Search results and research characteristics
In total, 436 records were identified and 87 duplicates were excluded. 39 articles remained after scanning the titles and abstracts, and among the 39 studies, 7 were excluded for not for human, 9 were excluded for insufficient HRs or other data, 3 were excluded because the included patients were repetitive in other studies, and 1 meta-analysis was excluded, and the flow diagram was shown in Fig. 1. Finally, 18 eligible studies were include in this meta-analysis. [5, 37, 14–16, 24–27, 18, 17, 38, 13, 30, 23, 20, 31, 21, 1, 19]. These eligible researches contained 5705 patients, involved 10 types of cancers, including the breast cancer (n = 2), renal cell carcinoma (n = 1), colorectal cancer (n = 4), ovarian cancer (n = 1), glioblastoma multiforme (n = 1), urothelial bladder cancer (n = 2), pancreatic adenocarcinoma (n = 4), esophageal cancer (n = 1), gastric cancer (n = 3) and lung adenocarcinoma (n = 1). In these studies, PODXL expression levels were evaluated by immunohistochemistry (IHC). The characteristics of the eligible articles were listed in Table 1.
Table 1
Characteristics of eligible studies in this meta-analysis.
Author | Year | Country | No. of Patient | Tumor type | Method | Cut-off | Outcome | Analysis | Antibody | NOS |
Somasiri | 2004 | Canada | 272 | Breast cancer | IHC | IHC ≥ 50% | CSS | K-M Curve | M | 7 |
Hsu | 2010 | Taiwan | 303 | Renal cell carcinoma | IHC | IHC score ≥ 1 | OS, CSS, MFS | Multivariate | P | 8 |
Larsson | 2011 | Sweden | 626 | Colorectal cancer | IHC | IHC score ≥ 3 | OS, CSS | Multivariate | P | 8 |
Cipollone | 2012 | Canada | 479 | Ovarian cancer | IHC | IHC score ≥ 1 | DFS | K-M Curve | M | 8 |
Larsson | 2012 | Sweden | 607 | Colorectal cancer | IHC | IHC score ≥ 3 | OS, DFS, TTR | Multivariate | P | 9 |
Binder | 2013 | America | 181 | Glioblastoma multiforme | IHC | NA | OS | Multivariate | NA | 7 |
Boman | 2013 | Sweden | 100 | Urothelial bladder cancer | IHC | IHC score ≥ 3 | OS | Multivariate | M/P | 7 |
Boman | 2013 | Sweden | 343 | Urothelial bladder cancer | IHC | IHC score ≥ 3 | OS, CSS, PFS | Multivariate | M/P | 8 |
Forse | 2013 | Canada | 698 | Breast cancer | IHC | IHC score ≥ 3 | DFS | Multivariate | P | 9 |
Kaprio | 2014 | Finland | 840 | Colorectal cancer | IHC | IHC score ≥ 3 | CSS | K-M Curve | M/P | 9 |
Heby | 2015 | Sweden | 175 | Pancreatic and periampullary adenocarcinoma | IHC | IHC score ≥ 2 | OS, DFS | Multivariate | P | 7 |
Laitinen | 2015 | Finland | 337 | Gastric cancer | IHC | IHC score ≥ 1 | CSS | Multivariate | M/P | 8 |
Saukkonen | 2015 | Finland | 189 | Pancreatic ductal adenocarcinoma | IHC | IHC score ≥ 3 | CSS | Multivariate | M/P | 7 |
Borg | 2016 | Sweden | 106 | Esophageal cancer | IHC | IHC score ≥ 1 | OS, TTR | K-M Curve | P | 7 |
Borg | 2016 | Sweden | 65 | Gastric cancer | IHC | IHC score ≥ 1 | OS, TTR | K-M Curve | p | 7 |
Chijiiwa | 2016 | Japan | 70 | Pancreatic cancer | IHC | IHC score ≥ 4 | OS, DFS | K-M Curve | M | 7 |
