Detection and clinical significance of plasma soluble podoplanin in patients with colorectal cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHAO Sai ¹ , DONG Yuan ² , SHI Lin ¹ , ZHANG Chen ¹ , SHAO Ziqi ¹ , ZHAO Yiming ³ ,  WANG Jian ¹

1. Department of General Surgery, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiagnsu 221006, P. R. China;
2. Central Laboratory of The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiagnsu 221006, P. R. China;
3. Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Blood Institute, Suzhou, Jiagnsu 215000, P. R. China;

Corresponding author：

WANG Jian, Email: 15005206620@163.com

Keywords：

colorectal cancer; podoplanin; clinical diagnosis

DOI：

10.7507/1007-9424.202310091

Video：

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Objective To explore the expression and clinical significance of plasma soluble podoplanin (sPDPN) in patients with colorectal cancer (CRC). Methods TCGA-READ, TCGA-COAD datasets were obtained to compare expression level of PDPN mRNA in CRC tissues and adjacent tissues, and to explore the relationship between expression of PDPN mRNA and the prognosis of CRC patients. A total of 85 CRC patients (CRC group) underwent surgery in the Second Affiliated Hospital of Xuzhou Medical University from November 2020 to December 2022, and 100 healthy volunteers from the hospital were collected as a control group to detect the expression levels of plasma sPDPN of the two groups, and exploring the relationship between sPDPN expression and the clinicopathological characteristics of the CRC patients. The ROC curves of sPNPD, sugar antigen 199 (CA199) and carcinoembryonic antigen (CEA) were drawn simultaneously, and the predictive value of sPDPN for CRC was explored by logistic regression model. Results The results of TCGA dataset showed that expression level of PDPN mRNA was upregulated in CRC tissues compared with adjacent tissues/paired adjacent tissues (P<0.05), and patients with high expression level of PDPN mRNA had better prognosis than low expression patients (P=0.045). The expression level of sPDPN was (3.50±1.77) ng/mL in CRC group, which was higher than (1.95±0.46) ng/mL of the control group (P<0.01). The expression level of sPDPN was higher in CRC patients at Ⅲ+Ⅳ clinical stage (P=0.026) and N1–2 stage (P=0.049). Compared with CA199 and CEA, sPDPN had the highest area uncer curve value of 0.882 (0.832, 0.932), and was an risk predictor of CRC [OR=14.339, 95%CI (5.649, 36.396), P<0.001]. Conclusion The sPDPN is highly expressed in the plasma of CRC patients and has a certain clinical utility for diagnosis of CRC, and evaluation of clinical staging and lymph node metastasis.

