Liguo Wang

RETRACTED: Mir-3150B-3P Inhibits the Proliferation and Invasion of Cervical Cancer Cells by Targeting Tnfrsf11A

The objective of this study was to determine the role of miR-3150b-3p in the cervical cancer (CC) progression. Real-time PCR and western blot analysis were conducted to test the expression of miR-3150b-3p, TNFRSF11a and p38 mitogen-activated protein kinase (MAPK) signaling pathway. The interaction between miR-3150b-3p and TNFRSF11a was verified by luciferase assay. Cell proliferation, migration and invasion were determined by CCK-8, wound healing and Transwell assays. In this study, we showed that miR-3150b-3p was significantly downregulated in CC cell lines. Additionally, miR-3150b-3p markedly attenuated the proliferation, migration and invasion of HeLa and SiHa cells. Moreover, we identified TNFRSF11a to be a novel target of miR-3150b-3p in CC cells. Enforced expression of TNFRSF11a abolished the antitumor effect of miR-3150b-3p. Besides, miR-3150b-3p was involved in the regulation of the p38 MAPK signaling pathway. In conclusion, our data suggested that miR-3150b-3p directly targets TNFRSF11a to inactivate the p38 MAPK signaling pathway, thus implicating miR-3150b-3p in the regulation of CC cell growth.

DNA2 protein destruction dictates DNA hyperexcision, cGAS–STING activation, and innate immune response in CDK12-deregulated cancers

CDK12 primarily functions as a transcription regulatory cyclin-dependent kinase (CDK) that controls mRNA elongation, splicing, and polyadenylation. The CDK12 gene is implicated in human cancers since it is frequently mutated and/or deleted in prostate and ovarian cancer but paradoxically amplified in breast cancer. Here, we demonstrate that CDK12 promotes serine-933 phosphorylation of DNA2, a nuclease/helicase critical for replication fork stress regulation, and the phosphorylation subsequently facilitates DNA2 polyubiquitination and degradation mediated by the APC/C CDC20 E3 ubiquitin ligase. CDK12 inactivation induces but amplification suppresses genome-wide expression of interferon response and antigen processing and presentation machinery genes in ovarian and breast cancer cells, respectively. Besides causing aberrant DNA2 stabilization, replication stress, genomic instability, and cytosolic double-stranded DNA (dsDNA) accumulation, CDK12 loss also triggers cGAS–STING activation and innate immune response, which can be reversed by forced expression of replication protein A (RPA) subunits or DNA2 depletion. Our findings identify DNA2 as a phosphorylation substrate of CDK12, connecting CDK12 to cell cycle regulation. These data also reveal DNA2 protein destruction as a critical mechanism that dictates genomic instability, cGAS–STING signaling activation, and innate immune response in CDK12-deregulated cancers.