PTBP3 mediates TGF-β-induced EMT and metastasis of lung adenocarcinoma

Abstract

Lung adenocarcinoma (LUAD) is associated with a poor prognosis due to early metastasis to distant organs. TGF-β potently induces epithelial-to-mesenchymal transition (EMT) and promotes invasion and metastasis of cancers. However, the mechanisms underlying this alteration are largely unknown. PTBP3 plays a critical role in RNA splicing and transcriptional regulation. Although accumulating evidence has revealed that PTBP3 exhibits a pro-oncogenic role in several cancers, whether and how PTBP3 mediates TGF-β-induced EMT and metastasis in LUAD remains unknown. The expression levels and prognostic value of PTBP3 were analyzed in human LUAD tissues and matched normal tissues. siRNAs and lentivirus-mediated vectors were used to transfect LUAD cell lines. Various in vitro experiments including western blot, qRT-PCR, a luciferase reporter assay, chromatin immunoprecipitation (ChIP), transwell migration and invasion assay and in vivo metastasis experiment were performed to determine the roles of PTBP3 in TGF-β-induced EMT and metastasis. PTBP3 expression was significantly upregulated in patients with LUAD, and high expression of PTBP3 indicated a poor prognosis. Intriguingly, we found that PTBP3 expression level in LUAD cell lines was significantly increased by exogenous TGF-β1 in a Smad-dependent manner. Mechanistically, p-Smad3 was recruited to the PTBP3 promoter and activated its transcription. In turn, PTBP3 knockdown abolished TGF-β1-mediated EMT through the inhibition of Smad2/3 expression. Furthermore, PTBP3 overexpression increased lung and liver metastasis of LUAD cells in vivo. PTBP3 is indispensable to TGF-β-induced EMT and metastasis of LUAD cells and is a novel potential therapeutic target for the treatment of LUAD.

MiR-297 inhibits tumour progression of liver cancer by targeting PTBP3

“…Existing studies show that PTBP3 overexpression induced epithelial-mesenchymal transition (EMT) and promotes the invasive growth and metastasis of breast tumor cells and lung adenocarcinoma cells [ 19 , 20 ]. To explore the mechanisms by which miR-297 suppresses HCC cell migration and invasion, western-blot analysis of EMT-related genes were performed.…”

“…Polypyrimidine tract binding protein 3 (PTBP3) plays a critical role in post-transcriptional regulation including alternative splicing (AS) regulation, maturation, transport, translation, RNA decay, storage and turnover [ 17 – 19 , 21 , 22 ]. PTBP3 was highly expressed in most tumours, such as breast invasive carcinoma, colon adenocarcinoma and hepatocellular carcinoma.…”

Agarose/crystalline nanocellulose (CNC) composites promote bone marrow-derived mast cell integrity, degranulation and receptor expression but inhibit production of de novo synthesized mediators

“…Ptbp3 encodes a protein that is critical in RNA splicing and transcriptional regulation ( Xie et al, 2022 ). The PTBP3 protein mediates TGF-β-induced epithelial-to-mesenchymal transition ( Dong et al, 2022 ) and can serve as an immunomodulatory biomarker of cancer ( Chen et al, 2022 ). Its expression and function in mast cells is unknown.…”

Receptor-Mediated Redox Imbalance: An Emerging Clinical Avenue against Aggressive Cancers

“…The pro-invasive and pro-metastatic roles of TGFβR are evident in a broad panel of cancers including colorectal cancer cells [ 26 ], triple negative breast cancer cells [ 27 ], prostate cancer cells [ 28 ], gastric cancer cells [ 29 ], pancreatic cancer cells [ 30 ], nasopharyngeal cancer cells [ 31 ], lung adenocarcinoma cells [ 32 ], and osteosarcoma cells [ 33 ]. The fundamental roles of TGFβ signaling in cancer metastasis has been attributed to its ability to foster cancer stemness, as exemplified by the elevated SOX4 expression in gastric cancers sustained by TGFβ over-activation [ 34 ].…”