1.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2.	Breiteneder-Geleff S, Soleiman A, Kowalski H, et al. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol, 1999, 154(2): 385-394.
3.	Schacht V, Ramirez MI, Hong YK, et al. T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J, 2003, 22(14): 3546-3556.
4.	Uhrin P, Zaujec J, Breuss JM, et al. Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood, 2010, 115(19): 3997-4005.
5.	Honma M, Minami-Hori M, Takahashi H, et al. Podoplanin expression in wound and hyperproliferative psoriatic epidermis: regulation by TGF-β and STAT-3 activating cytokines, IFN-γ, IL-6, and IL-22. J Dermatol Sci, 2012, 65(2): 134-140.
6.	Peters A, Pitcher LA, Sullivan JM, et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity, 2011, 35(6): 986-996.
7.	Miyamoto Y, Uga H, Tanaka S, et al. Podoplanin is an inflammatory protein upregulated in Th17 cells in SKG arthritic joints. Mol Immunol, 2013, 54(2): 199-207.
8.	Zhu X, Xu M, Zhao X, et al. The detection of plasma soluble podoplanin of patients with breast cancer and its clinical signification. Cancer Manag Res, 2020, 12: 13207-13214.
9.	Xu M, Wang X, Pan Y, et al. Blocking podoplanin suppresses growth and pulmonary metastasis of human malignant melanoma. BMC Cancer, 2019, 19(1): 599. doi: 10.1186/s12885-019-5808-9.
10.	Shibahara J, Kashima T, Kikuchi Y, et al. Podoplanin is expressed in subsets of tumors of the central nervous system. Virchows Arch, 2006, 448(4): 493-499.
11.	Brown KM, Domin C, Aranha GV, et al. Increased preoperative platelet count is associated with decreased survival after resection for adenocarcinoma of the pancreas. Am J Surg, 2005, 189(3): 278-282.
12.	Ayhan A, Bozdag G, Taskiran C, et al. The value of preoperative platelet count in the prediction of cervical involvement and poor prognostic variables in patients with endometrial carcinoma. Gynecol Oncol, 2006, 103(3): 902-905.
13.	赵星鹏, 赵益明. 平足蛋白生物学功能的研究进展与应用前景. 肿瘤研究与临床, 2016, 28(9): 634-637.
14.	Krishnan H, Miller WT, Blanco FJ, et al. Src and podoplanin forge a path to destruction. Drug Discov Today, 2019, 24(1): 241-249.
15.	Eisemann T, Costa B, Harter PN, et al. Podoplanin expression is a prognostic biomarker but may be dispensable for the malignancy of glioblastoma. Neuro Oncol, 2019, 21(3): 326-336.
16.	Tesfamariam B. Involvement of platelets in tumor cell metastasis. Pharmacol Ther, 2016, 157: 112-119.
17.	Lowe KL, Navarro-Nunez L, Watson SP. Platelet CLEC-2 and podoplanin in cancer metastasis. Thromb Res, 2012, 129 Suppl 1: S30-S37.
18.	Yao L, Liu Z, Zhu J, et al. Clinical evaluation of circulating microRNA-25 level change in sepsis and its potential relationship with oxidative stress. Int J Clin Exp Pathol, 2015, 8(7): 7675-7684.
19.	Parhar S, Kaur H, Vashist A, et al. Role of podoplanin in potentially malignant disorders and oral squamous cell carcinoma and its correlation with lymphangiogenesis. Indian J Cancer, 2015, 52(4): 617-622.
20.	La Vecchia S, Sebastián C. Metabolic pathways regulating colorectal cancer initiation and progression. Semin Cell Dev Biol, 2020, 98: 63-70.
21.	Carrasco-Ramírez P, Greening DW, Andrés G, et al. Podoplanin is a component of extracellular vesicles that reprograms cell-derived exosomal proteins and modulates lymphatic vessel formation. Oncotarget, 2016, 7(13): 16070-16089.
22.	Yeung KT, Yang J. Epithelial-mesenchymal transition in tumor metastasis. Mol Oncol, 2017, 11(1): 28-39.
23.	Ito S, Ishii G, Hoshino A, et al. Tumor promoting effect of podoplanin-positive fibroblasts is mediated by enhanced RhoA activity. Biochem Biophys Res Commun, 2012, 422(1): 194-199.
24.	Suzuki H, Onimaru M, Yonemitsu Y, et al. Podoplanin in cancer cells is experimentally able to attenuate prolymphangiogenic and lymphogenous metastatic potentials of lung squamoid cancer cells. Mol Cancer, 2010, 9: 287. doi: 10.1186/1476-4598-9-287.
25.	Chihara N, Madi A, Kondo T, et al. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature, 2018, 558(7710): 454-459.

