GNA14's interaction with RACK1 inhibits Hepatocellular Carcinoma progression through reducing MAPK/JNK and PI3K/AKT signaling pathway.

ABSTRACT: Gαq subfamily proteins play critical roles in many biological functions including cardiovascular development, angiogenesis and tumourgenesis of melanoma. However, the understanding of G Protein Subunit Alpha 14(GNA14) in diseases, especially in cancers is limited. Here, we revealed that GNA14 was significantly low-expression in human Hepatocellular Carcinoma (HCC) samples. Low GNA14 expression was correlated with aggressive clinicopathological features. Moreover, the overall survival (OS) and disease-free survival (DFS) of high GNA14 expression HCC patients were much better than low GNA14 expression group. Lentivirus-mediated GNA14 knockdown significantly promoted the growth of liver cancer in vitro and in vivo. However, opposing results were observed when GNA14 is up-regulated. Mechanistically, We identified Receptor For Activated C Kinase 1 (RACK1) as a binding partner of GNA14 by coimmunoprecipitation (co-IP) and mass spectrometry (MS). Glutathione-S-transferase (GST) pull-down assay further verified the direct interaction between GNA14 and RACK1. RNA-Seq and loss- and gain-of-function assays also confirmed that GNA14 reduced the activity of both MAPK/JNK and PI3K/AKT signaling pathways through RACK1. GNA14 synergized with U73122 (PLC inhibitor) to enhance this effect. Further studies suggested that GNA14 potentially competed with Protein Kinase C (PKC) to bind with RACK1, consequently reducing the stability of PKC. Moreover, we also showed that GNA14'supression of p-AKT protein level depended on sufficient RACK1 expression. In conclusion, we indicated a different role of GNA14, which acted as a suppressor inhibiting liver cancer progression through MAPK/JNK and PI3K/AKT signaling pathways. Due to this, GNA14 served as a potentially valuable prognostic biomarker for liver cancer.

SUBMITTER: Xu C 

PROVIDER: S-EPMC8598382 | biostudies-literature |

REPOSITORIES: biostudies-literature