Pharmacological Inhibition of miR-130 Family Suppresses Bladder Tumor Growth by Targeting Various Oncogenic Pathways via PTPN1

Abstract

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.

miRNA-451 regulates rhesus choroid-retinal endothelial cell function and proteome profile

“…In lung adenocarcinoma, PTPN1 inhibited cell growth and metastasis through the dephosphorylation of c-Met and PIK3R2 [52] . The latest research on bladder cancer by Monoe et al [53] revealed that PTPN1 knockdown resulted in the increase of cancer cell proliferation and migration, and miR-130-targeted LNA (locked nucleic acid) increased PTPN1 and exhibited as a promising therapeutic agent. However, PTPN1 was also found to be positively correlated with the progression of melanoma [54] and glioma [55] .…”

Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy

“…In clear cell renal cell carcinoma, PTPN3 and PTPN13 act as tumor suppressors by inactivating the AKT signaling pathway ( 124 , 125 ), whereas PTPN12 restrains the proliferation of renal cell carcinoma by inhibiting PI3K/mechanistic target of rapamycin (mTOR) pathway activity ( 126 ). In bladder cancer, PTPN1 and PTPN12 function as tumor suppressors to attenuate the growth, invasion and migration of cancer cells ( 127 , 128 ). However, PTPN23 can regulate the motility of bladder cancer cells ( 129 ).…”

“…By regulating PTPN1, the miRNAs described above serve as tumor suppressors in cancers. Conversely, by targeting PTPN1, a tumor suppressor in bladder cancer, the miR-130 family (miR-130b, miR-301a, and miR-301b) contributes to cancer development ( 127 ).…”

Non-invasive diagnostic potential of microRNA-203 in liquid biopsy of urothelial carcinoma of bladder

“…CD44-associated miRNAs include miR-9, miR-21, miR-34a, miR-130, miR-143, miR-199, and miR-203 [ 22 ]–[ 24 ]. miRNAs are broadly classified into oncogenic (oncomiR) and tumor-suppressive (Anti-oncomiR) miRNAs.…”