Taniuchi | 2016 | Japan | 102 | Pancreatic cancer | IHC | IHC score ≥ 3 | OS | Multivariate | P | 7 |
Kusumoto | 2017 | Japan | 114 | Lung adenocarcinoma | IHC | IHC score ≥ 1 | OS, DFS, CSS | K-M Curve | NA | 8 |
Yuan | 2018 | China | 87 | Colorectal cancer | IHC | IHC score ≥ 3 | OS | Multivariate | M | 7 |
Zhang | 2018 | China | 54 | Gastric cancer | IHC | IHC score ≥ 1 | OS, DFS | Multivariate | NA | 7 |
IHC, Immunohistochemistry; NA, Not Available; OS, Overall Survival; DFS, Disease-free Survival; CSS, Cancer-specific Survival; NOS, Newcastle-Ottawa Scale |
Meta-analysis of PODXL expression levels and locations on OS/ DFS/ CSS
A total of 11 eligible studies, including 13 cohorts and 2272 patients, were recruited to evaluate the expression level of PODXL on OS. The pooled HR and 95% CI indicated that high-expressed PODXL was significantly related to poor OS in patients with various cancers (HR = 2.33, 95% CI = 1.76–3.09, P < 0.0001) with a significant heterogeneity across these studies (I2 = 63.4%, P = 0.001) (Fig. 2a). In addition, there were 6 studies performed the relationships between PODXL expression levels and DFS, and 8 studies investigated the associations between PODXL expression levels and CSS respectively. Heterogeneity test indicated both the DFS (I2 = 73.4%, P = 0.002) and CSS (I2 = 70.0%, P = 0.002) should be analyzed using the random-effect model. Finally, the results indicated the association between the high expressed PODXL and the shorter DFS (HR = 1.76, 95% CI = 1.20–2.58, P = 0.004) or the shorter CSS (HR = 2.84, 95% CI = 1.85–4.38, P < 0.0001) (Fig. 2b-2c). On the other hand, among these eligible 18 papers, 5 studies involved the expression locations of PODXL and the prognosis of cancers, and only 2 studies, including 4 cohorts, showed the association between membrane expressed PODXL and poor OS (HR = 2.98, 95% CI = 1.29–6.90, P = 0.011), also by using the random-effect model (I2 = 84.7%, P < 0.0001) (Fig. 2d).
Subgroup analysis for OS
In order to find the source of heterogeneity, the subgroup analysis of OS was performed, and all of the 2272 patients were classified based on cancer types, analysis types, antibody types, ethnicities and sample sizes (Table 2). Single study which assessed the relationship between the expression and OS in renal cell carcinoma, glioblastoma multiforme, esophageal cancers and lung adenocarcinoma were defined as “other cancers” in the other cancers subgroup. Subgroup analysis showed that, high expressed PODXL were linked with poor OS in colorectal cancer (HR = 1.79, 95% CI = 1.35–2.37, P < 0.0001), pancreatic cancer (HR = 2.98, 95% CI = 1.95–4.55, P < 0.0001), urothelial bladder cancer (HR = 2.14, 95% CI = 1.48–3.10) and other cancers (HR = 2.60, 95% CI = 1.45–4.66, P = 0.001), but not in patients with the gastric cancer (HR = 2.76, 95% CI = 0.45–15.84, P = 0.256). In conclusion, high expressed level of PODXL was associated with poor OS in 6 types of cancers.
