PTPN Genes Expression Patterns in Digestive Tract Cancers.
Before expression profiling analysis, we refined the chromosome location of all PTPN gene family members through published literature review. The detailed information was summarized in Table 1.
Table 1
Basic characteristics of PTPN family genes
HGNC ID (gene) | Gene ID | Approved symbol | Synonym(s) | Exon | Chromosomal location |
HGNC:9642 | 5770 | PTPN1 | PTP1B | 10 | 20q13.13 |
HGNC:9650 | 5771 | PTPN2 | TCELLPTP | 15 | 18p11.21 |
TC-PTP |
TCPTP |
HGNC:9655 | 5774 | PTPN3 | PTPH1 | 33 | 9q31 |
HGNC:9656 | 5775 | PTPN4 | PTPMEG | 29 | 2q14.2 |
HGNC:9657 | 84867 | PTPN5 | STEP | 16 | 11p15.1 |
PTPSTEP |
STEP61 |
HGNC:9658 | 5777 | PTPN6 | HCP | 17 | 12p13.31 |
HCPH |
PTP-1C |
SHP-1 |
SHP1 |
HGNC:9659 | 5778 | PTPN7 | HEPTP | 12 | 1q32.1 |
LC-PTP |
HGNC:9661 | 5780 | PTPN9 | MEG2 | 13 | 15q24.2 |
HGNC:9644 | 5781 | PTPN11 | BPTP3 | 16 | 12q24.13 |
SH-PTP2 |
SHP-2 |
PTP2C |
SHP2 |
HGNC:9645 | 5782 | PTPN12 | PTPG1 | 19 | 7q11.23 |
PTP-PEST |
HGNC:9646 | 5783 | PTPN13 | PTP1E | 48 | 4q21.3 |
PTP-BAS |
PTPL1 |
PTP-BL |
HGNC:9647 | 5784 | PTPN14 | PEZ | 21 | 1q32.3-q41 |
HGNC:9649 | 26469 | PTPN18 | BDP1 | 15 | 2q21.1 |
HGNC:23423 | 26095 | PTPN20 | bA42B19.1 | 18 | 10q11.22 |
DKFZP566K0524 |
bA142I17.1 |
CT126 |
HGNC:9651 | 11099 | PTPN21 | PTPD1 | 23 | 14q31 |
PTPRL10 |
HGNC:9652 | 26191 | PTPN22 | Lyp | 24 | 1p13.2 |
Lyp1 |
Lyp2 |
HGNC:14406 | 25930 | PTPN23 | DKFZP564F0923 | 25 | 3p21.31 |
KIAA1471 |
HD-PTP |
All of these seventeen PTPN family members have been analyzed in our study. According to the analysis results of ONCOMINE, the expression of PTPN genes were different in all types of cancer and its matched normal tissues (Fig. 1). For EC samples, PTPN1, PTPN4, PTPN12, PTPN18 and PTPN21 were over-expressed, while PTPN3, PTPN11, PTPN13 and PTPN21 were downregulated. In GC tissues, the expression of PTPN5 and PTPN13 was decreased while at the same time PTPN2, PTPN12 and PTPN22 were highly expressed in patients. As for CRC patients, the expression of PTPN1, PTPN3, PTPN7, PTPN11, PTPN12, PTPN13 and PTPN14 was upregulated in patients with CRC, while PTPN2, PTPN18, PTPN20, PTPN21 and PTPN22 were expressed in a lower level in tissues. Comprehensively, the expression of PTPN12 was higher in EC, GC and CRC samples.
UALCAN was used to further verify the expression of PTPNs among ESCA, STAD, COAD, READ and their matched normal tissues in the TCGA datasets. As shown in the results of UALCAN (Fig. 2–5), there was a clear trend that the expression levels of PTPN1, PTPN2, PTPN4, PTPN6, PTPN7, PTPN9, PTPN12, PTPN22 and PTPN23 were statistically higher in samples of ESCA than in normal tissues; in STAD, PTPN1, PTPN2, PTPN3, PTPN4, PTPN6, PTPN7, PTPN9, PTPN11, PTPN12, PTPN18, PTPN22, and PTPN23 were significantly increased compared to normal samples; in COAD, PTPN1, PTPN2, PTPN4, PTPN11, PTPN12, PTPN13, and PTPN23 were overexpressed compared with normal samples, while PTPN9, PTPN18, PTPN21 and PTPN22 were lower than normal tissues; in READ, the expression levels of PTPN4, PTPN12, and PTPN23 were higher than normal samples while PTPN21 and PTPN22 were decreased in patients compared to normal groups. Taken together, the results above indicated that the expression status of PTPN4, PTPN12 and PTPN23 were upregulated in ESCA, STAD, COAD and READ. PTPN21 and PTPN22 were upregulated in ESCA and STAD but downregulated in COAD.
Correlations between PTPN Members and Clinicopathological Parameters.
