Top

BMC Cancer

Published in:

01-12-2020 | Glioblastoma | Research article

PODXL might be a new prognostic biomarker in various cancers: a meta-analysis and sequential verification with TCGA datasets

Authors: Siying He, Wenjie Du, Menglan Li, Ming Yan, Fang Zheng

Published in: BMC Cancer | Issue 1/2020

ABSRACT

Background

Several studies have investigated the associations between the podocalyxin-like protein (PODXL) expression quantity or locations and cancers survival, but the results were far from conclusive. Therefore, we proceeded a meta-analysis on PODXL in various human cancers to find its prognostic value and followed confirmation using the TCGA datasets.

Methods

We performed a systematic search, and 18 citations, including 5705 patients were pooled in meta-analysis. The results were verified with TCGA datasets.

Results

Total eligible studies comprised 5705 patients with 10 types of cancer. And the result indicated that PODXL high-expression or membrane-expression were significantly related to poor overall survival (OS). However, subgroup analysis showed a significant association between high expressed PODXL and poor OS in the colorectal cancer, pancreatic cancer, urothelial bladder cancer, renal cell carcinoma and glioblastoma multiforme. Then, we validated the inference using TCGA datasets, and the consistent results were demonstrated in patients with pancreatic cancer, glioblastoma multiforme, gastric cancer, esophageal cancer and lung adenocarcinoma.

Conclusion

The result of meta-analysis showed that high expressed PODXL was significantly linked with poor OS in pancreatic cancer and glioblastoma multiforme, but not in gastric cancer, esophageal cancer or lung adenocarcinoma. And the membrane expression of PODXL might also associate with poor OS. PODXL may act as tumor promotor and may serve as a potential target for antitumor therapy.

Available only for authorised users

Somasiri A, Nielsen JS, Makretsov N, McCoy ML, Prentice L, Gilks CB, et al. Overexpression of the anti-adhesin podocalyxin is an independent predictor of breast cancer progression. Cancer Res. 2004;64(15):5068–73. https://doi.org/10.1158/0008-5472.can-04-0240.CrossRefPubMed

McNagny KM, Pettersson I, Rossi F, Flamme I, Shevchenko A, Mann M, et al. Thrombomucin, a novel cell surface protein that defines thrombocytes and multipotent hematopoietic progenitors. J Cell Biol. 1997;138(6):1395–407.CrossRefPubMedPubMedCentral

Schopperle WM, Kershaw DB, DeWolf WC. Human embryonal carcinoma tumor antigen, Gp200/GCTM-2, is podocalyxin. Biochem Biophys Res Commun. 2003;300(2):285–90.CrossRefPubMed

Itai S, Yamada S, Kaneko MK, Sano M, Nakamura T, Yanaka M, et al. Podocalyxin is crucial for the growth of oral squamous cell carcinoma cell line HSC-2. Biochem Biophys Rep. 2018;15:93–6. https://doi.org/10.1016/j.bbrep.2018.07.008.CrossRefPubMedPubMedCentral

Larsson A, Johansson ME, Wangefjord S, Gaber A, Nodin B, Kucharzewska P, et al. Overexpression of podocalyxin-like protein is an independent factor of poor prognosis in colorectal cancer. Br J Cancer. 2011;105(5):666–72. https://doi.org/10.1038/bjc.2011.295.CrossRefPubMedPubMedCentral

Kershaw DB, Beck SG, Wharram BL, Wiggins JE, Goyal M, Thomas PE, et al. Molecular cloning and characterization of human podocalyxin-like protein. Orthologous relationship to rabbit PCLP1 and rat podocalyxin. J Biol Chem. 1997;272(25):15708–14.CrossRefPubMed

Li P, Karaczyn AA, McGlauflin R, Favreau-Lessard AJ, Jachimowicz E, Vary CP et al. Novel roles for podocalyxin in regulating stress myelopoiesis, Rap1a, and neutrophil migration. Exp Hematol. 2017;50:77–83.e6. doi:https://doi.org/10.1016/j.exphem.2017.04.001.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.CrossRefPubMed

Kerosuo L, Juvonen E, Alitalo R, Gylling M, Kerjaschki D, Miettinen A. Podocalyxin in human haematopoietic cells. Br J Haematol. 2004;124(6):809–18.CrossRefPubMed

10.

Porras G, Ayuso MS, Gonzalez-Manchon C. Leukocyte-endothelial cell interaction is enhanced in podocalyxin-deficient mice. Int J Biochem Cell Biol. 2018;99:72–9. https://doi.org/10.1016/j.biocel.2018.03.018.CrossRefPubMed

11.

