Widespread remodeling of the transcriptome is a signature of cancer; however, little is known about the post-transcriptional regulatory factors, including RNA-binding proteins (RBPs) that regulate mRNA stability, and the extent to which RBPs contribute to cancer-associated pathways. Here, by modeling the global change in gene expression based on the effect of sequence-specific RBPs on mRNA stability, we show that RBP-mediated stability programs are recurrently deregulated in cancerous tissues. Particularly, we uncovered several RBPs that contribute to the abnormal transcriptome of renal cell carcinoma (RCC), including PCBP2, ESRP2, and MBNL2. Modulation of these proteins in cancer cell lines alters the expression of pathways that are central to the disease and highlights RBPs as driving master regulators of RCC transcriptome. This study presents a framework for the screening of RBP activities based on computational modeling of mRNA stability programs in cancer and highlights the role of post-transcriptional gene dysregulation in RCC.
We confirm that the traditional and routinely reported histological parameters in RC post-NAC remain the most powerful prognosticators of disease course. The significance of TRG in the bladder remains unconfirmed.
High LASP1 expression correlated with metastatic recurrence rate between patients. The LASP1 expression is higher in UC1 and T24 cells than in UC13 and UC6 cells. Knockdown of LASP1 using siRNA inhibited cell growth, and was accompanied by an increase in p21 and p27, and a decreased of cyclin D1. Flow cytometry revealed that LASP1 knockdown induced G1 arrest. Conversely, stable LASP1 overexpression drove cell growth with an increase of cyclin D1 in UC6 and UC3 cells. The treatment of CDDP and GEM induced LASP1 expression in Western Blotting. Furthermore, compared with parental cell line, LASP1 is higher in T24 CDDP-R and RT112 CDDP-R cells than in parental cells. LASP1 ASO inhibited cell growth in RT112 CDDP-R and T24 CDDP-R cells. In the orthotopic bladder cancer model, systemic LASP1 ASO administration to athymic nude mice delayed tumor progression in T24 CDDP-R cells. CONCLUSIONS: These data revealed that LASP1 inhibition might be as a promising novel therapeutics modality in the treatment of chemoresistant bladder cancer.
Purpose: Radical cystectomy (RC), remains the “standard” treatment for Muscle Invasive Bladder Cancer (MIBC), but is associated with major impact on quality of life. Radiation therapy (RT) is an alternate treatment as it preserves the bladder. However, lack of local control remains problematic. Therefore, the use of a radio-sensitizer could overcome those challenges and limit side effects. In this sense, inhibiting the mTOR signaling pathway in combination with radiation is a promising therapeutic strategy. As the cyclin dependent kinase inhibitor p21 WAF1/Cip1 has been found to be associated with DNA damage repair and autophagy, which are two major pathways associated with radiation resistance, we sought to investigate the role of p21 in response to combination therapy in bladder cancer. Methods: Expression of p21 was characterized in different bladder cancer cell lines via Western Blotting. Correlation of p21 expression and response to mTOR inhibitor was done using proliferation assay. Knockdown of p21 was carried out via RNAi silencing. To assess the effect of the p21 expression in response to combination therapy, Clonogenic assay was done. Western blot was utilized to assess the effect of mTOR inhibition in p21 expression. In vivo, athymic mice were subcutaneously injected with bladder cancer cell lines. Treatment consisted of either placebo or combined RAD001 (12 hours prior to radiation) and fractionated IR. Tumor volume was measured at endpoint. Immunohistochemistry was used to detect the levels of p21 in paraffin-embedded mouse xenograft bladder cancer tissues treated with placebo, IR, RAD001 and in combination. Autophagy was investigate by LC3 cytoplasmic localization by immunofluoresecence and LC3 I/II levels were detected by Western Blot. Clevage of caspase-3 was used to determine apoptosis by Western Blot. Results: There was a significant correlation between the levels of p21 and sensitivity to mTOR inhibitor (P value <005). RAD001 induced a dose response decreased in the level of p21 expression. Addition of the mTOR inhibitor, along with knocking down p21 significantly inhibited colony formation compared to untreated p21-scramble cells. A significant effect in tumor volume was observed in vivo in the group treated with the combination arm of compared to all other groups (P value <005). Levels of p21 increased following the treatment with IR alone and in combination with RAD001, whereas a slight decrease was observed following the treatment with RAD001 alone. Addition of RAD001 induces autophagy, and point to the functional role of p21 in inhibiting autophagy as its knock-down was successful at increasing the levels of LC3 I/II even without RAD001 addition. Conclusion: Our in vitro and in vivo results support a functional role for p21 in mediating the response to combination therapy, thus promoting p21 as a potential player that can be modulated in the treatment of bladder cancer. Citation Format: Jose J. Mansure, Shraddha Solanki, Wael Alamjed, Roland Nassim, Fabio Cury, Simone Chevalier, Wassim Kassouf. p21 WAF1/Cip1 -mediated radiosensitization of bladder cancer cells by mTOR inhibitor, RAD001 disrupts the balance between autophagy and apoptosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1654.
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