Journal of Southern Medical University ›› 2025, Vol. 45 ›› Issue (4): 880-892.doi: 10.12122/j.issn.1673-4254.2025.04.24
Yutong LI1,2(
), Xingyu SONG1,2, Ruixu SUN1,2, Xuan DONG1,2, Hongwei LIU1,2()
Received:2025-02-17
Online:2025-04-20
Published:2025-04-28
Contact:
Hongwei LIU
E-mail:liyutong@gdmu.edu.cn;lhwhongwei@gdmu.edu.cn
Yutong LI, Xingyu SONG, Ruixu SUN, Xuan DONG, Hongwei LIU. A pan-cancer analysis of PYCR1 and its predictive value for chemotherapy and immunotherapy responses in bladder cancer[J]. Journal of Southern Medical University, 2025, 45(4): 880-892.
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URL: https://www.j-smu.com/EN/10.12122/j.issn.1673-4254.2025.04.24
Fig.1 Expression of PYCR1 in pan-cancer. A, B: mRNA and protein expression levels of PYCR1 in UCSC Xena and GTEx pan-cancer data. C, D: Differences in mRNA and protein expression levels of PYCR1 between cancer and adjacent tissues in 33 cancers. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs control group.
| Index | Cancers | HR | 95% CI | P |
|---|---|---|---|---|
| OS | SARC KIRP KIRC ESCA ACC LGG | 1.29 2.01 1.59 1.22 1.68 0.78 | 1.13-1.47 1.58-2.54 1.40-1.80 0.94-1.59 1.28-2.21 0.60-1.00 0.96-3.35 0.67-1.01 1.37-2.09 1.44-1.87 1.18-4.23 1.25-1.92 1.12-2.47 0.74-4.82 1.27-2.24 1.59-2.15 0.90-1.65 1.09-1.45 2.92-1003.87 2.27-4.20 | <0.001 <0.01 <0.01 0.022 0.022 0.017 |
| PFS | UVM LGG KIRP KIRC KICH ACC | 1.79 0.82 1.69 1.64 2.24 1.54 | 0.032 0.013 <0.01 <0.01 0.020 <0.01 | |
| DFS | ACC | 1.66 | 0.024 | |
| DSS | PCPG ACC KIRC ESCA SARC PRAD KIRP | 1.88 1.69 1.85 1.22 1.26 54.17 3.09 | 0.022 0.028 <0.01 0.043 0.047 0.030 <0.01 |
Tab.1 Prognostic significance of PYCR1 in pan-cancer
| Index | Cancers | HR | 95% CI | P |
|---|---|---|---|---|
| OS | SARC KIRP KIRC ESCA ACC LGG | 1.29 2.01 1.59 1.22 1.68 0.78 | 1.13-1.47 1.58-2.54 1.40-1.80 0.94-1.59 1.28-2.21 0.60-1.00 0.96-3.35 0.67-1.01 1.37-2.09 1.44-1.87 1.18-4.23 1.25-1.92 1.12-2.47 0.74-4.82 1.27-2.24 1.59-2.15 0.90-1.65 1.09-1.45 2.92-1003.87 2.27-4.20 | <0.001 <0.01 <0.01 0.022 0.022 0.017 |
| PFS | UVM LGG KIRP KIRC KICH ACC | 1.79 0.82 1.69 1.64 2.24 1.54 | 0.032 0.013 <0.01 <0.01 0.020 <0.01 | |
| DFS | ACC | 1.66 | 0.024 | |
| DSS | PCPG ACC KIRC ESCA SARC PRAD KIRP | 1.88 1.69 1.85 1.22 1.26 54.17 3.09 | 0.022 0.028 <0.01 0.043 0.047 0.030 <0.01 |
| Cancers | Description |
|---|---|
| CESC | Maturity-onset diabetes of the young, Glutathione metabolism, Melanoma Olfactory Transduction, Maturity-onset diabetes of the young, Ascorbic Acid Metabolism Taurine and Hypotaurine Metabolism, Taste transduction, Hedgehog signaling pathway Ascorbic Acid Metabolism, Autophagy, Pentose and Glucuronate Interconversions Lysine Degradation, Arginine and Proline Metabolism, Basal Cell Carcinoma Folate biosynthesis, Autophagy, Cytosolic DNA sensing by cGAS Other glycan degradation, Autophagy, Butanoate Metabolism Primary immunodeficiency, Viral myocarditis, Graft-Versus-Host Disease Viral myocarditis, Maturity-onset diabetes of the young, Glutathione metabolism |
| LUSC | |
| LIHC | |
| THYM | |
| LAML | |
| CHOL | |
| UCS | |
| THCA | |
| KICH | |
| HNSC | Ascorbic Acid Metabolism, Porphyrin and Chlorophyll Metabolism, Metabolism of xenobiotics by cytochrome P450 |
| UCEC | Olfactory Transduction, Autophagy, Autoimmune thyroid disorders |
| STAD | Dilated cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy, Hypertrophic cardiomyopathy |
| ACC | Glycosaminoglycan degradation, Hedgehog signaling pathway, Olfactory Transduction |
