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TRIM8 anti-proliferative action against chemo-resistant renal cell carcinoma.

Caratozzolo MF, Valletti A, Gigante M, Aiello I, Mastropasqua F, Marzano F, Ditonno P, Carrieri G, Simonnet H, D'Erchia AM, Ranieri E, Pesole G, Sbisà E, Tullo A - Oncotarget (2014)

Bottom Line: Recently, we identified TRIM8 as a new p53 modulator, which stabilizes p53 impairing its association with MDM2 and inducing the reduction of cell proliferation.These results suggest that down regulation of TRIM8 might be an alternative way to suppress p53 activity in RCC.Interestingly, we show that TRIM8 expression recovery in RCC cell lines renders these cells sensitive to chemotherapeutic treatments following p53 pathway re-activation.

View Article: PubMed Central - PubMed

Affiliation: Institute for Biomedical Technologies ITB, Bari, Italy. Contributed equally to this work.

ABSTRACT
In some tumours, despite a wild-type p53 gene, the p53 pathway is inactivated by alterations in its regulators or by unknown mechanisms, leading to resistance to cytotoxic therapies. Understanding the mechanisms of functional inactivation of wild-type p53 in these tumours may help to define prospective targets for treating cancer by restoring p53 activity. Recently, we identified TRIM8 as a new p53 modulator, which stabilizes p53 impairing its association with MDM2 and inducing the reduction of cell proliferation. In this paper we demonstrated that TRIM8 deficit dramatically impairs p53-mediated cellular responses to chemotherapeutic drugs and that TRIM8 is down regulated in patients affected by clear cell Renal Cell Carcinoma (ccRCC), an aggressive drug-resistant cancer showing wild-type p53. These results suggest that down regulation of TRIM8 might be an alternative way to suppress p53 activity in RCC. Interestingly, we show that TRIM8 expression recovery in RCC cell lines renders these cells sensitive to chemotherapeutic treatments following p53 pathway re-activation. These findings provide the first mechanistic link between TRIM8 and the drug resistance of ccRCC and suggest more generally that TRIM8 could be used as enhancer of the chemotherapy efficacy in cancers where p53 is wild-type and its pathway is defective.

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Related in: MedlinePlus

TRIM8 expression in renal cancer samples(A) TRIM8 mRNA expression in 20 ccRCC and 4 renal oncocytoma samples and their paired non-tumour tissues. Data are represented in box-plots showing median and 10th, 25th, 75th and 90th percentiles for each category of sample. The average expression (± standard error) is also reported as a dot on the right of the boxes. Expression data were measured respect to one normal sample chosen arbitrarily as calibrator and then normalized by the geometric mean of ACTB e RPL13 expression ratios. * p-value < 0.001. (B) Western blotting analysis of TRIM8 of two ccRCC patients representative of all.
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Figure 2: TRIM8 expression in renal cancer samples(A) TRIM8 mRNA expression in 20 ccRCC and 4 renal oncocytoma samples and their paired non-tumour tissues. Data are represented in box-plots showing median and 10th, 25th, 75th and 90th percentiles for each category of sample. The average expression (± standard error) is also reported as a dot on the right of the boxes. Expression data were measured respect to one normal sample chosen arbitrarily as calibrator and then normalized by the geometric mean of ACTB e RPL13 expression ratios. * p-value < 0.001. (B) Western blotting analysis of TRIM8 of two ccRCC patients representative of all.

Mentions: Twenty patients (10 males and 10 females; mean age: 63.8 ± 10.8 years), who underwent surgery for ccRCC at histological analysis, and 4 patients (all males; mean age: 63.25 ± 4.86) affected by RO were analysed for TRIM8 expression by qRT-PCR and western blotting (Figures 2A-B). The relatively low number of RO samples was due to the rarity of occurrence of this benign neoplasia. Two samples from each patient were available, one from renal cancer tissue and one from non-neoplastic surrounding renal epithelial tissue.


