Cirbp and csde1: two promissing rna binding proteins as potential biomarkers in breast cancer and melanoma
- Autores: Alberto INDACOCHEA CUSIRRAMOS
- Directores de la Tesis: Matilde Lleonart Pajarin (dir. tes.), Fátima Gebauer Hernández (codir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2020
- Idioma: español
- Tribunal Calificador de la Tesis: Diego Arango del Corro (presid.), Antonio Gentilella (secret.), Santiago Ramón y Cajal Agüeras (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
- Materias:
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- Resumen
Cancer is one of the most relevant public health problems worldwide. Despite recent advances in personalized medicine, there is a need for robust biomarkers that help untangle the complexity of tumors in clinical practice, and of therapeutic targets that allow for treatments with reduced toxicity. RNA binding proteins (RBPs) represent a promising source of both biomarkers and therapeutic targets. RBPs are the regulatory masters of post-transcriptional gene expression and comprise a family of more than 1000 members, from which only a few have been characterized in cancer. This thesis focuses on two RBPs: CIRBP and CSDE1.
CIRBP modulates the tumorigenic capacity of breast cancer cells, but its mechanisms and targets have been poorly characterized. In this work, we use an ex vivo breast cancer model to identify CIRBP targets transcriptome-wide and address its mechanisms of action. We find that CIRBP transcript levels correlate with breast cancer subtype and are an indicator of luminal A/B prognosis. CIRBP modulates cell growth and clonogenicity. RNA immunoprecipitation followed by high-throughput sequencing (RIP-Seq) identified 204 high confident CIRBP targets in MCF-7 cells. About 10% of these novel targets showed consistent changes after CIRBP modulation, and were highly interconnected with a network of known breast cancer genes. To test the potential of CIRBP-mediated regulation of these targets, we focused on Cystatin C (CST3), a known tumor suppressor. CST3 depletion restored the effects of CIRBP downregulation, indicating that CIRBP functions, at least in part, by downregulating CST3 levels. Our data provide a resource of CIRBP targets in breast cancer, and identify CST3 as a novel downstream mediator of CIRBP function.
CSDE1 promotes melanoma metastasis by increasing the synthesis of the EMT markers VIM and RAC1, while at the same time reducing the levels of PTEN mRNA, encoding a tumor suppressor. We have performed an exploratory analysis of CSDE1 levels and intracellular distribution in patient samples, using a home-made antibody that outperforms commercial antibodies in IHC. Contrary to expectations, our results show that CSDE1 levels decrease with malignancy. Notably, however, the intracellular distribution of CSDE1 changed with aggressiveness such that a high cytoplasmic/nuclear (C/N) ratio was significantly associated with poor progression-free survival in patients with metastasis from cutaneous melanoma that were naïve for treatment. The C/N ratio was predictive of outcome, as analyzed in two independent patients that were followed through the course of the disease. In addition, we found that VIM, and to a lesser degree RAC1 levels correlated with those of CSDE1, while PTEN did not correlate. Altogether, our results suggest that the CSDE1 C/N ratio is a promising predictor of treatment response and outcome in melanoma, and open the way for testing CSDE1 levels and distribution, perhaps together with VIM, in more focused studies.
