CTHRC1 expresses in cancer-associated fibroblasts and is associated with resistance to anti-androgen therapy in prostate cancer.

Background: CTHRC1 overexpresses in prostate cancer and is associated with the proliferation, invasion and migration of prostate cancer cells. However, the roles and mechanisms of CTHRC1 expression in prostate cancer prognosis and treatment outcomes remain unknown.

Objective: This study aimed to explore the expression and gene function of CTHRC1 in prostate cancer, investigate the prognostic value and potential effect in the treatment of prostate cancer.

Methods: Bulk and single-cell RNA sequencing analyses were used to evaluate the expression of CTHRC1 in prostate cancer. All data used in the study were obtained from publicly available sources to ensure transparency. Study enrolled 1999 cases of prostate cancer and 531 normal controls. Single-cell RNA sequencing profile included 62,995 cells from seven prostate primary tumors. CTHRC1 expression and prognosis analyses were conducted with these samples and verified by immunohistochemical staining. CIBERSORT algorithm was used to assess the tumor immune infiltrating cells based on bulk mRNA sequencing profiles. Genomics of drug sensitivity in cancer (GDSC) database was used to predict IC50 to anti-androgen therapy (ADT) drugs of the samples.

Results: CTHRC1 expressed in prostate cancer was higher than that in normal prostate tissue, and the expression increased with the progress of prostate cancer. CTHRC1 was the risk factor of progression-free interval (PFI). CTHRC1 was positively correlated with the infiltration of tumor-associated macrophages (TAMs). Myofibroblast-like cancer-associated fibroblasts (myCAFs) were the major CTHRC1 expressers in prostate cancer. TGF-β signaling activated in CTHRC1-positive myCAFs and was involved in TAMs polarization. Biological functions of myCAFs were enriched in hormone response and metabolism. CTHRC1 may regulate androgen receptor signaling through CCN2/CAV1/AR pathway. Moreover, ADT drug Bicalutamide and AZD3514 were less sensitive in the high CTHRC1 expression tumors.

Conclusions: As a potential molecular target of ADT resistance in prostate cancer, CTHRC1 provides a new promising molecular approach for the diagnosis and treatment of prostate cancer.