Horrillo A, Porras G, Ayuso MS, Gonzalez-Manchon C. Loss of endothelial barrier integrity in mice with conditional ablation of podocalyxin (Podxl) in endothelial cells. Eur J Cell Biol. 2016;95(8):265–76. https://doi.org/10.1016/j.ejcb.2016.04.006.CrossRefPubMed

12.

Vitureira N, Andres R, Perez-Martinez E, Martinez A, Bribian A, Blasi J, et al. Podocalyxin is a novel polysialylated neural adhesion protein with multiple roles in neural development and synapse formation. PLoS One. 2010;5(8):e12003. https://doi.org/10.1371/journal.pone.0012003.CrossRefPubMedPubMedCentral

13.

Forse CL, Yilmaz YE, Pinnaduwage D, O'Malley FP, Mulligan AM, Bull SB, et al. Elevated expression of podocalyxin is associated with lymphatic invasion, basal-like phenotype, and clinical outcome in axillary lymph node-negative breast cancer. Breast Cancer Res Treat. 2013;137(3):709–19. https://doi.org/10.1007/s10549-012-2392-y.CrossRefPubMed

14.

Larsson A, Fridberg M, Gaber A, Nodin B, Leveen P, Jonsson G, et al. Validation of podocalyxin-like protein as a biomarker of poor prognosis in colorectal cancer. BMC Cancer. 2012;12:282.CrossRefPubMedPubMedCentral

15.

Kaprio T, Hagstrom J, Fermer C, Mustonen H, Bockelman C, Nilsson O, et al. A comparative study of two PODXL antibodies in 840 colorectal cancer patients. BMC Cancer. 2014;14:494.CrossRefPubMedPubMedCentral

16.

Yuan D, Chen H, Wang S, Liu F, Cheng Y, Fang J. Identification of LEA, a podocalyxin-like glycoprotein, as a predictor for the progression of colorectal cancer. Cancer Med. 2018;7(10):5155–66. https://doi.org/10.1002/cam4.1765.CrossRefPubMedPubMedCentral

17.

Borg D, Hedner C, Nodin B, Larsson A, Johnsson A, Eberhard J, et al. Expression of podocalyxin-like protein is an independent prognostic biomarker in resected esophageal and gastric adenocarcinoma. BMC Clin Pathol. 2016;16:13. https://doi.org/10.1186/s12907-016-0034-8.CrossRefPubMedPubMedCentral

18.

Laitinen A, Bockelman C, Hagstrom J, Kokkola A, Fermer C, Nilsson O, et al. Podocalyxin as a prognostic marker in gastric Cancer. PLoS One. 2015;10(12):e0145079. https://doi.org/10.1371/journal.pone.0145079.CrossRefPubMedPubMedCentral

19.

Zhang J, Zhu Z, Wu H, Yu Z, Rong Z, Luo Z, et al. PODXL, negatively regulated by KLF4, promotes the EMT and metastasis and serves as a novel prognostic indicator of gastric cancer. Gastric Cancer. 2018. https://doi.org/10.1007/s10120-018-0833-y.

20.

Binder ZA, Siu IM, Eberhart CG, Ap Rhys C, Bai RY, Staedtke V, et al. Podocalyxin-like protein is expressed in glioblastoma multiforme stem-like cells and is associated with poor outcome. PLoS One. 2013;8(10):e75945. https://doi.org/10.1371/journal.pone.0075945.CrossRefPubMedPubMedCentral

21.

Kusumoto H, Shintani Y, Kanzaki R, Kawamura T, Funaki S, Minami M, et al. Podocalyxin influences malignant potential by controlling epithelial-mesenchymal transition in lung adenocarcinoma. Cancer Sci. 2017;108(3):528–35. https://doi.org/10.1111/cas.13142.CrossRefPubMedPubMedCentral

22.

Lin CW, Sun MS, Wu HC. Podocalyxin-like 1 is associated with tumor aggressiveness and metastatic gene expression in human oral squamous cell carcinoma. Int J Oncol. 2014;45(2):710–8. https://doi.org/10.3892/ijo.2014.2427.CrossRefPubMed

23.

Cipollone JA, Graves ML, Kobel M, Kalloger SE, Poon T, Gilks CB, et al. The anti-adhesive mucin podocalyxin may help initiate the transperitoneal metastasis of high grade serous ovarian carcinoma. Clin Exp Metastasis. 2012;29:239–52. https://doi.org/10.1007/s10585-011-9446-0).CrossRefPubMed

24.

