Dual activation of Hedgehog and Wnt/β-catenin signaling pathway caused by downregulation of SUFU targeted by miRNA-150 in human gastric cancer

Abstract

Mounting evidence has shown that miRNA-150 expression is upregulated in gastric cancer (GC) and is associated with gastric carcinogenesis, but the underlying oncogenic mechanism remains elusive. Here, we discovered that miRNA-150 targets the tumor suppressor SUFU to promote cell proliferation, migration, and the epithelial–mesenchymal transition (EMT) via the dual activation of Hedgehog (Hh) and Wnt signaling. MiRNA-150 was highly expressed in GC tissues and cell lines, and the level of this miRNA was negatively related to that of SUFU. In addition, both the miRNA-150 and SUFU levels were associated with tumor differentiation. Furthermore, miRNA-150 activated GC cell proliferation and migration in vitro . We found that miRNA-150 inhibitors repressed not only Wnt signaling by promoting cytoplasmic β-catenin localization, but also repressed Hh signaling and EMT. MiRNA-150 inhibition also resulted in significant tumor volume reductions in vivo , suggesting the potential application of miRNA-150 inhibitors in GC therapy. The expression of genes downstream of Hh and Wnt signaling was also reduced in tumors treated with miRNA-150 inhibitors. Notably, anti-SUFU siRNAs rescued the inhibitory effects of miRNA-150 inhibitors on Wnt signaling, Hh activation, EMT, cell proliferation, cell migration, and colony formation. Taken together, these findings indicate that miRNA-150 is oncogenic and promotes GC cell proliferation, migration, and EMT by activating Wnt and Hh signaling via the suppression of SUFU expression.

Single‐cell RNA‐seq dissecting heterogeneity of tumor cells and comprehensive dynamics in tumor microenvironment during lymph nodes metastasis in gastric cancer

“…Interestingly, higher GSVA scores of Wnt/β‐Catenin signaling pathway and NOTCH signaling were showed in MLN, indicating the association between Wnt/β‐Catenin signaling pathway and metastasis. However, GSVA score of Hedgehog signaling was higher in PT, which seemed opposite to its role in invasion and migration of cancer cells previously reported 16,17 . Genes associated with oxidative phosphorylation were suppressed in MLN.…”

A novel protein AXIN1-295aa encoded by circAXIN1 activates the Wnt/β-catenin signaling pathway to promote gastric cancer progression

“…Cell proliferation was determined using an EdU assay (Ribobio, Guangzhou). Following transfection for 48 h, cells were collected to conduct the assays, as previously described [ 25 ]. The cell proliferation rate was calculated by dividing the number of actively dividing cells (red) by the total number of cells (blue).…”

Noncoding RNAs related to the hedgehog pathway in cancer: clinical implications and future perspectives

“…If diagnostic biomarkers targeting multiple pathways simultaneously can be found, it will be a big step towards curing the malignant diseases that threaten human life. As stated in the study [ 124 ], Sufu targeted and down-regulated by oncogene miR-150 promotes the occurrence and metastasis of human gastric cancer through dual activation of Wnt/β-catenin and Hh pathways. Circular RNA circ102004 has carcinogenic effects in prostate cancer.…”

“…In addition, miRNA-326 [ 102 , 103 ], miR-361-3p [ 104 ], miR-338-3p [ 105 , 106 ], miR-182-5p [ 107 ], miR-1271 [ 108 ], miR-506-3p [ 109 ], miR-873-5p [ 110 ], miR-324-3p [ 111 ], miR-218 [ 112 ], miR-636 [ 113 ], miR-506 [ 114 ], miR-7-5p [ 115 , 116 ], miR-124 [ 117 ], miR-150 [ 118 ], miR-202-3p [ 119 ], miR-144-3p [ 120 ] and miR-141-3p [ 121 ] also act as cancer suppressors and interact with critical Hh signaling regulators (such as Ptch, Smo and Gli1) to regulate tumor progression. However, some up-regulated miRNAs, such as miR-212 [ 122 , 123 ], miR-150 [ 124 ], miR-9 [ 125 ], miR-224 [ 126 ], miR-214 [ 127 ] and miR-221 [ 128 ] have been reported in tumors that induce tumor formation and recurrence through Hh signaling cascades. Of course, several miRNAs (such as miR-150) have a dual role in different tumors, which can promote or inhibit the growth of cancer.…”