Smad7 inhibits metastasis, possibly by regulating cell-cell adhesion. Systemic expression of Smad7 may be a novel strategy for the prevention of metastasis of advanced cancers.

The Warburg effect is a well-known feature in cancer-specific metabolism. We previously reported on the role of microRNA (miR)-145 as a tumor-suppressor in human bladder cancer (BC) cells. In this study, we reveal that miR-145 decreases the Warburg effect by silencing KLF4 in BC cells. The expression levels of miR-145 were significantly lower in clinical BC samples and BC cell lines compared to those in normal tissues and HUC cells. Luciferase assay results showed that miR-145 directly bound to 3′UTR of KLF4, which was shown to be overexpressed in the clinical BC samples using Western blot analysis and immunohistochemistry. Remarkable growth inhibition and apoptosis were induced by the ectopic expression of miR-145 or by the gene silencing of KLF4 (siR-KLF4). Also, Warburg effect-related genes such as PTBP1/PKMs were regulated by the transfection of BC cells with miR-145 or siR-KLF4. These results thus indicate that the miR-145/KLF4/PTBP1/PKMs axis is one of the critical pathways that maintain the Warburg effect in BC carcinogenesis. MiR-145 perturbed the Warburg effect by suppressing the KLF4/PTBP1/PKMs pathway in BC cells, resulting in significant cell growth inhibition.

These findings confirm that the use of clusterin ASO may be a feasible strategy to enhance chemosensitivity for patients with advanced RCC.

The paper by Zellweger et al. builds on the continuing story of clusterin (TRPM‐2) in the development and progression of prostate cancer. This group have published a series of papers on this protein, showing that it correlates with progression to androgen‐independence and resistance to apoptosis. One of their recent papers has shown that ‘knocking out’ clusterin increases radiation sensitivity in prostate cancer cells. The current paper reports that increasing the expression of clusterin in LNCaP cells increases the cell's resistance to radiation‐induced apoptosis. Manipulating identified survival proteins has important implications in preventing androgen‐independent progression. Clusterin is such a survival protein and represents an important drug target in the near future. OBJECTIVE To evaluate the effect of clusterin overexpression on radiation‐induced tumour growth rates and apoptosis in human prostate LNCaP cells, as prostate cancer cells are relatively resistant to radiation‐induced apoptosis and local recurrences are common, but overexpression of the anti‐apoptotic protein clusterin can accelerate progression to androgen‐independence and to confer a chemoresistant phenotype in various prostate cancer models. MATERIALS AND METHODS Western blot analysis and immunohistochemistry were used to compare clusterin expression levels in parental (P) and clusterin‐transfected (T) LNCaP cells in vitro and in vivo. The effects of radiation on clusterin‐expression in both parental LNCaP/P and clusterin‐transfected LNCaP/T tumours were analysed by Northern blot analysis. The cellular response to radiation was determined up to 3 weeks after irradiation using tetrazolium and re‐growth assays, and cell‐cycle analysis by flow cytometry. RESULTS Clusterin mRNA expression increased from undetectable to low levels in LNCaP/P tumours after radiation and more than three‐fold in LNCaP/T tumours. Clusterin overexpression decreased the radiosensitivity in a time‐dependent manner, reducing the extent of growth arrest and apoptosis by up to 54%. Re‐growth assays showed that the improved survival rates of LNCaP/T cells after radiation did not change after 3 days, remaining constant over 3 weeks. CONCLUSIONS These results identify clusterin as a promoter of cell survival that may help mediate resistance to radiation‐induced apoptosis. Furthermore, clusterin overexpression seems to provide an extended protection against radiation‐induced cell cycle arrest and apoptosis.