Saukkonen K, Hagstrom J, Mustonen H, Juuti A, Nordling S, Fermer C, et al. Podocalyxin is a marker of poor prognosis in pancreatic ductal adenocarcinoma. PLoS One. 2015;10(6):e0129012. https://doi.org/10.1371/journal.pone.0129012.CrossRefPubMedPubMedCentral

25.

Heby M, Elebro J, Nodin B, Jirstrom K, Eberhard J. Prognostic and predictive significance of podocalyxin-like protein expression in pancreatic and periampullary adenocarcinoma. BMC Clin Pathol. 2015;15:10. https://doi.org/10.1186/s12907-015-0009-1.CrossRefPubMedPubMedCentral

26.

Taniuchi K, Furihata M, Naganuma S, Dabanaka K, Hanazaki K, Saibara T. Podocalyxin-like protein, linked to poor prognosis of pancreatic cancers, promotes cell invasion by binding to gelsolin. Cancer Sci. 2016;107(10):1430–42. https://doi.org/10.1111/cas.13018.CrossRefPubMedPubMedCentral

27.

Chijiiwa Y, Moriyama T, Ohuchida K, Nabae T, Ohtsuka T, Miyasaka Y, et al. Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL. Int J Oncol. 2016;48(4):1688–700. https://doi.org/10.3892/ijo.2016.3389.CrossRefPubMed

28.

Casey G, Neville PJ, Liu X, Plummer SJ, Cicek MS, Krumroy LM, et al. Podocalyxin variants and risk of prostate cancer and tumor aggressiveness. Hum Mol Genet. 2006;15(5):735–41. https://doi.org/10.1093/hmg/ddi487.CrossRefPubMed

29.

Heath EI, Heilbrun LK, Smith D, Schopperle WM, Ju Y, Bolton S, et al. Overexpression of the Pluripotent Stem Cell Marker Podocalyxin in Prostate Cancer. Anticancer Res. 2018;38(11):6361–6. https://doi.org/10.21873/anticanres.12994.CrossRefPubMedPubMedCentral

30.

Hsu YH, Lin WL, Hou YT, Pu YS, Shun CT, Chen CL, et al. Podocalyxin EBP50 ezrin molecular complex enhances the metastatic potential of renal cell carcinoma through recruiting Rac1 guanine nucleotide exchange factor ARHGEF7. Am J Pathol. 2010;176(6):3050–61. https://doi.org/10.2353/ajpath.2010.090539.CrossRefPubMedPubMedCentral

31.

Boman K, Larsson AH, Segersten U, Kuteeva E, Johannesson H, Nodin B, et al. Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer. Br J Cancer. 2013;108(11):2321–8. https://doi.org/10.1038/bjc.2013.215.CrossRefPubMedPubMedCentral

32.

Wang J, Zhao Y, Qi R, Zhu X, Huang C, Cheng S, et al. Prognostic role of podocalyxin-like protein expression in various cancers: A systematic review and meta-analysis. Oncotarget. 2017;8(32):52457–64. https://doi.org/10.18632/oncotarget.14199.CrossRefPubMed

33.

D M, A l, J T, G AD, Group TP. Preferred reporting items for systematic reviews and meta-analysis: the PRISMA statement. PLoS Med. 2009;6(7):e1000097 doi:10.1371/.CrossRef

34.

Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16. https://doi.org/10.1186/1745-6215-8-16.CrossRefPubMedPubMedCentral

35.

Zeng X, Zhang Y, Kwong JS, Zhang C, Li S, Sun F, et al. The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review. J Evid Based Med. 2015;8(1):2–10. https://doi.org/10.1111/jebm.12141.CrossRefPubMed

36.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98–W102. https://doi.org/10.1093/nar/gkx247.CrossRefPubMedPubMedCentral

37.

Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19(8):649–58. https://doi.org/10.1016/j.neo.2017.05.002.CrossRefPubMedPubMedCentral

38.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(Database issue):D447–52. https://doi.org/10.1093/nar/gku1003.CrossRefPubMed

39.

Xiaoli Jiao BTS, Huang DW, Stephens R, Baseler MW, Lane HC, Richard A. Lempicki. DAVID-WS: a stateful web service to facilitate gene/protein list analysis. Oxford J. 2012.

40.

Nielsen JS, Graves ML, Chelliah S, Vogl AW, Roskelley CD, McNagny KM. The CD34-related molecule podocalyxin is a potent inducer of microvillus formation. PLoS One. 2007;2(2):e237. https://doi.org/10.1371/journal.pone.0000237.CrossRefPubMedPubMedCentral

41.

