Research of expressions of E-cadherin and Lgr5 proteins in gastric cancer tissues_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

FENG Ning , LIN Feng , ZHANG Xu , XUE Fan , CUI Yougang , MA Yang ,  LIU Wenzhi

Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P. R. China;

Corresponding author：

LIU Wenzhi, Email: doc070735@yahoo.com

Keywords：

gastric cancer; Lgr5 protein; E-cadherin protein; tumor stem cell; immunohistochemistry; survival analysis

DOI：

10.7507/1007-9424.201909064

Video：

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Objective To detect expressions of Lgr5 and E-cadherin (E-cad) proteins in gastric cancer tissues and analyze their relationships with the clinicopathologic characteristics and prognosis of patients with gastric cancer.Methods The expressions of Lgr5 and E-cad proteins in the 69 patients with gastric cancer and adjacent normal gastric mucosa tissues were measured by the immunohistochemical SABC method, and the relationships between the Lgr5 or E-cad protein expression in the gastric cancer tissues and the clinicopathologic characteristics and the survival of patients with gastric cancer were analyzed.Results The expressions of Lgr5 and E-cad proteins were positive in 60 cases (87.0%) and 30 cases (43.5%) of gastric cancer tissues, respectively, and in 5 cases (16.7%) and 30 cases (100%) of adjacent normal gastric mucosa tissues. There was a significant difference in the positive rate of Lgr5 or E-cad protein expression in the different tissues, respectively (Lgr5 protein: χ²=45.814, P<0.001; E-cad protein: χ²=11.249, P=0.001). The positive rates of Lgr5 and E-cad protein expressions in the gastric cancer were related to the degree of differentiation and the depth of invasion. Meanwhile the positive rate of Lgr5 protein expression in the gastric cancer tissue was also related to the lymph node metastasis and Helicobacter pylori infection, while the positive rate of E-cad protein expression was not related to these (P>0.05). The 5-year total survival time had no significant difference in the patients between with positive and with negative expressions of Lgr5 protein (χ²=1.819, P=0.117), which had a significant difference in the patients between with positive and with negative expressions of E-cad protein (χ²=5.814, P=0.016). The positive expression of Lgr5 was negatively correlated with that of E-cad (r_s=−0.355, P=0.003).Conclusions Lgr5 protein may get involved in the mechanism of tumor invasion, lymph nodal metastasis, and low differentiation, while no relationship between the Lgr5 protein and prognosis has been confirmed. E-cad protein may get involved in the mechanism of tumor invasion and affect the prognosis of patients.

Citation： FENG Ning, LIN Feng, ZHANG Xu, XUE Fan, CUI Yougang, MA Yang, LIU Wenzhi. Research of expressions of E-cadherin and Lgr5 proteins in gastric cancer tissues. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(3): 309-314. doi: 10.7507/1007-9424.201909064 Copy