Table 2
Subgroup analysis of pooled HR for OS
Categories | No. of studies | No. of patients | Pooled HR (95%CI) | Heterogeneity |
Fix/Random | P-value | I2 (%) | P-value |
1. OS | 13 | 2272 | 2.33 (1.76, 3.09) | 0 | 63.4 | 0.001 |
2. Cancer type | 8 | | | | | |
1) Colorectal cancer | 3 | 834 | 1.79 (1.35, 2.37) | 0 | 0 | 0.499 |
2) Pancreatic cancer | 2 | 172 | 2.98 (1.95, 4.55) | 0 | 0 | 0.391 |
3) Gastric cancer | 2 | 119 | 2.76 (0.48, 15.84) | 0.256 | 59.9 | 0.114 |
4) Urothelial bladder cancer | 2 | 443 | 2.14 (1.48, 3.10) | 0 | 0 | 0.880 |
5) Other cancers | 4 | 704 | 2.60 (1.45, 4.66) | 0.001 | 83.3 | 0 |
3. Analysis | | | | | | |
1) K-M curve | 4 | 355 | 1.85 (1.17, 2.95) | 0.009 | 0 | 0.89 |
2) Multivariate | 9 | 2017 | 2.59 (1.77, 3.80) | 0 | 74.7 | 0 |
4. Antibody type | | | | | | |
1) Monoclonal antibody | 2 | 157 | 2.25 (1.36, 3.73) | 0.002 | 0 | 0.975 |
2) Polyclonal antibody | 6 | 1672 | 2.55 (1.45, 4.50) | 0.001 | 0 | 81.6 |
3) M + P | 2 | 443 | 2.14 (1.48, 3.10) | 0 | 0 | 0.880 |
5. Ethnicity | | | | | | |
1) European | 6 | 1361 | 1.84 (1.47, 2.30) | 0 | 0 | 0.834 |
2) Asian | 6 | 730 | 3.49 (2.02, 6.02) | 0 | 64.5 | 0.015 |
3) North American | 1 | 181 | 1.67 (1.23, 2.29) | | - | - |
6. Sample size | | | | | | |
1) < 150 | 8 | 628 | 2.46 (1.81, 3.33) | 0 | 0 | 0.536 |
4) ≥ 150 | 5 | 1644 | 2.36 (1.53, 3.65) | 0 | 81.3 | 0 |
OS, overall survival; HR, hazard ratio. |
And regarding the analysis type, we also found that the high expression of PODXL was significantly associated with the much shorter OS, when the studies were assessed with K-M curve. In the subgroups based on ethnicities, antibody types and sample sizes, we also found that, the relation between high expression level of PODXL and poor OS, except for patients from Asia or the sample size ≥ 150.
PODXL overexpression and relative clinical parameters
In order to obtain more clinical values of PODXL, we investigated the associations between PODXL expression levels and clinical parameters in several cancers (Table 3). From these results, we found that the expression level of PODXL was related with the TNM stage (HR = 1.63, 95% CI = 1.19–2.23, P = 0.002, fixed-effects), tumor grade (HR = 4.29, 95% CI = 1.84–9.99, P = 0.001, random-effects), differentiation (HR = 2.84, 95% CI = 1.82–4.42, P < 0.0001, fixed-effects), distant metastasis (HR = 5.46, 95% CI = 2.55–11.66, P < 0.0001, fixed-effects), lymph node metastasis (HR = 1.51, 95% CI = 1.03–2.22, P = 0.034, fixed-effects), neural invasion (HR = 2.43, 95% CI = 1.02–5.79, P = 0 .45, fixed-effects) and vascular invasion (HR = 2.27, 95% CI = 1.56–3.30, P < 0.0001, fixed-effects) significantly. Whereas, there was no significant correlations between PODXL expression and age (HR = 0.88, 95% CI = 0.71–1.10, P = 0.269, fixed-effects), gender (HR = 1.04, 95% CI = 0.82–1.32, P = 0.749, fix-effects) and tumor size (HR = 0.90, 95% CI = 0.61–1.34, P = 0.614, fixed-effects). As a result, these correlations indicated that the high expressed PODXL was associated with the advanced biological behavior in various cancers.
Table 3
Clinicopathological features of the enrolled studies with high expressed PODXL in patients with cancer.
