CDK12 regulates angiogenesis of advanced prostate cancer by IGFBP3.

Prostate cancer (PCa) is a prevalent malignancy among men, with a majority of patients presenting with distant metastases at the time of initial diagnosis. These patients are at a heightened risk of developing more aggressive castration­resistant PCa following androgen deprivation therapy, which poses a greater challenge for treatment. Notably, the inhibition of tumor angiogenesis should not be considered an ineffective treatment strategy. The regulatory role of CDK12 in transcriptional and post­transcriptional processes is essential for the proper functioning of various cellular processes. In the present study, the expression of CDK12 was first knocked down in cells using CRISPR or siRNA technology. Subsequently, RNA­seq analysis, co­immunoprecipitation, western blotting, reverse transcription­quantitative polymerase chain reaction and the LinkedOmics database were employed to reveal that CDK12 inhibits insulin like growth factor binding protein 3 (IGFBP3). Western blot analysis also demonstrated that CDK12 promoted VEGFA expression by inhibiting IGFBP3, which involves the Akt signaling pathway. Then, CDK12 was found to promote PCa cell proliferation, cell migration and angiogenesis by inhibiting IGFBP3 through cell proliferation assays, cell migration assays and tube formation assays, respectively. Finally, animal experiments were performed for in vivo validation. It was concluded that CDK12 promoted PCa and its angiogenesis by inhibiting IGFBP3.

N-Myc promotes angiogenesis and therapeutic resistance of prostate cancer by TEM8.

Although patients with early localized prostate cancer can survive longer, castration-resistant prostate cancer (CRPC) has gradually emerged with the use of androgen deprivation therapy (ADT). N-Myc and TEM8 play a vital role in the progression of several cancer types. However, the underlying mechanism of how N-Myc and TEM8 promote the progression of prostate cancer remains unclear. In this study, the expression of N-Myc and TEM8 was detected in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) tissues by immunohistochemistry (IHC). LNCaP cell lines were maintained in RPMI 1640 medium supplemented with 10% charcoal-stripped fetal bovine serum. Subsequently, R language software was used to verify our results. Tubule formation assay of human umbilical vein endothelial cell (HUVEC) was conducted to examine the effect of N-Myc and TEM8 overexpression on angiogenesis in prostate cancer cells. IHC results showed a positive correlation between the expression of N-Myc and TEM8 in prostate cancer tissues. Further analysis showed that N-Myc and TEM8 were associated with clinicopathological features and poor prognosis in prostate cancer patients. Moreover, the overexpression of N-Myc and TEM8 promoted proliferation of prostate cancer cells and angiogenesis. Additionally, N-Myc and TEM8 overexpression was associated with therapeutic resistance. We further found that N-Myc promoted angiogenesis and therapeutic resistance in prostate cancer via TEM8. Hence, targeting N-Myc/TEM8 pathway in prostate cancer would be a novel therapeutic strategy to enhance the treatment of prostate cancer patients.

N­Myc induces the tumor progression of prostate cancer by regulating FSCN1.

The oncoprotein N­Myc has a carcinogenic effect in numerous types of cancer, and it can cause castration resistance in prostate cancer (PCa), and leads to the development of small cell neuroendocrine cancer by regulating multiple target genes. Immunohistochemical staining, RT­qPCR, western blotting, wound healing and CCK­8 assays were used to detect the expression of N­Myc and FSCN1 as well as AR and CgA at the human level and cell level. The immunohistochemical results revealed that the protein levels of N­Myc proto­oncogene protein (N­Myc) and fascin (FSCN1) in PCa were significantly higher than that of hyperplastic tissues (P<0.05), and there was a weak correlation between them (P=0.002). In vitro, N­Myc and FSCN1 were overexpressed in LNCaP and C4­2 cell lines. The results revealed the promoting effect of N­Myc and FSCN1 on malignant progression of PCa. In addition, the endogenous FSCN1 was knocked down in the C4­2 cell line, and the results revealed that the silencing of FSCN1 enhanced the expression of N­Myc and weakened the expression of the neuroendocrine marker CgA. Therefore, the present findings indicated that N­Myc may promote the malignant process of PCa by regulating FSCN1 and FSCN1 may have a reverse regulatory effect on N­Myc.