SMG9 Serves as an Oncogene to Promote the Tumor Progression via EMT and Wnt/β-Catenin Signaling Pathway in Hepatocellular Carcinoma

Abstract

Background/Aims: SMG9 participates in the nonsense-mediated mRNA decay process that degrades mRNA harboring nonsense mutations introduced either at the level of transcription or RNA processing. However, little is known about the role of SMG9 in hepatocellular carcinoma (HCC). The objective of this research was to clarify the effects of SMG9 expression on HCC progression.Methods: Microarray data were acquired from NCBI Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database to bioinformatically analyze the differential expression of SMG9 between HCC patients and normal controls. SMG9 mRNA level was measured in sixteen sets of fresh tumor tissues and adjacent non-cancerous liver tissues (ANLTs) via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). SMG9 protein expression was analyzed in ninety-five sets of paired formalin-fixed and paraffin-embedded tissue specimens by immunohistochemistry (IHC). In addition, clinicopathological features of SMG9 in HCC were checked. For in vitro studies, small interfering RNA (siRNA) was used to silence SMG9 expression for exploring biological functions and underlying mechanisms of SMG9 in SMMC-7721 and HepG2.Results: We found that SMG9 was upregulated in HCC tissues and SMG9 levels were closely related to TNM stage, tumor number and tumor size. Cox regression and Kaplan–Meier proportional hazards analyses showed that high expression of SMG9 was associated with poor patient survival. Furthermore, proliferation, apoptosis resistance, migration and invasion of both SMMC-7721 and HepG2 cells were suppressed by SMG9 inhibition. In addition, EMT and the Wnt/β-catenin signaling pathway were involved in SMG9-mediated HCC progression.Conclusions: SMG9 may serve as a potential novel prognostic biomarker and therapeutic target in HCC patients.

SMG9 is a novel prognostic-related biomarker in glioma correlating with ferroptosis and immune infiltrates

“…SMG9 remarkably enhanced HCC cell line functioning, such as proliferation, cell cycle progression, apoptotic resistance, invasion, and migration. The epithelial–mesenchymal transition (EMT) and the Wnt/-catenin signaling pathway may be important in driving these processes [ 26 ]. In the previous study, SMG9, an element of the NMD mechanism, was shown to be a selective trigger for ferroptosis in human cancer cells.…”

“…SMG9, a 520-amino acid protein with centrally located nucleotide triphosphatase domains, enhances GPX4 disintegration during ferroptosis in response to RSL3, a GPX4 inhibitor [ 25 ]. Elevated SMG9 expression levels have been correlated with poor prognosis in hepatocellular carcinoma (HCC), suggesting its potential as a treatment target [ 26 ]. However, its utility as a biomarker for glioma and its involvement in gliomas remain unclear.…”

Ciliopathy-associated missense mutations in IFT140 are hypomorphic and have edgetic effects on protein interaction networks

“…Another interesting new interactor of IFT140 is SMG9. It has been implicated in brain, heart and eye development (Jin et al 2021). This is in line with the defects observed in patients suffering from ciliopathies associated to mutations in IFT140 (table 2).…”

Shanxian granule‑containing serum mediated inhibition of hepatic oval cell EMT and malignant transformation via the Wnt/β‑catenin signaling pathway

“…23 β-catenin is a key molecule in EMT and malignant transformation of liver cancer cells, and is highly expressed in liver cancer cells. 24 In the presence of Wnt ligands, Wnt ligands bind to the curled homologues and coreceptors on the cell membrane, causing the aggregation of scattered proteins, activating this pathway, GSK-3 inactivation, cytoplasmic β-catenin cannot be phosphorylated by GSK-3β, β-catenin gradually accumulates and enters the nucleus, interacts with the nuclear transcription factor T lymphocyte factor / lymphoid enhancer factor ( TCF / LEF ), regulates the expression of target genes such as c-myc, thereby regulating the malignant transformation of HOC and EMT 25,26 further leading to the formation of liver cancer.…”