The RAS pathway is among the most frequently activated signaling nodes in cancer. However, the mechanisms that alter RAS activity in human pathologies are not entirely understood. The most prevalent post-translational modification within the GTPase core domain of NRAS and KRAS is ubiquitination at lysine 128 (K128), which is significantly decreased in cancer samples compared to normal tissue. Here, we found that K128 ubiquitination creates an additional binding interface for RAS GTPase-activating proteins (GAPs), NF1 and RASA1, thus increasing RAS binding to GAP proteins and promoting GAP-mediated GTP hydrolysis. Stimulation of cultured cancer cells with growth factors or cytokines transiently induces K128 ubiquitination and restricts the extent of wild-type RAS activation in a GAP-dependent manner. In KRAS mutant cells, K128 ubiquitination limits tumor growth by restricting RAL/ TBK1 signaling and negatively regulating the autocrine circuit induced by mutant KRAS. Reduction of K128 ubiquitination activates both wild-type and mutant RAS signaling and elicits a senescence-associated secretory phenotype, promoting RAS-driven pancreatic tumorigenesis.
- Klíčová slova
- NF1, RAS Interactome, RAS Signaling, Senescence-Associated Secretory Phenotype, Ubiquitination,
- MeSH
- GTP-fosfohydrolasy metabolismus genetika MeSH
- lidé MeSH
- lysin metabolismus MeSH
- membránové proteiny metabolismus genetika MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- neurofibromin 1 MeSH
- protein aktivující GTPasu p120 metabolismus genetika MeSH
- protein-serin-threoninkinasy metabolismus genetika MeSH
- protoonkogenní proteiny p21(ras) * metabolismus genetika MeSH
- Ras proteiny metabolismus genetika MeSH
- signální transdukce MeSH
- ubikvitinace * MeSH
- vazba proteinů * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- GTP-fosfohydrolasy MeSH
- KRAS protein, human MeSH Prohlížeč
- lysin MeSH
- membránové proteiny MeSH
- neurofibromin 1 MeSH
- NF1 protein, human MeSH Prohlížeč
- NRAS protein, human MeSH Prohlížeč
- protein aktivující GTPasu p120 MeSH
- protein-serin-threoninkinasy MeSH
- protoonkogenní proteiny p21(ras) * MeSH
- Ras proteiny MeSH
- RASA1 protein, human MeSH Prohlížeč
- TBK1 protein, human MeSH Prohlížeč
Patients with high-grade endometrial carcinoma (EC) have an increased risk of tumor spread and lymph node metastasis (LNM). Preoperative imaging and CA125 can be used in work-up. As data on cancer antigen 125 (CA125) in high-grade EC are limited, we aimed to study primarily the predictive value of CA125, and secondarily the contributive value of computed tomography (CT) for advanced stage and LNM. Patients with high-grade EC (n = 333) and available preoperative CA125 were included retrospectively. The association of CA125 and CT findings with LNM was analyzed by logistic regression. Elevated CA125 ((>35 U/mL), (35.2% (68/193)) was significantly associated with stage III-IV disease (60.3% (41/68)) compared with normal CA125 (20.8% (26/125), [p < 0.001]), and with reduced disease-specific-(DSS) (p < 0.001) and overall survival (OS) (p < 0.001). The overall accuracy of predicting LNM by CT resulted in an area under the curve (AUC) of 0.623 (p < 0.001) independent of CA125. Stratification by CA125 resulted in an AUC of 0.484 (normal), and 0.660 (elevated). In multivariate analysis elevated CA125, non-endometrioid histology, pathological deep myometrial invasion ≥50%, and cervical involvement were significant predictors of LNM, whereas suspected LNM on CT was not. This shows that elevated CA125 is a relevant independent predictor of advanced stage and outcome specifically in high-grade EC.
- Klíčová slova
- CA125, advanced stage, endometrial cancer, high-grade, outcome,
- Publikační typ
- časopisecké články MeSH