Association of PTPN family genes expression status with different clinicopathological features of ESCA, STAD and COAD were analyzed in the study. For ESCA, no statistically association was found between PTPN members and clinicopathological parameters (Additional file 1: Table S1). For STAD, grade was significantly correlated with PTPN3, PTPN11, PTPN13, PTPN14, and PTPN18 (p = 0.015, 0.021, 0.005, 0.002 and 0.034, resp.) (Additional file 1: Table S2). In addition, PTPN5, PTPN7 and PTPN23 showed statistically association with pathological grade of STAD with a p value of no more than 0.001. Besides, PTPN20 expression was related with TNM stage (p = 0.002) and N stage (p = 0.038); PTPN22 was significantly related with grade (p < 0.001) and T stage (p = 0.039) (Additional file 1: Table S2). For COAD, TNM stage was correlated with expression of PTPN5, PTPN12, and PTPN14 (p = 0.049, 0.027, 0.002, resp.; Additional file 1: Table S3); N stage was associated with expression of PTPN5, PTPN12, and PTPN14 (p = 0.034, 0.018 and 0.004, resp.; Additional file 1: Table S3). According to the results above, PTPN5 and PTPN14 were associated with the clinicopathological parameters of both STAD and COAD.
Prognostic Roles of PTPN Family Genes.
The analysis results of the relationship between PTPN family genes and the prognosis of digestive tract cancers showed that for ESCA, elevated expression of PTPN20 was associated with a worse overall survival (OS) of ESCA in multivariate model (p = 0.038, adjusted HR = 1.982, 95% CI = 1.039–3.780; Table 2).
Table 2
Prognostic role of PTPN family genes in ESCA
GENE | Univariate analysis | | Multivariate analysis |
HR (95%CI) | P | | Adjusted HR (95%CI) | P |
PTPN1 | 0.831(0.427–1.615) | 0.585 | | 0.724(0.367–1.427) | 0.350 |
PTPN2 | 1.171(0.601–2.285) | 0.643 | | 1.075(0.546–2.119) | 0.834 |
PTPN3 | 1.020(0.514–2.026) | 0.954 | | 0.776(0.383–1.571) | 0.481 |
PTPN4 | 0.617(0.304–1.253) | 0.182 | | 0.758(0.348–1.648) | 0.484 |
PTPN5 | 0.982(0.494–1.952) | 0.958 | | 0.935(0.452–1.933) | 0.855 |
PTPN6 | 1.123(0.565–2.230) | 0.741 | | 1.398(0.678–2.886) | 0.364 |
PTPN7 | 0.839(0.432–1.630) | 0.605 | | 0.817(0.394–1.693) | 0.586 |
PTPN9 | 1.499(0.774–2.904) | 0.230 | | 1.302(0.666–2.546) | 0.440 |
PTPN11 | 0.632(0.293–1.362) | 0.241 | | 0.597(0.275–1.294) | 0.191 |
PTPN12 | 0.706(0.356–1.399) | 0.319 | | 0.518(0.254–1.057) | 0.071 |
PTPN13 | 0.695(0.332–1.453) | 0.334 | | 1.009(0.455–2.234) | 0.983 |
PTPN14 | 1.116(0.558–2.235) | 0.756 | | 1.439(0.687–3.016) | 0.335 |
PTPN18 | 0.875(0.453–1.693) | 0.692 | | 1.001(0.494–2.031) | 0.997 |
PTPN20 | 1.697(0.901–3.194) | 0.101 | | 1.982(1.039–3.780) | 0.038 |
PTPN21 | 0.627(0.279–1.409) | 0.259 | | 0.580(0.244–1.381) | 0.219 |
PTPN22 | 0.911(0.469–1.772) | 0.784 | | 0.576(0.264–1.255) | 0.165 |
PTPN23 | 0.664(0.318–1.387) | 0.276 | | 0.487(0.228–1.040) | 0.063 |
For STAD,decreased PTPN5 expression was associated with worse OS according to univariate analysis (p = 0.006, HR = 1.680, 95% CI = 1.162–2.429) and multivariate analysis (p = 0.004, adjusted HR = 1.753, 95% CI = 1.192–2.577), while elevated expression of PTPN6 indicated longer OS based on the results of univariate analysis (p = 0.028, HR = 0.633, 95% CI = 0.421–0.951) and multivariate analysis (p = 0.017, adjusted HR = 0.606, 95% CI = 0.402–0.915) (Table 3). Besides, univariate analysis exhibited that there was a significant association between decreased PTPN13 expression and decreased OS (p = 0.036, HR = 1.471, 95% CI = 1.026–2.109).