| SKCM | Primary immunodeficiency, Linoleic acid metabolism, Graft-Versus-Host Disease |
| LUAD | Olfactory Transduction, Autophagy, RIG-I-like Receptor signaling pathway |
| TGCT | Allograft rejection, Graft-Versus-Host Disease, Primary immunodeficiency |
| READ | Cytosolic DNA sensing by cGAS, Autoimmune thyroid disorders, Autophagy |
| LGG | Pentose and Glucuronate Interconversions, Ascorbic Acid Metabolism, Porphyrin and Chlorophyll Metabolism |
| BRCA | Olfactory Transduction, Cytosolic DNA sensing by cGAS, Autoimmune thyroid disorders |
| COAD | Taste transduction, Olfactory Transduction, Cytosolic DNA sensing by cGAS |
| BLCA | Maturity-onset diabetes of the young, Valine, Leucine, and Isoleucine Degradation, Graft-Versus-Host Disease |
Tab.2 Top 3 molecular functions regulated by PYCR1 in pan-cancer
| Cancers | Description |
|---|---|
| CESC | Maturity-onset diabetes of the young, Glutathione metabolism, Melanoma Olfactory Transduction, Maturity-onset diabetes of the young, Ascorbic Acid Metabolism Taurine and Hypotaurine Metabolism, Taste transduction, Hedgehog signaling pathway Ascorbic Acid Metabolism, Autophagy, Pentose and Glucuronate Interconversions Lysine Degradation, Arginine and Proline Metabolism, Basal Cell Carcinoma Folate biosynthesis, Autophagy, Cytosolic DNA sensing by cGAS Other glycan degradation, Autophagy, Butanoate Metabolism Primary immunodeficiency, Viral myocarditis, Graft-Versus-Host Disease Viral myocarditis, Maturity-onset diabetes of the young, Glutathione metabolism |
| LUSC | |
| LIHC | |
| THYM | |
| LAML | |
| CHOL | |
| UCS | |
| THCA | |
| KICH | |
| HNSC | Ascorbic Acid Metabolism, Porphyrin and Chlorophyll Metabolism, Metabolism of xenobiotics by cytochrome P450 |
| UCEC | Olfactory Transduction, Autophagy, Autoimmune thyroid disorders |
| STAD | Dilated cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy, Hypertrophic cardiomyopathy |
| ACC | Glycosaminoglycan degradation, Hedgehog signaling pathway, Olfactory Transduction |
| SKCM | Primary immunodeficiency, Linoleic acid metabolism, Graft-Versus-Host Disease |
| LUAD | Olfactory Transduction, Autophagy, RIG-I-like Receptor signaling pathway |
| TGCT | Allograft rejection, Graft-Versus-Host Disease, Primary immunodeficiency |
| READ | Cytosolic DNA sensing by cGAS, Autoimmune thyroid disorders, Autophagy |
| LGG | Pentose and Glucuronate Interconversions, Ascorbic Acid Metabolism, Porphyrin and Chlorophyll Metabolism |
| BRCA | Olfactory Transduction, Cytosolic DNA sensing by cGAS, Autoimmune thyroid disorders |
| COAD | Taste transduction, Olfactory Transduction, Cytosolic DNA sensing by cGAS |
| BLCA | Maturity-onset diabetes of the young, Valine, Leucine, and Isoleucine Degradation, Graft-Versus-Host Disease |
Fig.2 Correlation analysis between PYCR1 and tumor immunity score in pan-cancer.
Fig.3 PYCR1 regulates the level of immune cell infiltration in pan-cancer.
Fig.4 Potential of PYCR1 for assessing tumor mutation burden (TMB), microsatellite instability (MSI) and immune therapy benefits in pan-cancer. A: Correlation of PYCR1 with TMB and MSI. B: Correlation of PYCR1 with benefits of anti-PD-1 immunotherapy in SKCM patients in the SKCM immunotherapy cohort. C: Correlation of PYCR1 with benefits of anti-PD-L1 immunotherapy in RCC patients in the metastatic RCC immunotherapy cohort. D: Correlation of PYCR1 with immune checkpoint inhibitor therapy benefit in patients with BLCA in the IMvigor210 cohort.
