Long noncoding RNA SGO1-AS1 inactivates TGFβ signaling by facilitating TGFB1/2 mRNA decay and inhibits gastric carcinoma metastasis

Abstract

Background Although thousands of long noncoding RNAs (lncRNAs) have been annotated, only a few lncRNAs have been characterized functionally. In this study, we aimed to identify novel lncRNAs involved in the progression of gastric carcinoma (GC) and explore their regulatory mechanisms and clinical significance in GC. Methods A lncRNA expression microarray was used to identify differential lncRNA expression profiles between paired GCs and adjacent normal mucosal tissues. Using the above method, the lncRNA SGO1-AS1 was selected for further study. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) were performed to detect SGO1-AS1 expression in GC tissues. Gain-of-function and loss-of-function analyses were performed to investigate the functions of SGO1-AS1 and its upstream and downstream regulatory mechanisms in vitro and in vivo. Results SGO1-AS1 was downregulated in gastric carcinoma tissues compared to adjacent normal tissues, and its downregulation was positively correlated with advanced clinical stage, metastasis status and poor patient prognosis. The functional experiments revealed that SGO1-AS1 inhibited GC cell invasion and metastasis in vitro and in vivo. Mechanistically, SGO1-AS1 facilitated TGFB1/2 mRNA decay by competitively binding the PTBP1 protein, resulting in reduced TGFβ production and, thus, preventing the epithelial-to-mesenchymal transition (EMT) and metastasis. In addition, in turn, TGFβ inhibited SGO1-AS1 transcription by inducing ZEB1. Thus, SGO1-AS1 and TGFβ form a double-negative feedback loop via ZEB1 to regulate the EMT and metastasis. Conclusions SGO1-AS1 functions as an endogenous inhibitor of the TGFβ pathway and suppresses gastric carcinoma metastasis, indicating a novel potential target for GC treatment.

Signaling pathways and therapeutic interventions in gastric cancer

“… 352 However, depending on the cell type and physiological environment, TGF-β1 can exhibit opposite effects. TGF-β1 has a significant growth inhibitory effect on cells of epithelial origin by preventing cells from the G1-S phase in vitro, 353 , 354 and TGF-β1 expression is often reduced or absent in malignant tumors. 355 TGF-β1 can also inhibit the proliferation and induce apoptosis of GC cell lines HSC-39 and HSC-43 in vitro.…”

SGOL1-AS1 enhances cell survival in acute myeloid leukemia by maintaining pro-inflammatory signaling

“…SGOL1-AS1, has been previously studied in other cancer types, with varied associations between healthy and cancerous tissue in colorectal cancer, and gastric carcinoma ( Asad Samani and Peymani, 2021 ; Huang et al., 2021 ). Interestingly in the latter, SGOL1-AS1 has been characterized as a cytoplasmic lncRNA that is downregulated in gastric cancer cells.…”

“…Interestingly in the latter, SGOL1-AS1 has been characterized as a cytoplasmic lncRNA that is downregulated in gastric cancer cells. The different cellular localization observed in gastric cancer and AML could possibly reflect distinct SGOL1-AS1 isoforms expressed ( Huang et al., 2021 ). This may also explain why in gastric carcinoma SGOL1-AS1 is a marker of good prognosis ( Huang et al., 2021 ), while we observed that in AML patients high SGOL1-AS1 expression is associated with poor survival across different subtypes of AML.…”

“…Previous publications have shown that expression of this lncRNA is upregulated in lung and colorectal cancer ( Nasim et al., 2019 ; Asad Samani and Peymani, 2021 ). Furthermore, expression of SGOL1-AS1 in gastric carcinoma cells inhibits cell growth, migration and invasion ( Huang et al., 2021 ), by reducing TGF-β signaling.…”

Epithelial-mesenchymal transition-related long noncoding RNAs in gastric carcinoma

“…Transforming growth factor-β (TGF-β) family is a group of structurally related proteins, is involved many cellular functions, including EMT and migration, and many human diseases, including vascular diseases, autoimmune disorders, and carcinogenesis ( Syed, 2016 ). LncRNA Shugoshin-like protein 1-antisense 1 (SGO1-AS1) facilitates TGF-β1/2 mRNA decay by competitively binding to the PTBP1 protein, leading to impaired TGF-β production, and preventing EMT and metastasis ( Huang et al, 2021 ). Extracellular signal-regulated kinase (ERK) cascade can regulates proliferation, differentiation, survival, and apoptosis of cells, the mitogen extracellular signal-regulated kinase (MEK) functions as an upstream essential protein of ERK ( Liu W. et al, 2015 ).…”