A chemoresistance-associated proliferation gene signature identified by single-cell and machine learning analysis predicts prognosis in high-grade serous ovarian carcinoma.
TL;DR
This single-cell landscape of chemoresistance-associated proliferation genes delineates a nine-gene prognostic signature for HGSOC and confirms hub-gene overexpression in cisplatin-resistant cells, nominating therapeutic targets.
Abstract
Background
High-grade serous ovarian carcinoma (HGSOC) features extensive intratumoral heterogeneity, frequent chemoresistance and poor prognosis. Tumor proliferation kinetics reflected by tumor doubling time (TDT) are linked to therapeutic response, yet molecular drivers of chemoresistance-associated proliferation remain incompletely defined.
Methods
We integrated scRNA-seq (GSE154600) with bulk data (TCGA-OV, GTEx). Differential analyses of refractory/resistant versus sensitive tumors and tumor versus normal tissues, intersected with TDT-associated genes, identified 105 chemoresistance-associated proliferation genes. Consensus clustering and immune analyses were performed. A 117-algorithm machine-learning framework constructed a prognostic signature trained on TCGA-OV and validated in GSE26193. Survival was assessed by Kaplan-Meier Plotter. Hub genes were validated by qPCR and Western blot in paired sensitive (A2780, TYKnu) and cisplatin-resistant (A2780-DDP, TYKnu-DDP) cell lines.
Results
The genes enriched in cell-cycle and p53 signaling. Consensus clustering defined C1 and C2 subtypes with distinct immune microenvironments; C2 showed upregulation of DNA replication and cell-cycle programs. A nine-gene signature (BIRC5, CENPH, CKAP2, PAK1IP1, PBK, SDF2L1, TEAD4, TPM3, UBE2T) was established. High CENPH, CKAP2, PBK, TEAD4, TPM3 and UBE2T associated with inferior overall survival, while SDF2L1 was protective. These genes were predominantly expressed in malignant epithelial cells, SPP1+/TREM2+ macrophages and CAFs. qPCR confirmed upregulation of six genes in TYKnu-DDP cells; Western blot validated elevated SURVIVIN (BIRC5), CENPH, CKAP2, PAK1IP1 and PBK in resistant lines.
Conclusions
This single-cell landscape of chemoresistance-associated proliferation genes delineates a nine-gene prognostic signature for HGSOC and confirms hub-gene overexpression in cisplatin-resistant cells, nominating therapeutic targets.