Table 3
Prognostic role of PTPN family genes in STAD
GENE | Univariate analysis | | Multivariate analysis |
HR (95%CI) | P | | Adjusted HR (95%CI) | P |
PTPN1 | 1.238(0.857–1.788) | 0.255 | | 1.118(0.772–1.619) | 0.553 |
PTPN2 | 1.174(0.806–1.710) | 0.405 | | 1.219(0.836–1.779) | 0.304 |
PTPN3 | 0.879(0.592–1.306) | 0.524 | | 0.844(0.563–1.266) | 0.412 |
PTPN4 | 0.854(0.580–1.258) | 0.424 | | 0.802(0.543–1.183) | 0.265 |
PTPN5 | 1.680(1.162–2.429) | 0.006 | | 1.753(1.192–2.577) | 0.004 |
PTPN6 | 0.633(0.421–0.951) | 0.028 | | 0.606(0.402–0.915) | 0.017 |
PTPN7 | 1.065(0.731–1.551) | 0.743 | | 0.956(0.650–1.405) | 0.819 |
PTPN9 | 1.229(0.853–1.769) | 0.269 | | 1.233(0.855–1.778) | 0.263 |
PTPN11 | 1.373(0.951–1.984) | 0.091 | | 1.389(0.957–2.018) | 0.084 |
PTPN12 | 1.202(0.811–1.779) | 0.359 | | 1.152(0.778–1.707) | 0.479 |
PTPN13 | 1.471(1.026–2.109) | 0.036 | | 1.431(0.995–2.058) | 0.054 |
PTPN14 | 1.341(0.927–1.937) | 0.118 | | 1.350(0.924–1.973) | 0.121 |
PTPN18 | 1.158(0.787–1.705) | 0.456 | | 1.213(0.819–1.796) | 0.334 |
PTPN20 | 1.185(0.813–1.727) | 0.377 | | 1.389(0.946–2.040) | 0.094 |
PTPN21 | 1.237(0.852–1.797) | 0.264 | | 1.258(0.862–1.836) | 0.234 |
PTPN22 | 0.913(0.614–1.358) | 0.654 | | 0.844(0.561–1.271) | 0.418 |
PTPN23 | 0.954(0.655–1.390) | 0.806 | | 0.998(0.681–1.463) | 0.992 |
COAD patients with high PTPN5 expression showed increased hazards of death in univariate model (p = 0.021, HR = 1.947, 95% CI = 1.105–3.431; Table 4). Elevated expression of PTPN7 was significantly associated with the unfavorable OS for every COAD patients according to multivariate analysis (p = 0.013, adjusted HR = 2.043, 95% CI = 1.164–3.584; Table 4).
Table 4
Prognostic role of PTPN family genes in COAD
GENE | Univariate analysis | | Multivariate analysis |
HR (95%CI) | P | | Adjusted HR (95%CI) | P |
PTPN1 | 1.492(0.863–2.579) | 0.152 | | 1.476(0.841–2.588) | 0.175 |
PTPN2 | 1.136(0.653–1.975) | 0.652 | | 1.009(0.571–1.783) | 0.976 |
PTPN3 | 1.022(0.576–1.814) | 0.941 | | 0.912(0.505–1.649) | 0.761 |
PTPN4 | 1.003(0.565–1.780) | 0.993 | | 0.903(0.507–1.609) | 0.729 |
PTPN5 | 1.947(1.105–3.431) | 0.021 | | 1.681(0.945–2.991) | 0.077 |
PTPN6 | 0.825(0.859–2.553) | 0.158 | | 1.328(0.764–2.306) | 0.314 |
PTPN7 | 1.700(0.984–2.940) | 0.057 | | 2.043(1.164–3.584) | 0.013 |
PTPN9 | 0.825(0.428–1.593) | 0.567 | | 0.821(0.424–1.589) | 0.558 |
PTPN11 | 1.525(0.698–2.266) | 0.446 | | 1.618(0.885–2.959) | 0.118 |
PTPN12 | 1.525(0.885–2.629) | 0.129 | | 0.962(0.539–1.718) | 0.896 |
PTPN13 | 1.186(0.661–2.130) | 0.568 | | 1.105(0.607–2.010) | 0.744 |
PTPN14 | 1.706(0.978–2.977) | 0.060 | | 1.142(0.646–2.018) | 0.648 |
PTPN18 | 1.500(0.852–2.640) | 0.160 | | 1.503(0.835–2.706) | 0.174 |
PTPN20 | 1.218(0.699–2.125) | 0.487 | | 1.499(0.853–2.636) | 0.160 |
PTPN21 | 0.853(0.443–1.643) | 0.634 | | 0.808(0.418–1.564) | 0.528 |
PTPN22 | 1.622(0.945–2.782) | 0.079 | | 1.637(0.949–2.825) | 0.076 |
PTPN23 | 0.893(0.483–1.652) | 0.719 | | 0.519(0.268–1.002) | 0.051 |
From the results above we can see that the expression of PTPN5 was associated with the prognosis of both STAD and COAD.
Function and Interaction of PTPN Family Genes.
GO analysis was basically grouped into three terms including molecular function groups, cellular component groups and biological process groups. The top 5 enriched categories obtained from the analysis results of each group were showed in Fig. 6a. GO analysis revealed that PTPN proteins were mainly related to cytoplasmic side of plasma membrane. PTPN genes exert their functions primarily on peptidyl-tyrosine dephosphorylation and protein tyrosine phosphatase activity. Further, the interaction analysis of PTPN genes at the gene level was performed by GeneMANIA to clarify the correlations among colocalization, shared protein domains, co-expression, prediction and pathways (Fig. 6b). As the protein-protein interaction network of STRING analysis result revealed, interrelationships among PTPN gene family members were intricate (Fig. 6c).