynamics. Claret L, Girard P, Hoff PM, Van Cutsem E, Zuideveld KP, Jorga K, Fagerberg J, Bruno R. J. Clin. Oncol. 2009 Sep; 27(25): 4103-4108 Abstract: PURPOSE: We developed a drug-disease simulation model to predict antitumor response and overall survival in phase III studies from longitudinal tumor size data in phase II trials. METHODS: We developed a longitudinal exposure-response tumor-growth inhibition (TGI) model of drug effect (and resistance) using phase II data of capecitabine (n = 34) and historical phase III data of fluorouracil (FU; n = 252) in colorectal cancer (CRC); and we developed a parametric survival model that related change in tumor size and patient characteristics to survival time using historical phase III data (n = 245). The models were validated in simulation of antitumor response and survival in an independent phase III study (n = 1,000 replicates) of capecitabine versus FU in CRC. RESULTS: The TGI model provided a good fit of longitudinal tumor size data. A lognormal distribution best described the survival time, and baseline tumor size and change in tumor size from baseline at week 7 were predictors (P < .00001). Predicted change of tumor size and survival time distributions in the phase III study for both capecitabine and FU were consistent with observed values, for example, 431 days (90% prediction interval, 362 to 514 days) versus 401 days observed for survival in the capecitabine arm. A modest survival improvement of 39 days (90% prediction interval, -21 to 110 days) versus 35 days observed was predicted for capecitabine. CONCLUSION: The modeling framework successfully predicted survival in a phase III trial on the basis of capecitabine phase II data in CRC. It is a useful tool to support end-of-phase II decisions and design of phase III studies. This model is hosted on BioModels Database and identified by: MODEL1708310001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Among all cancers, colorectal cancer (CRC) is the 3rd most common and the 2nd leading cause of death worldwide. New therapeutic strategies are required to target cancer stem cells (CSCs), a subset of tumor cells highly resistant to present-day therapy and responsible for tumor relapse. CSCs display dynamic genetic and epigenetic alterations that allow quick adaptations to perturbations. Lysine-specific histone demethylase 1A (KDM1A), a FAD-dependent H3K4me1/2 and H3K9me1/2 demethylase, was found to be upregulated in several tumors and associated with a poor prognosis due to its ability to maintain CSCs staminal features. Here, we explored the potential role of KDM1A targeting in CRC by characterizing the effect of KDM1A silencing in differentiated and CRC stem cells (CRC-SCs). In CRC primary samples, KDM1A expression was associated with a worse prognosis, confirming its role as an independent negative prognostic factor of CRC. Consistently, biological assays such as methylcellulose colony formation, invasion, and migration assays demonstrated a significantly decreased self-renewal potential, as well as migration and invasion potential upon KDM1A silencing. Our untargeted omics approach (transcriptomic and proteomic) revealed the association of KDM1A silencing with CRC-SCs cytoskeletal and metabolism remodeling towards a differentiated phenotype (e.g., the activation of a collateral mitochondrial metabolic pathway independent from succinate-CoA ligase GDP-forming subunit beta 2, expressions of brush border’s protein villin, and ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2) suggesting a key role of KDM1A in cell metabolism. Also, KDM1A silencing resulted in a 3-fold increase in the expression of miR-506-3p. Lastly, loss of KDM1A markedly reduced 53BP1 DNA repair foci, implying the involvement of KDM1A in the DNA damage response. Overall, our results indicate that KDM1A plays a key role in CRC progression and therefore it represents a promising epigenetic target to prevent tumor relapse.

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The Oncogenic Role of Prostate Stem Cell Antigen (PSCA) in Colorectal Cancer: Implications for Targeted Therapy

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