TRIM8 anti-proliferative action against chemo-resistant renal cell carcinoma.

Caratozzolo MF, Valletti A, Gigante M, Aiello I, Mastropasqua F, Marzano F, Ditonno P, Carrieri G, Simonnet H, D'Erchia AM, Ranieri E, Pesole G, Sbisà E, Tullo A - Oncotarget (2014)

TRIM8 expression in renal cancer samples(A) TRIM8 mRNA expression in 20 ccRCC and 4 renal oncocytoma samples and their paired non-tumour tissues. Data are represented in box-plots showing median and 10th, 25th, 75th and 90th percentiles for each category of sample. The average expression (± standard error) is also reported as a dot on the right of the boxes. Expression data were measured respect to one normal sample chosen arbitrarily as calibrator and then normalized by the geometric mean of ACTB e RPL13 expression ratios. * p-value < 0.001. (B) Western blotting analysis of TRIM8 of two ccRCC patients representative of all.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4202135&req=5

Figure 2: TRIM8 expression in renal cancer samples(A) TRIM8 mRNA expression in 20 ccRCC and 4 renal oncocytoma samples and their paired non-tumour tissues. Data are represented in box-plots showing median and 10th, 25th, 75th and 90th percentiles for each category of sample. The average expression (± standard error) is also reported as a dot on the right of the boxes. Expression data were measured respect to one normal sample chosen arbitrarily as calibrator and then normalized by the geometric mean of ACTB e RPL13 expression ratios. * p-value < 0.001. (B) Western blotting analysis of TRIM8 of two ccRCC patients representative of all.
Mentions: Twenty patients (10 males and 10 females; mean age: 63.8 ± 10.8 years), who underwent surgery for ccRCC at histological analysis, and 4 patients (all males; mean age: 63.25 ± 4.86) affected by RO were analysed for TRIM8 expression by qRT-PCR and western blotting (Figures 2A-B). The relatively low number of RO samples was due to the rarity of occurrence of this benign neoplasia. Two samples from each patient were available, one from renal cancer tissue and one from non-neoplastic surrounding renal epithelial tissue.

Bottom Line: Recently, we identified TRIM8 as a new p53 modulator, which stabilizes p53 impairing its association with MDM2 and inducing the reduction of cell proliferation.These results suggest that down regulation of TRIM8 might be an alternative way to suppress p53 activity in RCC.Interestingly, we show that TRIM8 expression recovery in RCC cell lines renders these cells sensitive to chemotherapeutic treatments following p53 pathway re-activation.

View Article: PubMed Central - PubMed

Affiliation: Institute for Biomedical Technologies ITB, Bari, Italy. Contributed equally to this work.

ABSTRACT
In some tumours, despite a wild-type p53 gene, the p53 pathway is inactivated by alterations in its regulators or by unknown mechanisms, leading to resistance to cytotoxic therapies. Understanding the mechanisms of functional inactivation of wild-type p53 in these tumours may help to define prospective targets for treating cancer by restoring p53 activity. Recently, we identified TRIM8 as a new p53 modulator, which stabilizes p53 impairing its association with MDM2 and inducing the reduction of cell proliferation. In this paper we demonstrated that TRIM8 deficit dramatically impairs p53-mediated cellular responses to chemotherapeutic drugs and that TRIM8 is down regulated in patients affected by clear cell Renal Cell Carcinoma (ccRCC), an aggressive drug-resistant cancer showing wild-type p53. These results suggest that down regulation of TRIM8 might be an alternative way to suppress p53 activity in RCC. Interestingly, we show that TRIM8 expression recovery in RCC cell lines renders these cells sensitive to chemotherapeutic treatments following p53 pathway re-activation. These findings provide the first mechanistic link between TRIM8 and the drug resistance of ccRCC and suggest more generally that TRIM8 could be used as enhancer of the chemotherapy efficacy in cancers where p53 is wild-type and its pathway is defective.

Show MeSH
Related in: MedlinePlus