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Identification du facteur de transcription HOXA9 comme cible thérapeutique dans le carcinome à cellules rénales et ciblage par des ligands de l’ADN

Abstract : Kidney cancer accounts for 3% of adult cancers. It is a heterogeneous and insidiousdisease with a good prognosis when it is discovered early. Unfortunately, 5-year survivalremains below 10% when it is diagnosed at metastatic stages. Treatment is based onsurgery for localized tumors and on the use of systemic therapy for advanced ofmetastatic stages. Although, treatment has profoundly changed last decades, responsesrates don’t exceed 30%. Finding new therapeutic targets in this cancer is particularly important to improve patient care. For that, we are working on the role of the transcription factor HOXA9 and its inhibition with small molecules, able to compete withthe binding of HOXA9 to DNA, inhibit its transcriptional activity and therefore oncogenicprograms that it regulates. Two main compounds have been selected.First, we analyzed a genomic public database and showed that HOXA9 is overexpressed in papillary renal cell carcinoma and that its expression correlates withsurvival in clear cell renal cell carcinoma. Then, in two cellular models representing the two main histological subtypes of renal cell carcinoma, we showed that HOXA9 is stronglyexpressed and we evaluated biological effects following invalidation using RNAinterference. Biological effects were compared to the ones observed following treatmentwith inhibitory compounds. We showed that HOXA9 knock-down impairs cell survivaland cell migration and we observed the same effects with HOXA9 inhibitors.To identify direct and indirect HOXA9-regulated genes, a transcriptomic analysisupon invalidation of HOXA9 identified that HOXA9 regulates genes involved in the TNFαpathway, and in particular, genes already described in renal carcinoma such as BMP2.BMP2 is known to regulate cancer stem cell (CSC) features, so we evaluated the role ofHOXA9 in this population and showed that HOXA9 is overexpressed when cells formtumorspheres, a specific CSC feature. Moreover, HOXA9 invalidation abolished sphereformation. To confirm these results, HOXA9-knock-downed cells implanted orthotopically in the left kidney of immunodeficient mice showed that HOXA9 is required for cell tumorigenicity.Finally, to determine the role of HOXA9 in the formation of pulmonary metastases and its potential targeting in such cases, we generated a metastatic-derived cellular modeland we showed that invalidation of HOXA9 is associated with lung metastases reduction. Our results indicate that HOXA9 represents a pertinent therapeutic target in renal carcinoma and that the use of HOXA9 inhibitory DNA ligands could be a potential effective therapeutic strategy.
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Samy Jambon. Identification du facteur de transcription HOXA9 comme cible thérapeutique dans le carcinome à cellules rénales et ciblage par des ligands de l’ADN. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2018. Français. ⟨NNT : 2018LIL2S045⟩. ⟨tel-02882075⟩

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