Due to the cellular heterogeneity and complex pathogenesis of HCC, its fatality rate remains relatively high worldwide [20, 21]. In recent years, more and more evidence have shown that prognostic gene markers have great potential in the prognosis of HCC [8]. In this study, the PTGFRN gene was used as the research object, and 377 HCC patients from TCGA were evaluated and found factors related to high expression of PTGFRN, namely clinical stage, histological grade, and survival time. The potential functions and related pathways of PTGFRN in HCC were obtained by enrichment analysis. It further confirmed the correlation between PTGFRN and the malignant phenotype and prognosis of HCC, and clarified the importance of PTGFRN as a potential biomarker of HCC.
In this study, we used the TCGA database for bioinformatics assessment to explore the expression level of PTGFRN in HCC. Previous studies have shown that PTGFRN is overexpressed in renal cell carcinoma and glioblastoma multiforme and is closely associated with poor prognosis [14, 22]. In addition, PTGFRN has also been shown to be increased in lung tumors and is closely associated with lung tumor growth restriction and lung transplantation metastatic status [15]. We can see that the gene PTGFRN is highly expressed in many cancers, and we found that PTGFRN is also highly expressed in HCC patients. In addition, we analyzed the relevant expression data and found that the expression of PTGFRN in HCC was significantly higher than that of adjacent non-tumor tissues. Therefore, we speculated that the high expression of PTGFRN might affect the related progression of HCC, and carried out further analysis.
Next, we performed a series of correlation analyses in order to explore whether PTGFRN could be used as an independent target. In our study, we discovered increased expression PTGFRN in HCC associated with late-stage clinical and pathological features and predict a poor prognosis. The elevated expression level of PTGFRN at the high stage suggests a negative impact on the progression of HCC. Importantly, we found that the high expression of PTGFRN in tumor tissues is closely related to shorter OS and DFS. Global gene expression profile analysis of HCC tissue samples showed that PTGFRN mRNA expression was significantly up-regulated compared with normal liver tissue. The ROC curve of PTGFRN showed that its mRNA expression level had a high diagnostic value for HCC. Previous studies have not clarified the relationship between PTGFRN expression level and HCC tissue stage. However, the present study found that PTGFRN expression has a good predictive ability in low, high and histological grades. Through the analysis of HCC stage M and N, although the results were not statistically significant, it was undeniable that the expression level of PTGFRN in M1 and N1 stages was higher than that in M0 and N0 stages. In addition, multivariate Cox analysis showed that overexpression of PTGFRN was an independent risk factor affecting the survival of patients with HCC. Therefore, according to the data we analyzed above, PTGFRN can serve as a potential new therapeutic target and an independent prognostic factor for HCC. Moreover, we urgently need to understand how the high expression of PTGFRN affects the occurrence and development of HCC.
To further explore the potential pathways regulated by PTGFRN in HCC, we performed GSEA analysis of PTGFRN. We have observed that the high expression phenotype of PTGFRN is mainly enriched to “endocytosis”, “oocyte meiosis”, “cancer pathways”, “purine metabolism”, “renal cell carcinoma”, “regulation of actin cytoskeleton”, “glioma” and “ERBB signaling pathway”. Studies have pointed out that changes in the endocytosis of cancer cells will affect the changes in related cancer signaling pathways, thereby promoting the occurrence and development of tumors [23]. Zhou et al. [24] found that overexpression of SNX5 can promote the migration and invasion of HCC cells by mediating endocytosis. Qi et al. [25] found that CD147 was up-regulated in HCC, and its endocytosis played a key role in the occurrence, invasion, and distant metastasis of HCC. We suspect that the overexpression of PTGFRN may affect the progression of HCC by mediating endocytosis. In addition, related study has shown that purine nucleotides are the basic and necessary factors of tumor cell proliferation, abnormal purine metabolism can promote the rapid proliferation and growth of tumor cells [26]. For cancer pathways, overexpression of miR-296-5p has been reported to inhibit the oncogenic role of the ERBB signaling pathway in HCC with a favorable prognosis [27]. In addition to the ERBB pathway, oocyte meiosis and jak/stat pathways have also been shown to play an important role in the carcinogenesis or progression of HCC [28, 29]. Perhaps this prompted that HCC activates the various signaling pathway by increasing the expression of PTGFRN, which in turn leads to a poor prognosis for patients. GSEA results also showed that PTGFRN was involved in the regulation of the actin cytoskeleton. Actin regulatory proteins are considered to be a basic mechanism of cell migration. Studies have shown that actin regulatory proteins are considered to be the basic mechanism of cell migration. It is closely related to the poor prognosis of breast cancer and liver cancer, and is involved in the development of many cancers [30]. Based on GSEA, we also identified pathways associated with the cell cycle. However, the effect of transcriptional activation of PTGFRN on cell cycle progression and HCC progression still needs to be further studied. It can be seen that PTGFRN is related to many important pathways, and its up-regulation changes may affect the changes of a series of important pathways.
Finally, GO and KEGG enrichment analysis was performed on the co-expression genes of PTGFRN, and some important findings were obtained. The results showed that PTGFRN co-expressed genes were mainly involved in biological processes such as “PI3K-Akt signaling pathway”, “ECM-receptor interaction”, “extracellular matrix organization”, “cell development”, “angiogenesis”, “adhesion”, “TNF-α/NF-kB signaling pathway” and “epithelial-mesenchymal transformation”. As we all know, the growth and migration of solid tumor cells are closely related to angiogenesis. S Colin et al. found that the domain GS-168AT2 of PTGFRN can inhibit the proliferation and migration of human endothelial cells (hEC) in vitro and in vivo, and its anti-angiogenic activity is likely to be the main reason for the anti-tumor growth effect [15]. It indicated that PTGFRN might be involved in the malignant biological behavior of HCC. Moreover, our study also demonstrated that overexpression of PTGFRN was significantly associated with histological grade of HCC and predicted poor prognosis. In addition, the co-expression genes of PTGFRN are also importantly involved in the extracellular matrix organization (EMO) process. Previous studies have shown that EMO can provide a complex microenvironment for HCC cells and actively participate in the tumor development of HCC, such as angiogenesis, epithelial-mesenchymal transformation (EMT), invasion and metastasis [31, 32]. Besides, EMT is believed to play an important role in the anti-apoptosis, invasion, chemical drug resistance and other pathological processes of HCC cells [33, 34]. In addition, we found that PI3K-Akt and NF-kB signaling pathways were also significantly enriched. Studies have shown that NF-kB can act as downstream effectors of the PI3K-Akt pathway, and their abnormal activation is positively correlated with the malignant progression of HCC and leads to poor prognosis of HCC patients [35]. These enriched pathways suggest that PTGFRN may be involved in the progression of HCC at different stages. In addition, GO term enrichment analysis showed that PTGFRN may affect the cycle progression of tumor cells through cell adhesion and cell proliferation. Studies have confirmed that cell adhesion molecule overexpression can interact with ECM receptor, which is the key factor to accelerate the metastasis of HCC cells in blood vessels [36]. In addition, recent studies have shown that inhibition of PTGFRN can lead to a decrease in cell proliferation levels [14]. Furthermore, we reported for the first time that the expression of PTGFRN may also be related to chemotaxis, lateral plasma membrane, and inflammatory response pathways. But its regulatory mechanism needs to be further elucidated. In summary, the abundant GO and KEGG pathways explain the important role of PTGFRN in the progression of HCC to a certain extent.