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Breiteneder-Geleff S, Soleiman A, Kowalski H, et al. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol, 1999, 154(2): 385-394.
3. Schacht V, Ramirez MI, Hong YK, et al. T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J, 2003, 22(14): 3546-3556.
4. Uhrin P, Zaujec J, Breuss JM, et al. Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood, 2010, 115(19): 3997-4005.
5. Honma M, Minami-Hori M, Takahashi H, et al. Podoplanin expression in wound and hyperproliferative psoriatic epidermis: regulation by TGF-β and STAT-3 activating cytokines, IFN-γ, IL-6, and IL-22. J Dermatol Sci, 2012, 65(2): 134-140.
6. Peters A, Pitcher LA, Sullivan JM, et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity, 2011, 35(6): 986-996.
7. Miyamoto Y, Uga H, Tanaka S, et al. Podoplanin is an inflammatory protein upregulated in Th17 cells in SKG arthritic joints. Mol Immunol, 2013, 54(2): 199-207.
8. Zhu X, Xu M, Zhao X, et al. The detection of plasma soluble podoplanin of patients with breast cancer and its clinical signification. Cancer Manag Res, 2020, 12: 13207-13214.
9. Xu M, Wang X, Pan Y, et al. Blocking podoplanin suppresses growth and pulmonary metastasis of human malignant melanoma. BMC Cancer, 2019, 19(1): 599. doi: 10.1186/s12885-019-5808-9.
10. Shibahara J, Kashima T, Kikuchi Y, et al. Podoplanin is expressed in subsets of tumors of the central nervous system. Virchows Arch, 2006, 448(4): 493-499.
11. Brown KM, Domin C, Aranha GV, et al. Increased preoperative platelet count is associated with decreased survival after resection for adenocarcinoma of the pancreas. Am J Surg, 2005, 189(3): 278-282.
12. Ayhan A, Bozdag G, Taskiran C, et al. The value of preoperative platelet count in the prediction of cervical involvement and poor prognostic variables in patients with endometrial carcinoma. Gynecol Oncol, 2006, 103(3): 902-905.
13. 赵星鹏, 赵益明. 平足蛋白生物学功能的研究进展与应用前景. 肿瘤研究与临床, 2016, 28(9): 634-637.
14. Krishnan H, Miller WT, Blanco FJ, et al. Src and podoplanin forge a path to destruction. Drug Discov Today, 2019, 24(1): 241-249.
15. Eisemann T, Costa B, Harter PN, et al. Podoplanin expression is a prognostic biomarker but may be dispensable for the malignancy of glioblastoma. Neuro Oncol, 2019, 21(3): 326-336.
16. Tesfamariam B. Involvement of platelets in tumor cell metastasis. Pharmacol Ther, 2016, 157: 112-119.
17. Lowe KL, Navarro-Nunez L, Watson SP. Platelet CLEC-2 and podoplanin in cancer metastasis. Thromb Res, 2012, 129 Suppl 1: S30-S37.
18. Yao L, Liu Z, Zhu J, et al. Clinical evaluation of circulating microRNA-25 level change in sepsis and its potential relationship with oxidative stress. Int J Clin Exp Pathol, 2015, 8(7): 7675-7684.
19. Parhar S, Kaur H, Vashist A, et al. Role of podoplanin in potentially malignant disorders and oral squamous cell carcinoma and its correlation with lymphangiogenesis. Indian J Cancer, 2015, 52(4): 617-622.
20. La Vecchia S, Sebastián C. Metabolic pathways regulating colorectal cancer initiation and progression. Semin Cell Dev Biol, 2020, 98: 63-70.
21. Carrasco-Ramírez P, Greening DW, Andrés G, et al. Podoplanin is a component of extracellular vesicles that reprograms cell-derived exosomal proteins and modulates lymphatic vessel formation. Oncotarget, 2016, 7(13): 16070-16089.
22. Yeung KT, Yang J. Epithelial-mesenchymal transition in tumor metastasis. Mol Oncol, 2017, 11(1): 28-39.
23. Ito S, Ishii G, Hoshino A, et al. Tumor promoting effect of podoplanin-positive fibroblasts is mediated by enhanced RhoA activity. Biochem Biophys Res Commun, 2012, 422(1): 194-199.
24. Suzuki H, Onimaru M, Yonemitsu Y, et al. Podoplanin in cancer cells is experimentally able to attenuate prolymphangiogenic and lymphogenous metastatic potentials of lung squamoid cancer cells. Mol Cancer, 2010, 9: 287. doi: 10.1186/1476-4598-9-287.
25. Chihara N, Madi A, Kondo T, et al. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature, 2018, 558(7710): 454-459.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

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