Clinicopathological parameters | Studies | No. of patients | Risk of high PODXL OR (95% CI) | Significant Z | P-value | Heterogeneity I2 (%) | P-value | Model |
Age (< 65 vs ≥ 65) | 10 | 2905 | 0.88 (0.71, 1.10) | 1.11 | 0.269 | 42.6 | 0.084 | Fixed effects |
Gender (male vs female) | 11 | 3081 | 1.04 (0.82, 1.32) | 0.32 | 0.749 | 0 | 0.835 | Fixed effects |
Tumor size (< 5 cm vs ≥ 5 cm) | 5 | 1334 | 0.90 (0.61, 1.34) | 0.50 | 0.614 | 0 | 0.703 | Fixed effects |
TNM stage (III-IV vs I-II) | 12 | 2417 | 1.63 (1.19, 2.23) | 3.04 | 0.002 | 13.1 | 0.319 | Fixed effects |
Tumor grade (3–4 vs 1–2) | 6 | 2268 | 4.29 (1.84, 9.99) | 3.38 | 0.001 | 78.6 | 0 | Random effects |
Tumor differentiation (moderate/well vs poor) | 6 | 1429 | 2.84 (1.82, 4.42) | 4.62 | 0 | 0 | 0.559 | Fixed effects |
Distant metastasis (positive vs Negative) | 3 | 475 | 5.46 (2.55, 11.66) | 4.38 | 0 | 44.5 | 0.165 | Fixed effects |
Lymph node metastasis (positive vs negative) | 6 | 1574 | 1.51 (1.03, 2.22) | 2.11 | 0.034 | 0 | 0.614 | Fixed effects |
Neural invasion (positive vs negative) | 3 | 264 | 2.43 (1.02, 5.79) | 2.00 | 0.045 | 0 | 1.000 | Fixed effects |
Vascular invasion (positive or negative) | 6 | 1240 | 2.27 (1.56, 3.30) | 4.29 | 0 | 2.1 | 0.403 | Fixed effects |
Table 4
The difference of PODXL expression in cancers and corresponding normal tissues in TCGA datasets.
Types of cancer | TCGA dataset | No. of cancer tissues | No. of normal tissues | Log2(FC) | P value |
Adenoid cystic carcinoma | ACC | 77 | 128 | -1.068 | 1.10e-10 |
Breast invasion carcinoma | BRCA | 1085 | 291 | -0.514 | 4.01e-16 |
Cervical squamous cell carcinoma | CESC | 306 | 13 | -0.590 | 0.191 |
Esophagus cancer | ESCA | 182 | 286 | 1.391 | 5.97e-22 |
Glioblastoma multiforme | GBM | 163 | 207 | 0.866 | 1.12e-10 |
Head and neck squamous cell carcinoma | HNSCC | 519 | 44 | 0.656 | 0.123 |
Kidney chromophobe | KICH | 66 | 53 | -2.863 | 1.53e-10 |
Kidney renal clear cell carcinoma | KIRC | 523 | 100 | -0.732 | 1.85e-9 |
Kidney renal papillary cell carcinoma | KIRP | 286 | 60 | -4.247 | 1.31e-43 |
Acute myeloid leukemia | LAML | 173 | 70 | 1.210 | 3.26e-2 |
Liver hepatocellular carcinoma | LIHC | 369 | 160 | 1.508 | 8.20e-32 |
Lung adenocarcinoma | LUAD | 483 | 347 | -2.064 | 6.27e-122 |
Lung squamous cell carcinoma | LUSC | 486 | 338 | -2.832 | 3.86e-153 |
Ovarian serous cystadenocarcinoma | OVSC | 426 | 88 | 1.449 | 3.96e-14 |
Pancreatic adenocarcinoma | PAAD | 179 | 171 | 0.492 | 4.05e-5 |
Prostate carcinoma | PRAD | 492 | 152 | -0.479 | 0.044 |
Rectum adenocarcinoma | READ | 92 | 318 | 0.598 | 8.17e-8 |
Skin cutaneous melanoma | SKCM | 461 | 558 | -0.636 | 3.83e-6 |
Stomach adenocarcinoma | STAD | 408 | 211 | 1.597 | 1.64e-49 |
Testicular germ cell tumor | TGCT | 137 | 165 | 2.750 | 3.93e-30 |
Thyroid carcinoma | THCA | 512 | 337 | -0.796 | 6.95e-22 |
Uterine corpus endometrial carcinoma | UCEC | 174 | 91 | -0.797 | 2.97e-5 |
Uterine carcinosarcoma | UCS | 58 | 78 | -2.075 | 3.79e-12 |
Table 5
The difference of overall survival in cancer patients with high PODXL expression vs low/median expression.
