CDK12 Promotes Cervical Cancer Progression through Enhancing Macrophage Infiltration

Abstract

Cervical cancer (CC) is a commonly diagnosed and primary consideration of cancer patient death in female reproductive system malignancy. Cyclin-dependent kinase 12 (CDK12), as a transcription-associated CDK, plays important roles in tumor-promoting behaviors, whereas the underlying mechanisms of CDK12 in CC progression are still obscure. In this report, we investigated the role of CDK12 in cervical cancer. The current study identified CDK12 mRNA and protein expression remarkably upregulated in CC patients. Upregulated CDK12 was closely associated with CC progression and poor prognosis. In vitro and in vivo functional experiments showed that knockdown of CDK12 inhibited cancer cell proliferation and colony formation and promoted apoptosis. Further investigations demonstrated that CDK12 regulated the immune microenvironment to facilitate the progression of CC cells by promoting macrophage infiltration. Meanwhile, we first demonstrated that nuclear import of CDK12 is mediated by TNPO1 and might be a new therapeutic target in oncology. Collectively, this study pointed out the potential of CDK12 to serve as a novel therapeutic target in restricting CC proliferation and cell cycle process through promoting macrophage infiltration.

Increased Nuclear Transporter Importin 7 Contributes to the Tumor Growth and Correlates With CD8 T Cell Infiltration in Cervical Cancer

“…Gene set enrichment analysis (GSEA) showed that the PI3K-AKT signaling pathway and mTORC1 pathway were significantly altered ( Figure 5A ). Previous studies demonstrated that karyopherin-mediated cargo proteins may play an important role in promoting cancer progression ( Yang et al, 2021a ). Then, we found that only the high expression of GTF2I and TRIP12 was associated with the poor prognosis of CC patients in 32 different proteins ( Supplementary Figures 3A,B ).…”

The mechanism of BUD13 m6A methylation mediated MBNL1-phosphorylation by CDK12 regulating the vasculogenic mimicry in glioblastoma cells

“…Structure-activity relationship study of THZ531 derivatives found that CDK12/13 dual inhibitor BSJ-01-175 could treat Ewing’s sarcoma [ 43 ]. CDK12 promoted cervical cancer progression by enhancing macrophage infiltration [ 44 ]. Knockdown of CDK12 inhibited the proliferation of lung cancer and esophageal cancer cells [ 45 ].…”

TNPO1-Mediated Nuclear Import of FUBP1 Contributes to Tumor Immune Evasion by Increasing NRP1 Expression in Cervical Cancer

“…Clinical patient tissue microarray was bedded in paraffin for immunohistochemistry. IHC staining and score criteria were showed as previous research [ 21 ]. The primary antibody used was anti-FUBP1 (dilution 1 : 1000, ab181111, Abcam).…”

“…Whole-cell lysates and separate nuclear/cytoplasmic fractions were extracted from cells according to routine protocols. Western blotting and coimmunoprecipitation were executed as preceding description [ 21 ]. The antibodies against GAPDH (60004-1-Ig), Flag-tag (20543-1-AP), α -tubulin (11224-1-AP), Lamin B1 (12987-1-AP), and GST-tag (HRP-66001) were purchased from ProteinTech.…”

“…MS751 and Siha cells were transfected with si- FUBP1 -1, si- FUBP1 -2, or siNC. CCK-8 assay and colony formation assay were executed as preceding description [ 21 ].…”