Fig.6 Histological features of BLCA with high and low PYCR1 expressions. A: HE staining profile of BLCA tissue with high PYCR1 expression level (Original magnification: ×1000). B: HE staining profile of BLCA tissue with low PYCR1 expression level (×1000).
Fig.7 Effect of PYCR1 silencing on proliferative capacity of BLCA cell lines. A: mRNA expression levels of PYCR1 in BLCA cell lines and SV-HUC-1. **P<0.01 vs SV-HUC-1. B: Verification of PYCR1 silencing efficiency. C: Effect of PYCR1 silencing on proliferation of T24 and UM-UC-3 cells. *P<0.05, **P<0.01, ***P<0.001 vs si-NC.
Fig.8 Effect of high PYCR1 expression level on prognosis of BLCA patients.
| Characteristics | HR | 95% CI | P |
|---|---|---|---|
| Age (year) | 1.05 | 1.02-1.07 | <0.001 |
| Tumor classification | 1.25 | 1.04-1.49 | 0.016 |
| Copy number variation | 0.97 | 0.79-1.19 | 0.764 |
| Gender | 0.95 | 0.55-1.65 | 0.858 |
| Grade | 2.02 | 0.49-8.29 | 0.327 |
| Hypermethylation | 0.93 | 0.79-1.09 | 0.377 |
| Hypomethylation | 0.92 | 0.78-1.08 | 0.044 |
| Tumor mutation burden | 1.10 | 0.85-1.44 | 0.457 |
| PYCR1 | 1.23 | 0.99-1.87 | 0.032 |
| Race | 0.91 | 0.67-1.24 | 0.544 |
| Single nucleotide variation | 1.00 | 0.99-1.01 | 0.027 |
| Stage | 1.60 | 1.19-2.15 | 0.002 |
Tab.3 Univariate analysis for identifying prognostic risk factors for BLCA
| Characteristics | HR | 95% CI | P |
|---|---|---|---|
| Age (year) | 1.05 | 1.02-1.07 | <0.001 |
| Tumor classification | 1.25 | 1.04-1.49 | 0.016 |
| Copy number variation | 0.97 | 0.79-1.19 | 0.764 |
| Gender | 0.95 | 0.55-1.65 | 0.858 |
| Grade | 2.02 | 0.49-8.29 | 0.327 |
| Hypermethylation | 0.93 | 0.79-1.09 | 0.377 |
| Hypomethylation | 0.92 | 0.78-1.08 | 0.044 |
| Tumor mutation burden | 1.10 | 0.85-1.44 | 0.457 |
| PYCR1 | 1.23 | 0.99-1.87 | 0.032 |
| Race | 0.91 | 0.67-1.24 | 0.544 |
| Single nucleotide variation | 1.00 | 0.99-1.01 | 0.027 |
| Stage | 1.60 | 1.19-2.15 | 0.002 |
| Characteristics | HR | 95% CI | Assignment and Attributes | P |
|---|---|---|---|---|
| Age (year) | 1.04 | 1.02-1.07 | Continuous variable | 0.001 |
| Tumor classification | 1.16 | 0.95-1.41 | 0= LumP,1= LumNS,2= LumU,3= Stroma-rich,4= Ba/Sq,5= NE-like | 0.135 |
| Hypomethylation | 0.89 | 0.75-1.05 | Continuous variable | 0.162 |
| PYCR1 | 1.14 | 1.02-1.68 | Continuous variable | 0.006 |
| Single nucleotide variation | 1.00 | 0.99-1.01 | Continuous variable | 0.019 |
| Stage | 1.49 | 1.10-2.04 | 0= I-II,1= III-IV | 0.011 |
Tab.4 Multivariate analysis for identifying independent prognostic risk factors for BLCA
| Characteristics | HR | 95% CI | Assignment and Attributes | P |
|---|---|---|---|---|
| Age (year) | 1.04 | 1.02-1.07 | Continuous variable | 0.001 |
| Tumor classification | 1.16 | 0.95-1.41 | 0= LumP,1= LumNS,2= LumU,3= Stroma-rich,4= Ba/Sq,5= NE-like | 0.135 |
| Hypomethylation | 0.89 | 0.75-1.05 | Continuous variable | 0.162 |
| PYCR1 | 1.14 | 1.02-1.68 | Continuous variable | 0.006 |
| Single nucleotide variation | 1.00 | 0.99-1.01 | Continuous variable | 0.019 |
| Stage | 1.49 | 1.10-2.04 | 0= I-II,1= III-IV | 0.011 |
Fig.9 Construction of BLCA clinical DCA model based on clinical traits and PYCR1 expression levels.
