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. 2024 Aug 8:15:1435502.
doi: 10.3389/fimmu.2024.1435502. eCollection 2024.

Multi-omics pan-cancer analysis reveals the prognostic values and immunological functions of PPA2, with a spotlight on breast cancer

Jia-Ning Zhang #  1   2   3 , Bei-Bei Yang #  1   2   3 , Lin-Wei Li #  1   2   3 , Hao Xu  1   2   3 , Bin Wang  1   2   3 , Zi-Lu Yi  1   2   3 , Xi-Rui Zhou  1   2   3 , Hong Liu  1   2   3
Affiliations

Multi-omics pan-cancer analysis reveals the prognostic values and immunological functions of PPA2, with a spotlight on breast cancer

Jia-Ning Zhang et al. Front Immunol. .

Abstract

Background: Recently, the role of inorganic pyrophosphatase 2 (PPA2) has been remaining merely superficial in many tumors. Hence, the aim was to analyze the potential functions of PPA2 in pan-cancer, focusing on its role in breast cancer.

Methods: A systematic pan-cancer analysis conducted primarily utilizing various open databases such as TCGA and GTEx. We explored the clinical value of PPA2 as well as various biological functions, including expression levels and subcellular localization, multi-dimensional immune-correlation analysis, co-expression networks, and gene heterogeneity. In addition, we not only verified the function of PPA2 through cell experiments but also analyzed PPA2 at the single-cell level and its drug sensitivity.

Results: PPA2 is abnormally expressed in various tumors, and it is mainly distributed in mitochondria. Furthermore, the indicators (OS, DSS, DFI, and PFI) of analysis hint that PPA2 exhibits significant prognostic value. At the same time, the genomic heterogeneity (including TMB, MSI, MATH, and NEO) of PPA2 in pan-cancer was analyzed. Across multiple tumors, the results showed a close correlation between PPA2 expression levels and different immune signatures (such as immune cell infiltration). All of these indicate that PPA2 could potentially be applied in the guidance of immunotherapy. We also have demonstrated that PPA2 promoted the process of breast cancer. Finally, some potential therapeutic agents (such as Fulvestrant) targeting the abnormal expression of PPA2 are revealed.

Conclusion: In conclusion, the results demonstrated the great value of PPA2 in pan-cancer research, as well as its potential as a therapeutic target for breast tumors.

Keywords: PPA2; breast cancer; immunological function; multi-omics; pan-cancer analysis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Expression levels of PPA2 in different tumors and pathological stages by TCGA + GTEx database. (A) Expression levels of PPPA2 in different tumors vs corresponding controls were analyzed (B) Analysis of the expression difference of the PPA2 gene in samples of different clinical stages in each tumor. *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001.
Figure 2
Figure 2
Expression levels of PPA2 in different tumors and paired normal tissues were compared in transcriptome and protein levels. (A–H) PPA2 expression was significantly higher in colon adenocarcinoma (COAD), liver hepatocellular carcinoma (LIHC), Prostate adenocarcinoma (PRAD), Lung adenocarcinoma (LUAD), breast invasive carcinoma (BRCA), Stomach adenocarcinoma (STAD), Ovarian serous cystadenocarcinoma (OV), Thyroid carcinoma (THCA); (I, J) PPA2 expression was significantly lower in Kidney renal clear cell carcinoma (KIRC), Skin Cutaneous Melanoma (SKCM).
Figure 3
Figure 3
Univariate COX regression analysis of PPA2 with prognostic indicators in pan-cancer. (A) Correlation between PPA2 expression and OS; (B), Correlation between PPA2 expression and DSS. (C) Correlation between PPA2 expression and DFI; (D) Correlation between PPA2 expression and DFI.
Figure 4
Figure 4
PPA2 gene mutation in various cancers. cBioPortal was used to display the alteration frequency of different mutation types (A) and mutation sites (B) of PPA2 in pan-cancer. (C) The R84Q alteration mutation site was shown in the 3D protein structure of PPA2.
Figure 5
Figure 5
The Protein-protein interaction analysis of PPA2. (A) PPA2-related genes were obtained from the BioGRID web tool (B) GEPIA2.0 showed positive correlations between PPA2 and six genes (LAMTOR3, CDS1, EIF4E, LRBA, PLA2G12A, and ARFIP1). (C) The heatmap indicated that PPA2 expression was positively correlated with these genes (CDS1, EIF4E, LRBA, PLA2G12A, and ARFIP1) in pan-cancer.
Figure 6
Figure 6
The analysis of RNA gene modification and promoter methylation levels for PPA2. (A) The relationship between PPA2 expression and RNA gene modification (B–N) The relationship between PPA2 expression and promoter methylation levels among pan-caner.
Figure 7
Figure 7
The association between PPA2 expression levels and gene heterogeneity. (A) Correlation between PPA2 expression and TMB; (B) Correlation between PPA2 expression and MSI (C) Correlation between PPA2 expression and MATH; (D) Correlation between PPA2 expression and NEO.
Figure 8
Figure 8
The Immuno-correlation analysis for PPA2. The immuno-correlation cell infiltration analysis (A) with PPA2 among different tumors. The immune checkpoint pathway analysis (B) and the marker genes of five immune pathways (C) for PPA2.
Figure 9
Figure 9
The expression levels of PPA2 at single-cell levels. (A, B) The relationship between PPA2 expression and different functional states in tumors was explored by the CancerSEA tool. ***p < 0.001. (C) PPA2 expression profiles were shown at single cells from RB, UM and BRCA by T-SNE diagram.
Figure 10
Figure 10
PPA2 knockdown inhibited the progression in breast tumor cells. PPA2 knockdown inhibited proliferation in MCF-7 cells (A, B) and MDA-MB-231 cells (E, F); PPA2 knockdown inhibited migration and invasion in MCF-7 cells (C, D) and MDA-MB-231 cells (G, H).
Figure 11
Figure 11
Correlations between PPA2 expression levels and different drug sensitivities. The PPA2 expression was related to drug susceptibility in breast cancer (A–W).
See this image and copyright information in PMC

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