Downregulation of PRAME Suppresses Proliferation and Promotes Apoptosis in Hepatocellular Carcinoma Through the Activation of P53 Mediated Pathway

Abstract

Background/Aims: The expression of PRAME and its role in hepatocellular carcinoma (HCC) remain unknown. The aim of this study was to examine the functional role of PRAME in HCC development and exploring the molecular mechanism. Methods: We first detected PRAME expression in 96 human HCC tissue samples and correlated with clinicopathological characteristics and prognosis of the patients. We then established stable HCC cell lines with PRAME overexpression and knockdown followed by functional analysis in vitro. Further, we examined the relationship between PRAME and p53 pathway in vitro by using Western blotting. Finally, PRAME expression was detected to evaluate its correlation with p-p53 and p53 pathway related apoptotic proteins in xenograft tumor mouse model using immunohistochemistry. Results: PRAME expression was significantly higher in HCC tissues than in adjacent non-tumor tissues and their expression was positively correlated with alpha fetoprotein levels and tumor size. In addition, PRAME expression was associated with AJCC stage and is a potential biomarker of poor prognosis regarding 5-year overall survival in HCC. In vitro studies, we found that PRAME expression was higher in HCC cell lines than in normal hepatic cell line. Inhibited cell proliferation and increased cell apoptosis was observed in PRAME knockdown HCC cells. Futher, increased cell apoptosis was correlated with the proportion of cells in G0/G1 stage, activated p53 mediated apoptosis, and increased cyclin p21 expression. Xenograft analysis in nude mice also found that PRAME knockdown inhibited tumorigenesis while PRAME overexpression had opposite effect. Conclusions: In HCC, PRAME serves as a potential biomarker for poor prognosis and novel therapeutic target in treating this cancer. PRAME is a potential biomarker of poor prognosis in HCC. PRAME surpresses HCC cell death in vitro and in vivo by regulating p53 apoptotic signaling and may serve as a potential therapeutic target in HCC.

Cancer testis antigen PRAME: An anti‐cancer target with immunomodulatory potential

“… 5 , 8 , 9 , 10 , 11 , 12 Several studies suggest that PRAME can induce cell proliferation, reduce cytotoxic drug sensitivity and inhibit apoptosis in a variety of cancers. 13 , 14 , 15 , 16 The restricted, highly tumour‐specific expression of PRAME in conjunction with its oncogenic functions support the rationale for therapeutic targeting of PRAME in cancer.…”

“…High PRAME tumour expression has been associated with poor prognosis in several solid tumours, increased risk of metastases and shorter disease‐free and overall survival, 7 whereas it has been found to predict a more favourable outcome in acute myeloid and lymphoblastic leukaemia 5,8‐12 . Several studies suggest that PRAME can induce cell proliferation, reduce cytotoxic drug sensitivity and inhibit apoptosis in a variety of cancers 13‐16 . The restricted, highly tumour‐specific expression of PRAME in conjunction with its oncogenic functions support the rationale for therapeutic targeting of PRAME in cancer.…”

Improving the diversity of captured full-length isoforms using a normalized single-molecule RNA-sequencing method

“…8e ). Among them, two genes, preferentially expressed antigen in melanoma ( PRAME ) and Janus kinase and microtubule interacting protein 1 ( JAKMIP1 ), were reported as cancer/testis (CT) genes that were selectively expressed in testis and cancers 21 , 22 . DUSP13 , TRAPPC3L, and solute carrier family 26 member 8 ( SLC26A8 ) were also selectively or highly expressed in testis and therefore could represent new CT genes 23 – 26 .…”

The Mechanistic Differences in HLA-Associated Carbamazepine Hypersensitivity

“…However, no decrease in viability of the recombinant cell lines could be observed after treatment with CBZ, neither on cellular level (data not shown) nor in the proteomic analyses. This might be due to the strongly regulated antiapoptotic protein PRAMEF20 and MAML2 [78,79]. Furthermore, translational activity and metabolic activity are not reduced, as proteins such as NSUN4 are upregulated and LPIN1 are downregulated [80,81].…”