Bladder cancer causes an estimated 150,000 deaths per year worldwide. Although 15% of the recurrent bladder cancer becomes an invasive type, currently used targeted therapy for malignant bladder cancer is still not efficient. We focused on the miR-130 family (miR-130b, miR-301a, and miR-301b) that was significantly upregulated in bladder cancer specimens than that of the normal urothelial specimens. We analyzed the functional significance of miR-130 family using a 5637 bladder cancer cell line and revealed that miR-130 family of inhibitors suppressed cell migration and invasion by downregulating focal adhesion kinase (FAK) and Akt phosphorylation. Mechanistic analyses indicate that the miR-130 family directly targets phosphatase and tensin homolog deleted from chromosome 10 (PTEN), resulting in the upregulation of FAK and Akt phosphorylation. In clinical bladder cancer specimens, downregulation of PTEN was found to be closely correlated with miR-130 family expression levels. Overall, the miR-130 family has a crucial role in malignant progression of bladder cancer and thus the miR-130 family could be a promising therapeutic target for invasive bladder cancer.
Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer-related death worldwide. Although many molecular-targeted drugs for NSCLC have been developed in recent years, the 5-year survival rate of patients with NSCLC remains low. Therefore, an improved understanding of the molecular mechanisms underlying the biology of NSCLC is essential for developing novel therapeutic strategies for the treatment of NSCLC. In this study, we examined the role of miR-130b in NSCLC. Our results showed that high expression of miR-130b in clinical specimens was significantly associated with poor overall survival in patients with NSCLC. Moreover, miR-130b expression was significantly increased in NSCLC clinical specimens from patients with vascular and lymphatic invasion. Consistent with this, overexpression of miR-130b promoted invasion and matrix metalloproteinase-2 (MMP-2) activity in A549 cells. Argonaute2 immunoprecipitation and gene array analysis identified tissue inhibitor of metalloproteinase-2 (TIMP-2) as a target of miR-130b . Invasion activity promoted by miR-130b was attenuated by TIMP-2 overexpression in A549 cells. Furthermore, TIMP-2 concentrations in serum were inversely correlated with relative miR-130b expression in tumor tissues from the same patients with NSCLC. Overall, miR-130b was found to act as an oncomiR, promoting metastasis by downregulating TIMP-2 and invasion activities in NSCLC cells.
Previously, we have revealed that the miR-130 family (miR-130b, miR-301a, and miR-301b) functions as an oncomiR in bladder cancer. The pharmacological inhibition of the miR-130 family molecules by the seed-targeting strategy with an 8-mer tiny locked nucleic acid (LNA) inhibits the growth, migration, and invasion of bladder cancer cells by repressing stress fiber formation. Here, we searched for a functionally advanced target sequence with LNA for the miR-130 family with low cytotoxicity and found LNA #9 (A(L)^i^i^A(L)^T(L)^T(L)^G(L)^5(L)^A(L)^5(L)^T(L)^G) as a candidate LNA. LNA #9 inhibited cell growth in vitro and in an in vivo orthotopic bladder cancer model. Proteome-wide tyrosine phosphorylation analysis suggested that the miR-130 family upregulates a wide range of receptor tyrosine kinases (RTKs) signaling via the expression of phosphorylated Src (pSrcTyr416). SILAC-based proteome analysis and a luciferase assay identified protein tyrosine phosphatase non-receptor type 1 (PTPN1), which is implicated as a negative regulator of multiple signaling pathways downstream of RTKs as a target gene of the miR-130 family. The miR-130-targeted LNA increased and decreased PTPN1 and pSrcTyr416 expressions, respectively. PTPN1 knockdown led to increased tumor properties (cell growth, invasion, and migration) and increased pSrcTyr416 expression in bladder cancer cells, suggesting that the miR-130 family upregulates multiple RTK signaling by targeting PTPN1 and subsequent Src activation in bladder cancer. Thus, our newly designed miR-130 family targeting LNA could be a promising nucleic acid therapeutic agent for bladder cancer.
Bladder cancer causes an estimated 150,000 deaths per year worldwide. However, no major improvements in clinical outcomes have been achieved in the past several decades; therefore, a promising therapeutic agent is required. Recent studies revealed the existence of multiple subtypes of bladder cancer with distinct molecular signatures. To create novel therapeutics for such heterogeneous cancers, a target molecule should regulate various cancer-related signaling pathways. Here, we focused on the oncogenic miR-130 family (miR-130b, miR-301a, and miR-301b) as a novel therapeutic target for bladder cancer. The pharmacological inhibition of miR-130 family molecules by seed-targeting with an 8-mer tiny locked nucleic acid (LNA) inhibited 5637 bladder cancer cell growth, migration, and invasion by repressing stress fiber formation. Moreover, the miR-130-targeted LNA suppressed the phosphorylation of both FAK and Akt, resulting in the upregulation of two protein phosphatases, phosphatase and tensin homolog and protein tyrosine phosphatase, non-receptor type 11. In addition, administration of miR-130 family-targeted LNA significantly suppressed tumor growth in an in vivo bladder cancer xenograft model. Taken together, the miR-130 family-targeted LNA is expected to be a promising therapeutic agent for bladder cancer.
Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer death worldwide. Although recent advances in understanding the pathogenic mechanism of NSCLC has led to the development of targeted treatments, these treatments are only applicable to a limited number of patients. Therefore, the development of a novel therapeutic drug for NSCLC is urgently needed. Here, we focused on miR-301a and miR-301b, belonging to the miR-130 family, because recently, it was reported that miR-130b functions as an oncomiR in NSCLC. The miR-301a and miR-301b were significantly upregulated in NSCLC tissues compared to those in matched-pair adjacent normal lung tissues. Overexpression of miR-301a/b promoted cell proliferation and miR-301b further promoted migration ability in NSCLC cells. Conversely, knockdown of miR-301a and miR-301b significantly suppressed cell proliferation and migration. Moreover, transactivating domain-containing p63 (TAp63), a close relative of the p53 tumor suppressor, was a target gene of both miR-301a and miR-301b in NSCLC cells. These findings showed that miR-301a and miR-301b might function as oncomiRs by targeting TAp63 in NSCLC.
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