The Role of the oncogene prostate tumor overexpressed-1 and the regulation of mRNA translation in prostate cancer progression and chemoresistance /

• Autores: Verónica Cánovas Hernández
• Directores de la Tesis: Rosanna Paciucci Barzanti (dir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2017
• Idioma: español
• Tribunal Calificador de la Tesis: Jaume Farrés Vicén (presid.), Antonio García de Herreros Madueño (secret.), Angela Greco (voc.)
• Programa de doctorado: Programa de Doctorado en Bioquímica, Biología Molecular y Biomedicina por la Universidad Autónoma de Barcelona
• Materias:
  • Química
    • Bioquímica
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en:  DDD  TDX 
• Resumen

  • Metastatic prostate cancer is presently incurable. Prostate tumor overexpressed 1 (PTOV1) is expressed at high levels in prostate cancer and other neoplasias in association with a more aggressive disease and poor clinical outcomes. One main objective of this thesis is to study PTOV1 function in prostate cancer progression and its role in the development and maintenance of resistance to current therapies, mainly chemotherapy with taxanes. We showed here that PTOV1 increased cell motility and invasion of prostate cancer cells inducing a partial epithelial-to-mesenchymal transition promoting the translation of c-Jun protein, Snail1 and Vimentin. In support of the relevance of PTOV1 in prostate cancer progression, its knockdown significantly inhibited the tumorigenic and metastatic potentials of PC-3 prostate cancer cells. Transduction of PTOV1 in docetaxel-sensitive Du145 and PC3 cells significantly increased cell survival after docetaxel exposure and induced docetaxel-resistance genes expression (ABCB1, CCNG2 and TUBB2B). In addition, PTOV1 induced prostatospheres formation and self-renewal genes expression (ALDH1A1, LIN28A, MYC and NANOG). In contrast, Du145 and PC3 cells knockdown for PTOV1 significantly accumulated in the G2/M phase, presented a concomitant increased subG1 peak, and cell death by apoptosis. These effects were enhanced in docetaxel-resistant cells. Analyses of tumor datasets show that PTOV1 expression significantly correlated with prostate tumor grade, drug resistance (CCNG2) and self-renewal (ALDH1A1, MYC) markers. These genes are concurrently overexpressed in most metastatic lesions. Metastases also show PTOV1 genomic amplification in significant co-occurrence with docetaxel-resistance and self-renewal genes. Our findings identify PTOV1 as a promoter of docetaxel-resistance and self-renewal characteristics for castration resistant prostate cancer. The concomitant increased expression of PTOV1, ALDH1A1 and CCNG2 in primary tumors, may predict metastasis and bad prognosis. In addition high expression of PTOV1 in breast and ovarian tumors are associated with bad response to chemotherapy and lower overall survivals. Altogether, data point to a pro-oncogenic role of PTOV1 in different tumors and indicate that it is a candidate gene for patient prognosis.

    A second main objective is to study the role of translation deregulation in aggressive prostate cancer, in particular in the cells resistance to most conventional therapies used in metastatic in prostate cancer. Most attempts to determine the mRNA profile of androgen independent cells and chemoresistant cells have made use of total RNA for gene expression analysis. However, several lines of evidence suggest that translational control is a central regulator of gene expression in cancer. By using polysome profiling coupled to RNA-seq approach we aim to discern selective regulation of a subset of mRNAs among resistant cells that might help us to elucidate the mechanisms operating in the control of RNA translational in prostate cancer progression, especially in the development of resistance to current therapies.