MiR-552-3p Promotes Malignant Progression of Gallbladder Carcinoma by Reactivating the Akt/β-catenin Signaling Pathway Due to Inhibition of the Tumor Suppressor Gene

Background: Gallbladder carcinoma (GBC) remains a highly lethal disease worldwide. MiR-552 family members promote the malignant progression of a variety of digestive system tumors, but the role of miR-552-3p in GBC has not been elucidated. miR-552-3p was predicted to target the 3'-untranslated region (3'UTR) of the mRNA for the tumor suppressor gene "repulsive guidance molecule BMP co-receptor a" (). The aim of the present study was to clarify the roles and mechanisms of miR-552-3p targeting in the malignant progression of GBC.

Methods: : expression of miR-552-3p was detected by real-time quantitative PCR (qRT-PCR) in tumor and non-tumor adjacent tissues (NATs). Lentivirus-miR-552-3p was employed to knockdown this miRNA in GBC cell lines. Stem cell-related transcription factors and markers were assessed by qRT-PCR. Cell Counting Kit-8 (CCK-8), sphere formation and transwell assays were used to determine the malignant phenotypes of GBC cells. Targeting the 3'UTR of by miR-552-3p was verified by integrated analysis including bioinformatics prediction, luciferase assays, measures of changes of gene expression and rescue experiments. : mouse models of subcutaneous tumors and lung metastases were established to observe the effect of miR-552-3p on tumorigenesis and organ metastasis, respectively.

Results: MiR-552-3p was abnormally highly expressed in GBC tissues and cancer stem cells. Interference with miR-552-3p in SGC-996 and GBC-SD cells significantly inhibited GBC stem cell expansion. Reciprocally, miR-552-3p promoted GBC cell proliferation, migration and invasion both and ; hence, interference with this miRNA impeded the malignant progression of GBC. Furthermore, the important tumor suppressor gene was identified as a target of miR-552-3p. The effects of miR-552-3p on cell proliferation and metastasis were abrogated or enhanced by gain or loss of function, respectively. Mechanistically, miR-552-3p promoted GBC progression by reactivating the Akt/β-catenin pathway and epithelial-mesenchymal transformation (EMT). Clinically, miR-552-3p correlated with multi-malignant characteristics of GBC and acted as a prognostic marker for GBC outcome.

Conclusions: MiR-552-3p promotes the malignant progression of GBC by inhibiting the mRNA of the tumor suppressor gene , resulting in reactivation of the Akt/β-catenin signaling pathway.