ESR Project 8: Define prostate-specific cellular mechanism of TRIB3’s tumour suppressor actions
Tribbles proteins (and specifically TRIB3) have been implicated in the regulation of cancer progression in animal models. Likewise, TRIB3 up-regulation has been shown to play an important role in the mechanism of action of several anticancer agents and specifically cannabinoids (Velasco et al, 2015). Thus, the genetic inactivation of Trib3 enhances the tumorigenic properties of different types of cancer cells including hepatocellular carcinoma cell lines an effect that relies on the overstimulation of the mTORC2/AKT/FOXO axis (Salazar et al, 2015).
The tumor suppressor Phosphatase and Tensin Homolog (PTEN) is considered one of the main negative regulators of the Phosphatidyl Inositol 3-Kinase (PI3K) pathway and is reduced or absent in approximately 70% of PCa´s (Trotman et al, 2003). Thus PTEN has been proposed to be a tumor-susceptibility gene for prostate cancer.
Experiments performed by the IdISSC group showed that lesions in the prostate of Pten+/- animals were enhanced by TRIB3 genetic inactivation (Salazar et al, 2015). Likewise, the IdISSC group also found a correlation between genetic inactivation of TRIB3 and an increase in the development of hepatocellular carcinomas.
In this context my project involves investigating the role of TRIB3 in prostate and hepatocellular carcinoma. Specifically, we will: (i) generate prostate cancer cell lines in which Trib3 has been genetically inhibited (knock-down and knock out using CRISPR/Cas9) and overexpressed: (ii) analyze the effect of Trib3 silencing and/overexpression on the tumorigenic capacity of prostate cancer cell lines in vitro and in vivo. (iii) characterize in vitro the responses (e.g. lipid synthesis, migration) of TRIB3-deficient/overexpressing prostate and hepatocellular carcinoma cell lines to inflammatory cytokines. (iv) investigate the effect of TRIB3 inactivation on the development and progression of HCC and prostate cancer in vivo.
To this latter aim, (a) we will study the mechanisms by which TRIB3 inactivation enhances steatosis and HCC in Trib3 -/- x Gnmt -/-. [Gnmt knock-out mice spontaneously develop HCC (Martinez et al, 2008)]; and (b) we will generate and characterize the phenotype of prostate-selective double Trib3 and Pten KO mice.
This study will be helpful in identifying the role of TRIB3 in prostate cancer and HCC. Establishing its role on the regulation of the interplay between immune system, adipose tissue and transformed epithelial tissue. It would also help in the identification of possible novel anticancer treatments based in the modulation of the levels and function of TRIB3.
Supervisors: Guillermo Velasco and Mar Lorente
- Velasco, S. Hernandez-Tiedra, D. Davila, M. Lorente, The use of cannabinoids as anticancer agents, Prog. Neuropsychopharmacol. Biol. Psychiatry, 64 (2016), pp. 259-266
- Luz Martínez-Chantar M, Vázquez-Chantada M, Ariz U, et al. Loss of the Glycine N-Methyltransferase Gene Leads to Steatosis and Hepatocellular Carcinoma in Mice. Hepatology (Baltimore, Md). 2008;47(4):1191-1199. doi:10.1002/hep.22159.
- Salazar M, Lorente M, García-Taboada E, Pérez Gómez E, Dávila D, et al (2015a) TRIB3 suppresses tumorigenesis by controlling mTORC2/AKT/ FOXO signaling, Molecular & Cellular Oncology, 2(3): e980134
- Trotman LC, Niki M, Dotan ZA, Koutcher JA, Di Cristofano A, Xiao A, et al. (2003) Pten dose dictates cancer progression in the prostate, PLoS Bio, 1(3): 385-396