DNA primase subunit 1 deteriorated progression of hepatocellular carcinoma by activating AKT/mTOR signaling and UBE2C-mediated P53 ubiquitination

Abstract

Background DNA primase subunit 1 (PRIM1) has been reported as a novel oncogene in several cancer types. However, its roles in hepatocellular carcinoma (HCC) remain unclear. This study aimed to investigate underlying mechanisms of PRIM1 and identify it as a potential molecular target for HCC. Methods Hub genes were screened between HCC tissues and normal liver tissues in 3 gene expression omnibus (GEO) datasets and the cancer genome atlas (TCGA). The expression features and prognostic value of one of the hub genes PRIM1 were analyzed by bioinformatic analyses and immunohistochemistry. Loss-of-function and gain-of-function studies were used to investigate the regulatory role of PRIM1 in HCC cells. Real-time (RT)-qPCR, western blotting, and ubiquitin immunoprecipitation assays were performed to explore the underlying mechanisms. The xenograft model was employed to detect the roles of PRIM1 in tumor growth in vivo. Finally, the 3D spheroid model was conducted to validate the role of PRIM1 in tumor growth and sorafenib resistance. Results The hub genes of HCC were screened in multiple bioinformatic datasets. PRIM1, as one of the hub genes, was significantly overexpressed in HCC tissues in mRNA and protein levels. In addition, high expression of PRIM1 indicated poor prognosis of HCC patients in TCGA, ICGC, and Nantong cohorts. Overexpression of PRIM1 promoted the proliferation, migration/invasion, and sorafenib resistance of HCC cells, with the decrease in apoptosis and cell cycle arrest. Mechanically, PRIM1 facilitated epithelial-mesenchymal transition (EMT) process and the activity of PI3K/AKT/mTOR signaling of HCC cells. Additionally, PRIM1 could cause the ubiquitination and degradation of P53 by upregulating Ubiquitin Conjugating Enzyme E2 C (UBE2C). Furthermore, knockdown of PRIM1 significantly inhibited the growth of xenograft tumors and HCC cells-derived spheroids with enhanced sorafenib resistance. Conclusion This study implies that PRIM1 may play a key role in the progression of HCC and may serve as a potential target for HCC treatment.

Exploring the Expression and Prognostic Value of the TCP1 Ring Complex in Hepatocellular Carcinoma and Overexpressing Its Subunit 5 Promotes HCC Tumorigenesis

“…The Cancer Genome Atlas is one of the largest publicly available cancer database of alterations in the oncogenic genome. Abundance of potential cancer biomarkers and cancerassociated gene in HCC have been discovered by using TCGA database and other public platforms (22,23), however, the molecular mechanisms of HCC development are still incompletely understood. The ATP-dependent chaperone TRiC directly assists in the folding of up to 10% of all cytosolic proteins (4), and acts as an important regulator of cancer development by promoting the folding and activity of cancerrelated proteins such as VHL, p53, and STAT3 (9)(10)(11).…”

P53 suppresses the progression of hepatocellular carcinoma via miR‐15a by decreasing OGT expression and EZH2 stabilization

“… 38 , 39 P53, the ubiquitination and degradation of which may be involved in the PRIM1‐promoted proliferation, migration/invasion and sorafenib resistance of HCC cells, has also been reported to induce cancerous cell apoptosis in HCC. 40 , 41 , 42 P53 and miR‐15a share a positive loop, which is important for tumour suppression in HCC by miR‐15a. OGT is a GlcNAc transferase, which catalyses serine and threonine residues of intracellular proteins with O‐GlcNAc modification.…”

Expression Levels of Three Key Genes CCNB1, CDC20, and CENPF in HCC Are Associated With Antitumor Immunity

“…Therefore, it is meaningful to identify new markers for HCC diagnosis. Some studies reported that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) and DNA primase subunit 1 (PRIM1) might be potential molecular targets for HCC ( 41 , 42 ). Those two molecular targets regulated the proliferation, migration, and invasion of HCC cells.…”