PRRC2A Promotes Hepatocellular Carcinoma Progression and Associates with Immune Infiltration

Abstract

Purpose Hepatocellular carcinoma (HCC) has high morbidity and poor prognosis due to the propensity of recurrence and metastasis. Emerging studies have confirmed that proline-rich coiled-coil2A (PRRC2A) plays a crucial role in tumorigenesis and immunoregulation. However, its expression status and biological functions in HCC remain poorly documented. Methods The presence and prognostic value of PRRC2A were determined by a tissue microarray (TMA) cohort and multiple databases, mainly from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Clinical Proteomic Tumor Analysis Consortium (CPTAC). Functional enrichment analysis was applied to identify the mechanisms of PRRC2A in HCC. The biological function of PRRC2A in HCC progression in vitro was determined by CCK-8, colony formation, EdU, transwell migration and invasion assays. Moreover, the Estimation of STromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE), single-sample gene set enrichment analysis (ssGSEA), tumor immune dysfunction and exclusion (TIDE) algorithms, immunophenoscore (IPS) and public available immunotherapy cohorts were performed to classify their associations with tumor-infiltrating immune cells and immunotherapy. Results PRRC2A was upregulated in HCC at both mRNA and protein levels. High PRRC2A expression was correlated with poor prognosis and could be an independent risk factor. Functional enrichment analysis demonstrated that elevated PRRC2A was significantly correlated with the activation of various oncogenic pathways. Additionally, in vitro experiments confirmed that silencing PRRC2A could suppress the proliferation and metastasis capacities of HCC cells. More importantly, PRRC2A was negatively associated with many anti-tumor immune cells, but positively related to the expression of markers of exhaustive T cells. And HCC patients with high PRRC2A were more likely to be nonresponsive to immunotherapy. Conclusion This study explored the predictive value and biological roles of PRRC2A in HCC progression and indicated that it might be a potential biomarker for HCC patients and a predictor for immunotherapy.

Identification of a CD4+ conventional T cells-related lncRNAs signature associated with hepatocellular carcinoma prognosis, therapy, and tumor microenvironment

“…and our results suggested a higher infiltration rate of resting myeloid DCs in the high-risk group, which may contribute to a poorer immune response. The data from the ESTIMATE method showed that the high-risk group had a higher immune score, which could represent the higher levels of immune cell infiltration in the TME and was consistent with previous studies (58,59). However, our study showed that high risk patients had poor immunotherapy response and high immune cell infiltration levels did not mean a better immunotherapy response.…”

PRRC2 proteins impact translation initiation by promoting leaky scanning

“…Although their molecular functions are not completely understood, the PRRC2 proteins appear to have clinical relevance. Mutations in PRRC2A are associated with multiple cancers, including non-Hodgkin-Lymphoma ( 13 ), lung cancer ( 14 ), ER-positive breast cancer ( 15 ) and hepatocellular carcinoma, where they promote progression and immune infiltration ( 16 ). A PRRC2B-ALK gene fusion was found in an aggressive malignant neoplasm ( 17 ), and PRRC2C was found to have a different pattern of alternative splicing in non-small lung tumors compared to healthy lung ( 18 ).…”

PRRC2 proteins regulate translation initiation by promoting leaky scanning

“…1A-B). Since these proteins have been linked to disease (16–19,22), we decided to study them in detail. We confirmed that PRRC2B and PRRC2C interact with eIFs by co-immunoprecipitation with endogenous eIF3B, eIF4G1 and eIF4E (Figure 2G).…”

“…Although their molecular functions are not completely understood, the PRRC2 proteins appear to have clinical relevance. Mutations in PRRC2A are associated with multiple cancers, including non-Hodgkin-Lymphoma (16), lung cancer (17), ER-positive breast cancer (18) and hepatocellular carcinoma, where they promote progression and immune infiltration (19). A PRRC2B-ALK gene fusion was found in an aggressive malignant neoplasm (20), and PRRC2C was found to have a different pattern of alternative splicing in non-small lung tumors compared to healthy lung (21).…”