Zhang J, Zhu Z, Sheng J, Yu Z, Yao B, Huang K, et al. miR-509-3-5P inhibits the invasion and lymphatic metastasis by targeting PODXL and serves as a novel prognostic indicator for gastric cancer. Oncotarget. 2017;8(21):34867–83. https://doi.org/10.18632/oncotarget.16802.CrossRefPubMedPubMedCentral

42.

Amo L, Tamayo-Orbegozo E, Maruri N, Eguizabal C, Zenarruzabeitia O, Rinon M, et al. Involvement of platelet-tumor cell interaction in immune evasion. Potential role of podocalyxin-like protein 1. Front Oncol. 2014;4:245. https://doi.org/10.3389/fonc.2014.00245.CrossRefPubMedPubMedCentral

43.

Larsson AH, Lehn S, Wangefjord S, Karnevi E, Kuteeva E, Sundström M, et al. Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer. J Transl Med. 2016;14(1):128. https://doi.org/10.1186/s12967-016-0882-0.CrossRefPubMedPubMedCentral

44.

Fröse J, Chen MB, Hebron KE, Reinhardt F, Hajal C, Zijlstra A, et al. Epithelial-Mesenchymal transition induces Podocalyxin to promote extravasation via Ezrin signaling. Cell Rep. 2018;24(4):962–72. https://doi.org/10.1016/j.celrep.2018.06.092.CrossRefPubMedPubMedCentral

45.

Lee WY, Kuo CC, Lin BX, Cheng CH, Chen KC, Lin CW. Podocalyxin-Like Protein 1 Regulates TAZ Signaling and Stemness Properties in Colon Cancer. Int J Mol Sci. 2017;18(10). https://doi.org/10.3390/ijms18102047.

46.

Zhi Q, Chen H, Liu F, Han Y, Wan D, Xu Z, et al. PODXL promotes gastric cancer progression through interacting with RUFY1 protein. Cancer Sci. 2018. https://doi.org/10.1111/cas.13864.

47.

Taniuchi K, Tsuboi M, Sakaguchi M, Saibara T. Measurement of serum PODXL concentration for detection of pancreatic cancer. Onco Targets Ther. 2018;11:1433–45. https://doi.org/10.2147/ott.s155367.CrossRefPubMedPubMedCentral

48.

Buganim Y, Madar S, Rais Y, Pomeraniec L, Harel E, Solomon H, et al. Transcriptional activity of ATF3 in the stromal compartment of tumors promotes cancer progression. Carcinogenesis. 2011;32(12):1749–57. https://doi.org/10.1093/carcin/bgr203.CrossRefPubMed

49.

Itai S, Ohishi T, Kaneko MK, Yamada S, Abe S, Nakamura T, et al. Anti-podocalyxin antibody exerts antitumor effects via antibody-dependent cellular cytotoxicity in mouse xenograft models of oral squamous cell carcinoma. Oncotarget. 2018;9(32):22480–97. https://doi.org/10.18632/oncotarget.25132.CrossRefPubMedPubMedCentral

50.

Borg D, Larsson AH, Hedner C, Nodin B, Johnsson A, Jirstrom K. Podocalyxin-like protein as a predictive biomarker for benefit of neoadjuvant chemotherapy in resectable gastric and esophageal adenocarcinoma. J Transl Med. 2018;16(1):290. https://doi.org/10.1186/s12967-018-1668-3.CrossRefPubMedPubMedCentral

Title: PODXL might be a new prognostic biomarker in various cancers: a meta-analysis and sequential verification with TCGA datasets
Authors: Siying He
Wenjie Du
Menglan Li
Ming Yan
Fang Zheng
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Glioblastoma
Glioblastoma
Gastric Cancer
Gastric Cancer
Glioblastoma
Pancreatic Cancer
Pancreatic Cancer
Published in: BMC Cancer / Issue 1/2020
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-020-07108-5

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

ABSRACT

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2020

Meta-analysis examining overall survival in patients with pancreatic cancer treated with second-line 5-fluorouracil and oxaliplatin-based therapy after failing first-line gemcitabine-containing therapy: effect of performance status and comparison with other regimens

The impact of high-intensity interval training exercise on breast cancer survivors: a pilot study to explore fitness, cardiac regulation and biomarkers of the stress systems

Black patients referred to a lung cancer screening program experience lower rates of screening and longer time to follow-up

Prognostic role of vitamin D receptor in breast cancer: a systematic review and meta-analysis

Current status of the clinical use of PD-1/PD-L1 inhibitors: a questionnaire survey of oncologists in China

Age-related differences in breast cancer mortality according to race/ethnicity, insurance, and socioeconomic status

Keynote webinar | Spotlight on antibody–drug conjugates in cancer