Cancer type | No. of cancer tissues | P value |
High | Low/Median | Total |
ACC | 20 | 59 | 79 | 0.37 |
BLCA | 102 | 304 | 406 | 0.34 |
BRCA | 272 | 809 | 1081 | 0.4 |
CESC | 73 | 218 | 291 | 0.77 |
CHOL | 9 | 27 | 36 | 0.57 |
COAD | 69 | 210 | 279 | 0.32 |
ESCA | 46 | 138 | 184 | 0.16 |
GBM | 39 | 113 | 152 | 0.041 |
HNSCC | 130 | 389 | 519 | 0.3 |
KICH | 15 | 49 | 64 | 0.35 |
KIRC | 134 | 397 | 531 | < 0.0001 |
KIRP | 72 | 215 | 287 | 0.0037 |
LAML | 43 | 120 | 163 | 0.64 |
LIHC | 93 | 272 | 365 | 0.82 |
LUAD | 125 | 377 | 502 | 0.37 |
LUSC | 126 | 368 | 494 | 0.33 |
DLBC | 12 | 35 | 47 | 0.21 |
MESO | 22 | 63 | 85 | 0.23 |
OVSC | 76 | 227 | 303 | 0.95 |
PAAD | 45 | 132 | 177 | 0.013 |
PCPG | 45 | 134 | 179 | 0.13 |
PRAD | 125 | 372 | 497 | 0.92 |
READ | 42 | 123 | 165 | 0.44 |
SARC | 65 | 194 | 259 | 0.12 |
SKCM | 115 | 344 | 459 | 0.22 |
TGCT | 34 | 100 | 134 | 0.29 |
THYM | 30 | 89 | 119 | 0.78 |
THCA | 127 | 377 | 504 | 0.87 |
UCS | 15 | 41 | 56 | 0.58 |
UCEC | 136 | 407 | 543 | 0.006 |
UVM | 20 | 60 | 80 | 0.36 |
ACC, adrenocortical carcinoma; BLCA, bladder urothelial carcinoma; BRCA, breast invasion carcinoma; CESE, cervical squamous cell carcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSCC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LAML, acute myeloid leukemia; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; DLBC, lymphoid neoplasm diffuse large B-cell lymphoma; MESO, mesothelioma; OVSC, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; TGCT, testicular germ cell tumors; THYM, thymoma; THCA, thyroid carcinoma; UCS, uterine carcinosarcoma; UCEC, uterine corpus endometrial carcinoma; UVM, uveal melanoma. |
Sensitivity analysis and publication bias
We performed sensitivity analysis to determine whether an individual study could affected the overall result. Results of association studies between PODXL expression and OS and CSS demonstrated that single study had no influence on the result of meta-analysis (Fig. 3). Funnel plots and Begg’s test were performed and the results showed no publication bias existed in studies on associations between PODXL overexpression and OS (P = 0.502), DFS (P = 0.133) and CSS (P = 0.266). And no publication bias existed in our meta-analysis on associations between PODXL membrane expression and OS (P = 1.000) as well (Fig. 4).
The expression Data of PODXL Extracted from TCGA Datasets
The differences of PODXL expression level between various tumor tissues and corresponding normal tissues were obtained with GEPIA, which was a common web-based tool that can provide a quick and customizable survey of function based on TCGA and GTEx data [35]. PODXL was detected in 23 types of cancers, and the result that the PODXL expression was significantly much higher than the corresponding normal tissues was found in 9 types of cancers, including the esophagus cancer, glioblastoma multiforme, acute myeloid leukemia, liver hepatocellular carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, testicular germ cell tumor.
Validation of prognostic correlation by TCGA datasets
To validate the clinical prognosis indication value of PODXL, we explored TCGA datasets by using UALCAN, which was an interactive online tool that could analyze the expression data of genes in TCGA [36]. And among the 31 types of cancers, 9040 patients, the significant association between high expressed PODXL and poor OS was found in 3 types of cancers, including the glioblastoma multiforme, kidney renal papillary cell carcinoma and pancreatic adenocarcinoma. But there were adverse results in kidney renal clear cell carcinoma and uterine corpus endometrial carcinoma, which showed a significant correlation between the low expressed PODXL and poor OS (Fig. 5).
A joint result of our meta-analysis and TCGA datasets validation identified the correlation between the expression level of PODXL and the glioblastoma multiforme, pancreatic adenocarcinoma, esophagus cancer, gastric cancer and lung adenocarcinoma.