Integrated analysis of single-cell RNA-seq and bulk RNA-seq revealed key genes for bone metastasis and chemoresistance in prostate cancer

Background: Prostate Cancer (PCa) is a serious malignancy. The main causes of PCa aggravation and death are unexplained resistance to chemotherapy and bone metastases.

Objective: This study aimed to investigate the molecular mechanisms associated with the dynamic processes of progression, bone metastasis, and chemoresistance in PCa.

Methods: Through comprehensive analysis of single-cell RNA Sequencing (scRNA-seq) data, Gene Expression Omnibus (GEO) tumor progression and metastasis-related genes were identified. These genes were subjected to lasso regression modeling using the Cancer Genome Atlas (TCGA) database. Tartrate-resistant Acid Phosphatase (TRAP) staining and real-time quantitative PCR (RT-qPCR) were used to evaluate osteoclast differentiation. CellMiner was used to confirm the effect of LDHA on chemoresistance. Finally, the relationship between LDHA and chemoresistance was verified using doxorubicin-resistant PCa cell lines.

Results: 7928 genes were identified as genes related to tumor progression and metastasis. Of these, 7 genes were found to be associated with PCa prognosis. The scRNA-seq and TCGA data showed that the expression of LDHA was higher in tumors and associated with poor prognosis of PCa. In addition, upregulation of LDHA in PCa cells induces osteoclast differentiation. Additionally, high LDHA expression was associated with resistance to Epirubicin, Elliptinium acetate, and doxorubicin. Cellular experiments demonstrated that LDHA knockdown inhibited doxorubicin resistance in PCa cells.

Conclusions: LDHA may play a potential contributory role in PCa initiation and development, bone metastasis, and chemoresistance. LDHA is a key target for the treatment of PCa.

Bone metastasis; Chemoresistance; LDHA; Prostate cancer; Single-cell RNA sequencing.