POLM variant G312R promotes ovarian tumorigenesis through genomic instability and COL11A1-NF-κB axis.
Yue XiaoMaowei NiZhiguo ZhengYufeng LiuMingyu YinShuyu MaoYe ZhaoBing TianLiangyan WangHong XuYuejin HuaPublished in: American journal of physiology. Cell physiology (2024)
In ovarian cancer (OC), identifying key molecular players in disease escalation and chemoresistance remains critical. Our investigation elucidates the role of the DNA polymerase mu (POLM), especially G312R mutation, in propelling oncogenesis through dual pathways. POLM G312R markedly augments the ribonucleotide insertion capability of POLM, precipitating genomic instability. In addition, our research reveals that POLM G312R perturbs collagen alpha-1 (XI) chain (COL11A1) expression-a gene that plays a key role in oncogenesis-and modulates the NF-κB signaling pathway, alters the secretion of downstream inflammatory cytokines, and promotes tumor-macrophage interactions. We illustrate a bidirectional regulatory interaction between POLM, particularly its G312R variant, and COL11A1. This interaction regulates NF-κB signaling, culminating in heightened malignancy and resistance to chemotherapy in OC cells. These insights position the POLM as a potential molecular target for OC therapy, shedding light on the intricate pathways underpinning POLM variant disease progression. NEW & NOTEWORTHY Our research reveals that POLM plays an important role in ovarian cancer development, especially the mutation G312R. We uncover the POLM G312R mutation as a driver of genomic instability in ovarian cancer via aberrant ribonucleotide incorporation. We reveal that POLM G312R upregulates COL11A1 and activates NF-κB signaling, contributing to tumor progression and chemoresistance. This study identifies the POLM-COL11A1-NF-κB axis as a novel oncogenic pathway.
Keyphrases
- signaling pathway
- pi k akt
- induced apoptosis
- lps induced
- cell cycle arrest
- copy number
- oxidative stress
- nuclear factor
- poor prognosis
- epithelial mesenchymal transition
- genome wide
- single molecule
- inflammatory response
- transcription factor
- adipose tissue
- immune response
- randomized controlled trial
- circulating tumor
- mesenchymal stem cells
- cell death
- toll like receptor
- cell proliferation
- cell free
- replacement therapy
- double blind