Identification of subtype-specific master regulatory long non-coding RNAs of gastric cancer through a network-based approach

Gastric cancer (GC) remains a formidable challenge in oncology owing to its high mortality rate and limited treatment options. Importantly, the highly heterogeneous nature of GC poses a significant hurdle to selecting patients for optimized therapy. Like other cancer types, several molecular subtyping systems have been introduced to GC based on transcriptome and genomic profiles. In a recent study, GC was classified into four subtypes according to microsatellite stability (MS) and an epithelial-mesenchymal transition (EMT) signature: MSS/EMT, MSI, MSS/TP53+, and MSS/TP53-. Of note, the MSS/EMT subtype is associated with high risk of recurrence and poorer survival. However, the regulatory mechanisms underlying this aggressive MSS/EMT subtype remain elusive. Recent studies on long non-coding RNAs (lncRNAs) have revealed their critical roles in regulating cancer initiation, progression, and metastasis. Herein, we employed a multi-dimensional network approach to systematically interrogate the regulatory roles of lncRNAs specifically in the MSS/EMT GC subtype. Using master regulator analysis, we identified a key master regulator LINC00968, a clinically relevant lncRNA associated with GC progression. Our analysis revealed that LINC00968 played a pivotal role in regulating the EMT pathway by upregulating two potential target genes, FGF1 and PDGFRB. Furthermore, we performed ceRNA analysis by integrating lncRNA, mRNA, and miRNA expression profiles, indicating that LINC00968 may promote GC progression through upregulation of PDGFRB by sponging miR-423-5p. Moreover, survival analyses in independent datasets confirmed the clinical relevance of our findings, underscoring the significance of the identified lncRNA and putative target genes. Overall, our study highlights the robustness of the integrative network-based approach in dissecting the lncRNA heterogeneity of GC and provides novel insights into the regulatory mechanisms underlying the highly aggressive MSS/EMT subtype of GC. Our results also provide potential novel therapeutic targets for this deadly disease.