Oncogenic RAS-induced senescence in human primary thyrocytes: molecular effectors and inflammatory secretome involved
Maria Grazia Vizioli1, Joana Santos2, Silvana Pilotti3
1Molecular Mechanism Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, UK.
Abstract:
Oncogene-induced senescence (OIS) is a robust and sustained antiproliferative response to oncogenic stress and constitutes an efficient barrier to tumour progression. We have recently proposed that OIS may be involved in the pathogenesis of thyroid carcinoma by restraining tumour progression as well as the transition of well differentiated to more aggressive variants. Here, an OIS inducible model was established and used for dissecting the molecular mechanisms and players regulating senescence in human primary thyrocytes. We show that oncogenic RAS induces senescence in thyrocytes as judged by changes in cell morphology, activation of p16INK4a and p53/p21CIP1 tumour suppressor pathways, senescence-associated β-galactosidase (SA-β-Gal) activity, and induction of proinflammatory components including IL-8 and its receptor CXCR2. Using RNA interference (RNAi) we demonstrate that p16INK4a is necessary for the onset of senescence in primary thyrocytes as its depletion rescues RAS-induced senescence. Furthermore, we found that IL-8/CXCR2 network reinforces the growth arrest triggered by oncogenic RAS, as its abrogation is enough to resume proliferation. Importantly, we observed that CXCR2 expression coexists with OIS markers in thyroid tumour samples, suggesting that CXCR2 contributes to senescence, thus limiting thyroid tumour progression.
Insights
Oncogene-induced senescence (OIS) halts thyroid cancer progression by activating tumor suppressors like p16INK4a. The IL-8/CXCR2 pathway reinforces this growth arrest, suggesting CXCR2
Area of Science:
- Cellular biology
- Cancer research
- Molecular oncology
Background:
- Oncogene-induced senescence (OIS) is a critical tumor suppressor mechanism.
- OIS is proposed to play a role in thyroid carcinoma pathogenesis, limiting tumor progression and dedifferentiation.
- Understanding OIS in thyroid cells is crucial for cancer therapy.
Purpose of the Study:
- To establish an OIS-inducible model in human primary thyrocytes.
- To dissect the molecular mechanisms and key players regulating senescence in thyroid cells.
- To investigate the role of the IL-8/CXCR2 axis in oncogenic RAS-induced senescence.
Main Methods:
- Development of an OIS-inducible model in primary human thyrocytes.
- Assessment of senescence markers: cell morphology, p16INK4a, p53/p21CIP1 pathways, SA-β-Gal activity, and IL-8/CXCR2 expression.
- RNA interference (RNAi) to deplete p16INK4a and assess its necessity for senescence.
- Abrogation of the IL-8/CXCR2 network to evaluate its impact on proliferation.
Main Results:
- Oncogenic RAS successfully induced senescence in thyrocytes, confirmed by multiple established markers.
- p16INK4a was found to be essential for the initiation of RAS-induced senescence; its depletion rescued the senescent phenotype.
- The IL-8/CXCR2 signaling pathway was induced during OIS and was crucial for reinforcing the growth arrest.
- Blocking the IL-8/CXCR2 network allowed proliferation to resume, highlighting its role in maintaining senescence.
- CXCR2 expression was observed alongside OIS markers in thyroid tumor samples.
Conclusions:
- p16INK4a is a critical mediator of oncogene-induced senescence in human thyroid cells.
- The IL-8/CXCR2 axis plays a significant role in reinforcing oncogene-induced senescence and limiting thyroid tumor progression.
- Targeting the IL-8/CXCR2 pathway could be a therapeutic strategy in thyroid cancer.
Related Concept Videos
02:15Replicative Cell Senescence
02:15Replicative Cell Senescence
02:38The Ras Gene
Ras is a...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:23Abnormal Proliferation
02:38The Ras Gene