PTBP3 contributes to the metastasis of gastric cancer by mediating CAV1 alternative splicing

Abstract

Polypyrimidine tract-binding protein 3 (PTBP3) is an essential RNA-binding protein with roles in RNA splicing, 3′ end processing and translation. Although increasing evidence implicates PTBP3 in several cancers, its role in gastric cancer metastasis remains poorly explored. In this study, we found that PTBP3 was upregulated in the gastric cancer tissues of patients with lymph node metastasis. Patients with high PTBP3 expression levels had significantly shorter survival than those with low PTBP3 expression. Overexpression/knockdown of PTBP3 expression had no effect on proliferation, whereas it regulated migration and invasion in vitro. In addition, when a mouse xenotransplant model of MKN45 was established, knockdown of PTBP3 in MKN45 cells caused the formation of tumours that were smaller in size than their counterparts, with suppression of tumour lymphangiogenesis and metastasis to regional lymph nodes. Furthermore, we identified caveolin 1 (CAV1) as a downstream target of PTBP3. RNA immunoprecipitation (RIP) assays and dual-luciferase reporter gene assays indicated that PTBP3 interacted with the CU-rich region of the CAV1 gene to downregulate CAV1α expression. Knockdown of CAV1α abrogated the reduction of FAK and Src induced by PTBP3 knockdown. In summary, our findings provide experimental evidence that PTBP3 may function as a metastatic gene in gastric cancer by regulating CAV1 through alternative splicing.

RNA-binding proteins in tumor progression

“…PTBP3 may regulate CAV1 through alternative splicing and become a metastasis gene for gastric cancer. Promoted HCC cell proliferation and metastasis both in vitro and in vivo regulation EMT [ 46 – 48 ] PTBP1 RNA transport, RNA translation Acute myeloid FLT3 Upregulation FLT3-ITD-positive cells, FLT3-ITD-negative cells circMYBL2 regulates FLT3 translation by recruiting PTBP1 to promote FLT3-ITD AML progression. Promotes proliferation and differentiation [ 49 ] NELFE mRNA stability, RNA translation Hepatocellular carcinoma MYC-related genes, SYNGR2 Upregulation Clinical HCC samples NELFE is an oncogenic protein that causes imbalance in the HCC transcriptome by regulating MYC signaling.…”

WGCNA Co-Expression Network Analysis Reveals ILF3-AS1 Functions as a CeRNA to Regulate PTBP1 Expression by Sponging miR-29a in Gastric Cancer

“…PTBP3 has also been found to play important roles in lung adenocarcinoma, glioblastoma multiforme, squamous cell carcinoma, and gastric cancer. In gastric cancer, PTBP3 contributes to the cancer metastasis by mediating CAV1 alternative splicing (Liang et al, 2018). Inhibition of PTBP3 induces apoptosis and cell cycle arrest, and enhances the cytotoxicity of 5-fluorouracil in gastric cancer cells (Liang et al, 2017).…”

Splicing Regulator p54nrb/Non–POU Domain–Containing Octamer‐Binding Protein Enhances Carcinogenesis Through Oncogenic Isoform Switch of MYC Box–Dependent Interacting Protein 1 in Hepatocellular Carcinoma

“…Recent studies have unveiled the crucial modulation of RBPs in AS and their roles in different physiological and pathological conditions. (27)(28)(29)(30)(31) DHX9 is a multifunctional RBP that regulates RNA splicing, processing, transport, and transcription. In liver cancer, DHX9 participates in disease progression by regulating circular RNA SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 5 (SMARCA5) splicing.…”