miR-637 Prevents Glioblastoma Progression by Interrupting ZEB2/WNT/β-catenin Cascades

Abstract

Glioblastomas (GBMs) are the most frequent primary malignancies in the central nervous system. Aberrant activation of WNT/β-catenin signaling pathways is critical for GBM malignancy. However, the regulation of WNT/β-catenin signaling cascades remains unclear. Presently, we observed the increased expression of ZEB2 and decreased expression of miR-637 in GBM. The expression of miR-637 was negatively correlated with expression of ZEB2. miR-637 overexpression overcame the ZEB2-enhanced cell proliferation and G1/S phase transition. In addition, miR-637 suppressed canonical WNT/β-catenin pathways by targeting WNT7A directly. Gain-and loss-of-function experiments in U251 mice demonstrated that miR-637 inhibited cell proliferation and arrested the G1/S phase transition, leading to tumor growth suppression. The collective ndings suggest that ZEB2 and WNT/β-catenin cascades merge at miR-637 and the ectopic expression of miR-637 disturbs ZEB2/WNT/β-Catenin-mediated GBM growth. The ndings should inform improved β-catenin-targeted therapy against GBM.

Dysfunction and ceRNA network of the tumor suppressor miR-637 in cancer development and prognosis

“…As shown in Table 1, miR-637 expression was decreased in 18 cancers. Among them, the expression level of miR-637 in various cancer tissues was significantly lower than that in adjacent tissues, including glioblastoma and lowgrade gliomas (GBM/LGG) [8][9][10][11], papillary thyroid carcinoma (PTC) [12,13], non-small cell lung cancer (NSCLC) [14], gastric cancer (GC) [15][16][17], hepatocellular carcinoma (HCC) [18][19][20][21], CRC [22], pancreatic ductal adenocarcinoma (PDAC) [23], human cholangiocarcinoma (CHOL) [24], oral squamous cell carcinoma (OSCC) [25], prostate cancer (PCa) [26], ovarian cancer (OC) [27,28], triple-negative breast cancer (TNBC) [29], cervical cancer (CCa) [30], osteosarcoma (SaOS) [31,32], multiple myeloma (MM) [33], chronic myeloid leukemia (CML) [34]. In addition, the expression level of miR-637 was lower in the cell lines of various cancer cells than the corresponding normal cell lines, including PTC [12,13], GC [17], HCC [18,21], OSCC [35], PDAC [23], CHOL [36], TNBC [37], breast cancer (BRCA) [38], SaOS [31], etc.…”

“…1). These miR-637-targeted genes include HMGA1 [42], CDK6 [50], and WNT7A [10] in glioma, HEMGN in PTC [12], APLN in GC [15], USP21 in HCC [51], LY6E [36] and CTSB [24] in CHOL, NUPR1 in OSCC [25] and MM [33], HDAC4 in SaOS [32], ABL1 in CML [34], KLK4 in OC [28], PLXNB2 in OC [27], AKT1 in TNBC [37], PTC [13], and HCC [18,20], AKT3 in TNBC [37], and RING1 in CCa [30].…”

“…Wnt1 and Wnt7, encoded by miR-637 targets WNT1 and WNT7A, can coil Frizzled (FZDs) family receptors and recruit Dvl1 to activate the Wnt/β-catenin pathway [63]. In cancer, low levels of miR-637 lead to upregulation of Wnt1 in CRC [56] and Wnt7 in GBM [10] and activate the Wnt/β-catenin pathway, thereby promoting cancer cell invasion, metastasis, metabolism, and inflammation [64].…”

Loss of miR-637 promotes cancer cell stemness via WASH/IL-8 pathway and serves as a novel prognostic marker in esophageal squamous cell carcinoma

“…Previously, miR-637 has been reported to inhibit tumor progression in several types of cancers though various mechanisms [26][27][28]. In glioma, miR-637 represses tumor cell proliferation and migration by targeting Akt1 [26].…”

“…In glioma, miR-637 represses tumor cell proliferation and migration by targeting Akt1 [26]. In addition, miR-637 retards glioblastoma progression via the ZEB2/WNT/beta-catenin cascades [27]. Moreover, miR-637 has been observed to inhibit tumor cell proliferation and invasion by targeting AKT1 in liver cancer [28].…”