Bioinformatics Analysis Combined With Experiments Predicts PUDP as a Potential Prognostic Biomarker for Hepatocellular Carcinoma Through Its Interaction With Tumor Microenvironment

Abstract

Hepatocellular carcinoma (HCC) is one of the deadliest tumors in the world and is notorious for poor prognosis. There is mounting evidence that pseudouridine performs key functions in the initiation and progression of several cancers. A previous study demonstrated that Pseudouridine 5’-phosphatase (PUDP) may be a novel prognostic biomarker in colorectal cancer. However, in the past, we have paid little attention to PUDP and we are still not clear about its function and role in cancer. In this study, a pan-cancer analysis of PUDP expression and prognosis was performed firstly using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data and we found that PUDP may be a potential oncogene for HCC. Then the most potential upstream microRNA contributing to PUDP was identified as let-7c-5p through expression analysis, correlation analysis, and survival analysis. Subsequently, the result of single cell RNA sequencing (scRNA-seq) demonstrated that PUDP was significantly highly expressed on malignant cells. In addition, there are significantly positive correlations between PUDP and tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression, especially with tumor-promoting immune cells such as T cell regulatory (Treg), Myeloid-derived suppressor cell (MDSC), cancer-associated fibroblast (CAF). Moreover, we found the methylation level of three loci was positively correlated with PUDP expression and four loci were negatively correlated. 15 pairs of HCC and normal adjacent tissues from HCC patients who were treated at our center were used to verify the results of the bioinformatics analysis and the results of experiments are similar to the bioinformatics analysis. Our study demonstrated that HCC patients with high PUDP expression are less likely to benefit from immunotherapy, and in addition, we explored the relationship between PUDP and anticancer drugs. Finally, we explored the clinical relevance of PUDP, identified PUDP as an independent risk factor for HCC patients and constructed a prognostic model, used International Cancer Genome Consortium (ICGC) data to do external validation. Collectively, our study demonstrated that high expression of PUDP suggested a poor prognosis and low response to immunotherapy, providing new insight into the treatment and prognosis of HCC.

Identified Gefitinib Metabolism-Related lncRNAs can be Applied to Predict Prognosis, Tumor Microenvironment, and Drug Sensitivity in Non-Small Cell Lung Cancer

“…We concluded that the TIDE composite score was not significant between the high-risk and low-risk subgroups, while MDSC, CAF expression, and risk score were significantly and positively correlated. regulatory (Treg), MDSC, and CAF (70). Next, we identified compounds that might be used to treat patients with NSCLC, and anticancer therapy with various drugs might be indicated for patients with higher risk scores.…”

“…We concluded that the TIDE composite score was not significant between the high-risk and low-risk subgroups, while MDSC, CAF expression, and risk score were significantly and positively correlated. Yu et al revealed a significant positive correlation between PUDP and tumor immune cell infiltration, immune cell biomarkers, and immune checkpoint expression, particularly with pro-tumor immune cells such as T cell regulatory (Treg), MDSC, and CAF ( 70 ). Next, we identified compounds that might be used to treat patients with NSCLC, and anticancer therapy with various drugs might be indicated for patients with higher risk scores.…”

The role of RNA modification in hepatocellular carcinoma

“…RNA modifications play a key role in regulating cell fate, an important regulator of HCC, in tumorigenesis and disease progression (Han et al, 2018;Pea et al, 2021;Braghini et al, 2022). The m6A, m7G, m5C, m1A, m3C, and ψ RNA modifications dynamically regulate the development of HCC, providing new strategies and possibilities for selecting possible therapeutic targets and investigating precisely directed intervention strategies for future HCC therapy (Tian et al, 2019;Bolatkan et al, 2022;Liu et al, 2022;Ren et al, 2022;Tong et al, 2022;Yu et al, 2022). As the most intensively studied RNA modification, m6A, and its regulators regulate the proliferation, migration, invasion, and EMT processes of HCC cells and are promising targets for HCC therapy (Zhou et al, 2019b;Liu et al, 2020a;Wang et al, 2020b;Zhang et al, 2020c;Qu et al, 2020;Wu et al, 2020;Zhu et al, 2020;Li et al, 2021e;Wei, 2021;Gu et al, 2022;Ren et al, 2022).…”

“…One study found that oxidatively modified cytoplasmic protein disulfide bond isomerase 3 (PDIA3) in HCC promoted DKC1-mediated survival of HCC and that DKC1 is a worthwhile target for HCC prediction and treatment (Ko et al, 2018). Except for DKC1, Ψ 5′phosphatase (PUDP) has been identified as a potential oncogene for HCC (Yu et al, 2022). PUDP positively correlates with tumor immune cell infiltration, and immune checkpoint expression and causes poor prognosis and a poor response to immunotherapy in HCC patients (Yu et al, 2022).…”

“…Except for DKC1, Ψ 5′phosphatase (PUDP) has been identified as a potential oncogene for HCC (Yu et al, 2022). PUDP positively correlates with tumor immune cell infiltration, and immune checkpoint expression and causes poor prognosis and a poor response to immunotherapy in HCC patients (Yu et al, 2022). These studies suggest that Ψ and its modulators can be a potential biomarker and treatment target in HCC treatment.…”