Fig.10 Molecular mechanism of PYCR1 for promoting BLCA progression. A, B: GO and KEGG signaling pathway enrichment analysis circle diagram of PYCR1 co-expressed genes.
Fig.11 Drug sensitivity analysis of BLCA with high PYCR1 expressions.
Fig.12 Virtual screening of small molecule drugs based on PYCR1 expression profiling. A: Screening for small molecule drugs in BLCA patients based on PYCR1 expression profile using XSum algorithm. B: Likely compound structures of candidate small molecule inhibitors of PYCR1. C: Known PYCR1 inhibitor Pycr1-IN-1 is used as the positive control.
| Ligands | ID | Cavity volume (Å3) | Vina score (kcal/mol) | Center (x, y, z) |
|---|---|---|---|---|
| Pycr1-IN-1 | C1 | 436 | -5.2 | 34, 58, 14 |
| C2 | 377 | -4.5 | 31, 63, 1 | |
| C3 | 316 | -4.7 | 9, 60, -6 | |
| Exisulind | C2 | 377 | -7.1 | 31, 63, 1 |
| C4 | 232 | -7.1 | 1, 66, -5 | |
| C3 | 316 | -6.8 | 9, 60, -6 | |
| Fasudil | C1 | 436 | -7 | 34, 58, 14 |
| C4 | 232 | -6.5 | 1, 66, -5 | |
| C5 | 142 | -6.4 | 40, 83, -2 | |
| Butein | C4 | 232 | -6.6 | 1, 66, -5 |
| C2 | 377 | -6.5 | 31, 63, 1 | |
| C1 | 436 | -6.3 | 34, 58, 14 | |
| Iloprost | C1 | 436 | -6.3 | 34, 58, 14 |
| C2 | 377 | -6.2 | 31, 63, 1 | |
| C4 | 232 | -6.1 | 1, 66, -5 | |
| W-13 | C1 | 436 | -6.2 | 34, 58, 14 |
| C2 | 377 | -6 | 31, 63, 1 | |
| C4 | 232 | -5.9 | 1, 66, -5 |
Tab.5 Conformational binding energies of small molecule inhibitor-PYCR1 protein complexes （Top 3）
| Ligands | ID | Cavity volume (Å3) | Vina score (kcal/mol) | Center (x, y, z) |
|---|---|---|---|---|
| Pycr1-IN-1 | C1 | 436 | -5.2 | 34, 58, 14 |
| C2 | 377 | -4.5 | 31, 63, 1 | |
| C3 | 316 | -4.7 | 9, 60, -6 | |
| Exisulind | C2 | 377 | -7.1 | 31, 63, 1 |
| C4 | 232 | -7.1 | 1, 66, -5 | |
| C3 | 316 | -6.8 | 9, 60, -6 | |
| Fasudil | C1 | 436 | -7 | 34, 58, 14 |
| C4 | 232 | -6.5 | 1, 66, -5 | |
| C5 | 142 | -6.4 | 40, 83, -2 | |
| Butein | C4 | 232 | -6.6 | 1, 66, -5 |
| C2 | 377 | -6.5 | 31, 63, 1 | |
| C1 | 436 | -6.3 | 34, 58, 14 | |
| Iloprost | C1 | 436 | -6.3 | 34, 58, 14 |
| C2 | 377 | -6.2 | 31, 63, 1 | |
| C4 | 232 | -6.1 | 1, 66, -5 | |
| W-13 | C1 | 436 | -6.2 | 34, 58, 14 |
| C2 | 377 | -6 | 31, 63, 1 | |
| C4 | 232 | -5.9 | 1, 66, -5 |
Fig.13 Interaction pattern of candidate compounds with protein receptors. A-F: 3D interaction pattern diagram between candidate small molecule inhibitors and receptor protein PYCR1. Gray stick model represents subsequent small molecule inhibitors, the blue stick model represents PYCR1 side chain amino acid residues, the pink dashed line represents hydrophobic interactions, the green dashed line represents hydrogen bonding interactions, and the yellow dashed line represents alkyl interactions.
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