PA2G4 promotes the metastasis of hepatocellular carcinoma by stabilizing FYN mRNA in a YTHDF2-dependent manner

Abstract

Background Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with high mortality. Advanced stage upon diagnosis and cancer metastasis are the main reasons for the dismal prognosis of HCC in large part. The role of proliferation associated protein 2G4 (PA2G4) in tumorigenesis and cancer progression has been widely investigated in various cancers. However, whether and how PA2G4 participates in HCC metastasis is still underexplored. Results We found that the mRNA and protein levels of PA2G4 were higher in HCC samples than in normal liver tissues, and high expression of PA2G4 in HCC was correlated with a poor prognosis, by an integrative analysis of immunohistochemistry (IHC), western blot and bioinformatic approach. Moreover, the expression of PA2G4 was elevated in HCC patients with metastases than those metastasis-free. Cell migration, invasion, phalloidin staining and western blot analyses demonstrated that PA2G4 promoted epithelial to mesenchymal transition (EMT) of HCC cells in vitro. And a lung metastasis animal model exhibited that PA2G4 enhanced metastatic ability of HCC cells in vivo. RNA-sequencing combined with dual luciferase reporter assay and evaluation of mRNA half-time indicated that PA2G4 increased FYN expression by stabilizing its mRNA transcript. Recovering the impaired FYN level induced by PA2G4 knockdown rescued the impeded cell mobilities. Furthermore, endogenous immunoprecipitation (IP) and in-situ immunofluorescence (IF) showed that YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) was the endogenous binding patterner of PA2G4. In addition, RNA binding protein immunoprecipitation (RIP) and anti- N6-methyladenosine immunoprecipitation (MeRIP) assays demonstrated that FYN mRNA was N6-methyladenosine (m6A) modified and bound with PA2G4, as well as YTHDF2. Moreover, the m6A catalytic ability of YTHDF2 was found indispensable for the regulation of FYN by PA2G4. At last, the correlation of expression levels between PA2G4 and FYN in HCC tissues was verified by IHC and western blot analysis. Conclusions These results indicate that PA2G4 plays a pro-metastatic role by increasing FYN expression through binding with YTHDF2 in HCC. PA2G4 may become a reliable prognostic marker or therapeutic target for HCC patients.

FYN: emerging biological roles and potential therapeutic targets in cancer

“…A TCGA cancer database analysis based on genes related to lipid metabolism in colon adenocarcinoma found that FYN gene expression was associated with the activation of the EMT pathway [132]. It has been shown in another study that increased FYN expression may contribute to hepatocellular carcinoma metastasis [133].The Wnt5-Fzd2-FYN-Stat3 axis contributes to the EMT program, cell migration, and multiple tumor metastases, and the FYN inhibitor Dasatinib inhibits this process [122].…”

LINC00173 facilitates tumor progression by stimulating RAB1B‐mediated PA2G4 and SDF4 secretion in nasopharyngeal carcinoma

“…PA2G4 can be induced into the nucleus by the pseudogene PA2G4P4 to inhibit glioblastoma cell apoptosis [ 41 ]. It can bind YTHDF2 to increase FYN expression and promote hepatocellular carcinoma metastasis [ 42 ]. Moreover, PA2G4 is reported to be regulated by noncoding RNA [ 43 , 44 ].…”

Nucleophosmin 1 is a prognostic marker of gastrointestinal cancer and is associated with m6A and cuproptosis

“…According to the sum of the correlations of these 385 genes in gastrointestinal cancer, we screened the 30 genes with the strongest correlations, which are RARS1, BTF3, HSPA4, NSA2, HNRNPA1, EIF3M, CCT4, OLA1, UIMC1, G3BP1, NACA, RSL1D1, ETF1, MRPS27, RBM22, CCT8, GEMIN5, LARS1, PA2G4, CDK7, NIFK, RSL24D1, EIF3E, THG1L, INTS13, UBE2D2, RPS23, DIMT1, RIOK2, and TTC27 respectively. Previous studies have reported that overexpression of BTF3, CCT8, CDK7, ELF3M, G3BP1, HSPA4, OLA1, and RSL1D1 can contribute to the occurrence and development of CRC ( Goh et al, 2011 ; Zhou et al, 2019 ; Zhou et al, 2021b ; Liao et al, 2021 ; Zhang et al, 2021 ; Liu et al, 2022a ; Liu et al, 2022b ; Li et al, 2022 ), overexpression of CCT4 and PA2G4 can contribute to the occurrence and development of LIHC( Li et al, 2021a ; Sun et al, 2022 ), overexpression of DIMT1 and HNRNPA1 can contribute to the occurrence and development of STAD ( Liu et al, 2017 ; Zhu et al, 2022 ), and overexpression of EIF3E and UIMC1 can contribute to the ESCA occurrence and development ( Xu et al, 2018 ; Yang et al, 2018 ). Therefore, we believe that these genes have the potential to be called diagnostic and therapeutic targets of gastrointestinal cancer.…”