Intravesical administration of exogenous microRNA-145 as a therapy for mouse orthotopic human bladder cancer xenograft

Inamoto, Teruo; Taniguchi, Kohei; Takahara, Kiyoshi; Iwatsuki, Ayako; Takai, Tomoaki; Komura, Kazumasa; Yoshikawa, Yuki; Uchimoto, Taizo; Saito, Kenkichi; Tanda, Naoki; Kouno, Junko; Minami, Koichiro; Uehara, Hirofumi; Hirano, Hajime; Nomi, Hayahito; Kiyama, Satoshi; Akao, Yukihiro; Azuma, Haruhito

doi:10.18632/oncotarget.4129

Cited by 28 publications

(37 citation statements)

References 22 publications

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“…We previously reported that ectopic expression of miR-145 induces apoptosis through the downregulation of c-Myc and socs7 in bladder cancer cells [9–11]. We thus confirmed this effect by performing assays to evaluate apoptotic cell death in T24 and 253J B-V cells after the transfection of these cells with miR-145 or siR-KLF4.…”

Section: Resultssupporting

confidence: 72%

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MiR-145 negatively regulates Warburg effect by silencing KLF4 and PTBP1 in bladder cancer cells

et al. 2017

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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.

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Section: Resultssupporting

confidence: 72%

“…We have already reported that intravesical administration of exogenous miR-145 exhibits an anti-tumor effect in a human bladder cancer xenograft model [11]. We are thus now aiming to compare the efficacy of intravesical delivery of exogenous miR-145 to that of BCG in the xenografted model mice.…”

Section: Discussionmentioning

confidence: 99%

MiR-145 negatively regulates Warburg effect by silencing KLF4 and PTBP1 in bladder cancer cells

et al. 2017

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“…MiR-145 is often down-regulated in cancer tissues and restoration of miR-145 suppressed cancer cell invasion by reversing the EMT phenotype [12,28]. MiR-145 acts as a tumor suppressor in bladder cancer [29]. However, the mechanism of miR-145 down-regulation is still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Double‐negative feedback loop between long non‐coding RNA TUG1 and miR‐145 promotes epithelial to mesenchymal transition and radioresistance in human bladder cancer cells

et al. 2015

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a b s t r a c tLncRNAs have a critical role in the regulation of cellular processes such as cancer progression and metastasis. In the present study, we confirmed that TUG1 was overexpressed in bladder cancer tissues and established cell lines. Knockdown of TUG1 inhibited bladder cancer cell metastasis both in vitro and in vivo. Furthermore, we found that TUG1 promoted cancer cell invasion and radioresistance through inducing epithelial-to-mesenchymal transition (EMT). Interestingly, TUG1 decreased the expression of miR-145 and there was a reciprocal repression between TUG1 and miR-145 in an Argonaute2-dependent manner. ZEB2 was identified as a down-stream target of miR-145 and TUG1 exerted its function through the miR-145/ZEB2 axis. In summary, our data indicated that blocking TUG1 function may be an effective anti-cancer therapy.

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“…Intravesical treatment of siRNA was performed as previously described [42]. Two weeks later, intravesical treatment was initiated.…”

Section: Methodsmentioning

confidence: 99%

Collagen type IV alpha 1 (COL4A1) and collagen type XIII alpha 1 (COL13A1) produced in cancer cells promote tumor budding at the invasion front in human urothelial carcinoma of the bladder

et al. 2017

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Current knowledge of the molecular mechanism driving tumor budding is limited. Here, we focused on elucidating the detailed mechanism underlying tumor budding in urothelial cancer of the bladder. Invasive urothelial cancer was pathologically classified into three groups as follows: nodular, trabecular, and infiltrative (tumor budding). Pathohistological analysis of the orthotopic tumor model revealed that human urothelial cancer cell lines MGH-U3, UM-UC-14, and UM-UC-3 displayed typical nodular, trabecular, and infiltrative patterns, respectively. Based on the results of comprehensive gene expression analysis using microarray (25 K Human Oligo chip), we identified two collagens, COL4A1 and COL13A1, which may contribute to the formation of the infiltrative pattern. Visualization of protein interaction networks revealed that proteins associated with connective tissue disorders, epithelial-mesenchymal transition, growth hormone, and estrogen were pivotal factors in tumor cells. To evaluate the invasion pattern of tumor cells in vitro, 3-D collective cell invasion assay using Matrigel was performed. Invadopodial formation was evaluated using Gelatin Invadopodia Assay. Knockdown of collagens with siRNA led to dramatic changes in invasion patterns and a decrease in invasion capability through decreased invadopodia. The in vivo orthotopic experimental model of bladder tumors showed that intravesical treatment with siRNA targeting COL4A1 and COL13A1 inhibited the formation of the infiltrative pattern. COL4A1 and COL13A1 production by cancer cells plays a pivotal role in tumor invasion through the induction of tumor budding. Blocking of these collagens may be an attractive therapeutic approach for treatment of human urothelial cancer of the bladder.

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Intravesical administration of exogenous microRNA-145 as a therapy for mouse orthotopic human bladder cancer xenograft

Cited by 28 publications

References 22 publications

MiR-145 negatively regulates Warburg effect by silencing KLF4 and PTBP1 in bladder cancer cells

MiR-145 negatively regulates Warburg effect by silencing KLF4 and PTBP1 in bladder cancer cells

Double‐negative feedback loop between long non‐coding RNA TUG1 and miR‐145 promotes epithelial to mesenchymal transition and radioresistance in human bladder cancer cells

Collagen type IV alpha 1 (COL4A1) and collagen type XIII alpha 1 (COL13A1) produced in cancer cells promote tumor budding at the invasion front in human urothelial carcinoma of the bladder

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