Genetic Analysis of Platelet-Related Genes in Hepatocellular Carcinoma Reveals a Novel Prognostic Signature and Determines PRKCD as the Potential Molecular Bridge

Abstract

Background Hepatocellular carcinoma (HCC) belongs to a representative lethality gastrointestinal malignancy, and comprehensive management of HCC remains intractable at present on account of its invasive biological feature that is easy to relapse and early metastasis. The intimate connection between platelets and tumor progression has been widely reported, and platelet-related indicators are also used in the clinical practice of carcinoma. This work is designed to investigate the significance of platelet-related genes in the prognostic prediction of patients with HCC and their potential role in the cross-talk between HCC cells and platelets in the tumor microenvironment. Methods By integrating the RNA-seq data and clinicopathological information of HCC patients, we extracted prognosis-associated platelet-related genes based on the univariate cox analysis and further established a relevant prognostic signature via the lasso cox regression analysis, and two independent HCC cohorts were used as external validation. Multiple bioinformatics methods were utilized to explore the underlying functional discrepancy between different risk groups classified by the risk model. And in vitro proliferation, invasion, and migration assays were conducted to investigate the effect of platelet stimulation on HCC cells’ viability and motility, and flow cytometric analysis was exerted to demonstrate the influence of HCC cells on platelet activation. Results A novel platelet-related risk model was developed and patients both in the training and testing cohorts were divided into distinct risk subgroups according to the median risk score. It was observed that the high-risk status was closely associated with poor prognosis and worse clinicopathological parameters. Meanwhile, an obvious discrepancy in the constitution of the immune microenvironment also indicated that distinct immune status might be a potential determinant affecting prognosis as well as immunotherapy reactiveness. Moreover, in vitro experiments demonstrated that PRKCD could act as a molecular bridge between tumor cells and platelets, which could either participate in regulating tumor malignant phenotype or mediating platelet activation. Conclusions In brief, this work reveals a novel platelet-related risk signature for prognostic evaluation of HCC patients and confirms that PRKCD is a key messenger in HCC cell-platelet interaction and plays a crucial role in mediating platelet-induced tumor progression.

A novel NHEJ gene signature based model for risk stratification and prognosis prediction in hepatocellular carcinoma

“…Considering the increase in data-driven biological research, and ease of access to corresponding data from public databases, many studies concentrated on the relationship between RNA-seq data of specific gene sets and individual outcomes with the of numerous public databases [19]. For examples, pyroptosis-associated, platelet-related and ferroptosis-related genes were reported to predict prognosis and demonstrate immune infiltration in HCC patients [20][21][22]. However, there have not yet been studies of NHEJ-related genes for predicting the prognosis of HCC patients.…”

Identification of platelet-related subtypes and diagnostic markers in pediatric Crohn’s disease based on WGCNA and machine learning

“…We then employed the “sva” packages to normalize and correct for batch effects in the training set ( 20 ). Additionally, for the acquisition of platelet-related genes (PRGs), we utilized a gene set consisting of 300 PRGs identified in a previous similar study ( 11 ).…”

“…Mature molecular typing strategies are able to predict the optimal therapeutic strategy prior to patient treatment, thereby substantially improving patient prognosis (8). In previous reports, the molecular subtyping of diseases such as hepatocellular carcinoma, osteoarthritis, and rheumatoid arthritis, for example, has laid the foundation for their individualized treatment (9)(10)(11). Therefore, the development of molecular subtyping of PCD based on its molecular features is crucial for improving the accuracy of clinical treatment decisions and deepening our understanding of PCD.…”

Prediction of Prognosis in Patients with Sepsis Based on Platelet-Related Genes

“…Three hundred PRGs that related to biological function of platelet ( Supplementary Table 1S ) were collected from the Molecular Signatures Database (MSigDB) ( ) based on methods used by Li et al. 11 .…”

“…We did a comprehensive search of the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/) to obtain sepsis-related datasets (GSE65682). Three hundred PRGs that related to biological function of platelet (supplementary Table 1s) were collected from the Molecular Signatures Database (MSigDB) (http://www.broad.mit.edu/gsea/msigdb/) based on methods used by Li et al [11].…”