1.	Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature, 2007, 449(7165): 1003-1007.
2.	Buczacki SJ, Zecchini HI, Nicholson AM, et al. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature, 2013, 495(7439): 65-69.
3.	Sato T, Vries RG, Snippert HJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature, 2009, 459(7244): 262-265.
4.	Schepers AG, Snippert HJ, Stange DE, et al. Lineage tracing reveals Lgr5⁺ stem cell activity in mouse intestinal adenomas. Science, 2012, 337(6095): 730-735.
5.	Ajani JA, D’Amico TA, Almhanna K, et al. Gastric Cancer, Version 3. 2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 2016, 14(10): 1286-1312.
6.	Yin X, Farin HF, van Es JH, et al. Niche-independent high-purity cultures of Lgr5⁺ intestinal stem cells and their progeny. Nat Methods, 2014, 11(1): 106-112.
7.	Metcalfe C, Kljavin NM, Ybarra R, et al. Lgr5⁺ stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell, 2014, 14(2): 149-159.
8.	Morgan RG, Molnár E, Jones RF, et al. Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells: implications for targeting cancer stem cells. Br J Cancer, 2015, 112(4): 714-719.
9.	Sato K, Uehara T, Iwaya M, et al. Correlation of clinicopathological features and LGR5 expression in colon adenocarcinoma. Ann Diagn Pathol, 2019, 40: 161-165.
10.	Nagata H, Ishihara S, Abe H, et al. LGR5 expression predicts peritoneal recurrence after curative resection of primary colon cancer. Br J Cancer, 2019, 120(10): 996-1002.
11.	Jing N, Huang T, Guo H, et al. LncRNA CASC15 promotes colon cancer cell proliferation and metastasis by regulating the miR-4310/LGR5/Wnt/β-catenin signaling pathway. Mol Med Rep, 2018, 18(2): 2269-2276.
12.	Zhou X, Geng L, Wang D, et al. R-spondin1/LGR5 ACtivates TGFβ signaling and suppresses colon cancer metastasis. Cancer Res, 2017, 77(23): 6589-6602.
13.	Jia Y, Li Z, Cheng X, et al. Depletion of death-associated protein-3 induces chemoresistance in gastric cancer cells through the β-catenin/LGR5/Bcl-2 axis. J Investig Med, 2019, 67(5): 856-861.
14.	Carmon KS, Gong X, Yi J, et al. LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1-Rac1 pathway. J Biol Chem, 2017, 292(36): 14989-15001.
15.	de Sousa e Melo F, Kurtova AV, Harnoss JM, et al. A distinct role for Lgr5⁺ stem cells in primary and metastatic colon cancer. Nature, 2017, 543(7647): 676-680.
16.	Shimokawa M, Ohta Y, Nishikori S, et al. Visualization and targeting of LGR5⁺ human colon cancer stem cells. Nature, 2017, 545(7653): 187-192.
17.	Kurata A, Yamada M, Ohno SI, et al. Expression level of microRNA-200c is associated with cell morphology in vitro and histological differentiation through regulation of ZEB1/2 and E-cadherin in gastric carcinoma. Oncol Rep, 2018, 39(1): 91-100.
18.	Schizas D, Moris D, Michalinos A, et al. E-cadherin in gastric carcinomas: Relations with histological parameters and its prognostic value. J BUON, 2017, 22(2): 383-389.
19.	Kojima K, Minatani N, Ushiku H, et al. Prediction of onset of remnant gastric cancer by promoter DNA methylation of CDO1/HOPX/Reprimo/E-cadherin. Oncotarget, 2019, 10(25): 2423-2434.
20.	Tang Y, Yang G, Zhang J, et al. E-cadherin is required for the homeostasis of Lgr5⁺ gastric antral stem cells. Int J Biol Sci, 2019, 15(1): 34-43.
21.	Lin Y, Zhang CS, Li SJ, et al. LncRNA LOC554202 promotes proliferation and migration of gastric cancer cells through regulating p21 and E-cadherin. Eur Rev Med Pharmacol Sci, 2018, 22(24): 8690-8697.
22.	Bahnassy AA, Helal TE, El-Ghazawy IM, et al. The role of E-cadherin and Runx3 in Helicobacter Pylori-associated gastric carcinoma is achieved through regulating P21waf and P27 expression. Cancer Genet, 2018, 228-229: 64-72.
23.	Zhao K, He J, Wang YF, et al. EZH2-mediated epigenetic suppression of EphB3 inhibits gastric cancer proliferation and metastasis by affecting E-cadherin and vimentin expression. Gene, 2019, 686: 118-124.
24.	Jang M, Koh I, Lee JE, et al. Increased extracellular matrix density disrupts E-cadherin/β-catenin complex in gastric cancer cells. Biomater Sci, 2018, 6(10): 2704-2713.
25.	Chen Z, Wu J, Huang W, et al. Long non-coding RNA RP11-789C1.1 suppresses epithelial to mesenchymal transition in gastric cancer through the RP11-789C1.1/MiR-5003/E-cadherin axis. Cell Physiol Biochem, 2018, 47(6): 2432-2444.

1. Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature, 2007, 449(7165): 1003-1007.
2. Buczacki SJ, Zecchini HI, Nicholson AM, et al. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature, 2013, 495(7439): 65-69.
3. Sato T, Vries RG, Snippert HJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature, 2009, 459(7244): 262-265.
4. Schepers AG, Snippert HJ, Stange DE, et al. Lineage tracing reveals Lgr5⁺ stem cell activity in mouse intestinal adenomas. Science, 2012, 337(6095): 730-735.
5. Ajani JA, D’Amico TA, Almhanna K, et al. Gastric Cancer, Version 3. 2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 2016, 14(10): 1286-1312.
6. Yin X, Farin HF, van Es JH, et al. Niche-independent high-purity cultures of Lgr5⁺ intestinal stem cells and their progeny. Nat Methods, 2014, 11(1): 106-112.
7. Metcalfe C, Kljavin NM, Ybarra R, et al. Lgr5⁺ stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell, 2014, 14(2): 149-159.
8. Morgan RG, Molnár E, Jones RF, et al. Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells: implications for targeting cancer stem cells. Br J Cancer, 2015, 112(4): 714-719.
9. Sato K, Uehara T, Iwaya M, et al. Correlation of clinicopathological features and LGR5 expression in colon adenocarcinoma. Ann Diagn Pathol, 2019, 40: 161-165.
10. Nagata H, Ishihara S, Abe H, et al. LGR5 expression predicts peritoneal recurrence after curative resection of primary colon cancer. Br J Cancer, 2019, 120(10): 996-1002.
11. Jing N, Huang T, Guo H, et al. LncRNA CASC15 promotes colon cancer cell proliferation and metastasis by regulating the miR-4310/LGR5/Wnt/β-catenin signaling pathway. Mol Med Rep, 2018, 18(2): 2269-2276.
12. Zhou X, Geng L, Wang D, et al. R-spondin1/LGR5 ACtivates TGFβ signaling and suppresses colon cancer metastasis. Cancer Res, 2017, 77(23): 6589-6602.
13. Jia Y, Li Z, Cheng X, et al. Depletion of death-associated protein-3 induces chemoresistance in gastric cancer cells through the β-catenin/LGR5/Bcl-2 axis. J Investig Med, 2019, 67(5): 856-861.
14. Carmon KS, Gong X, Yi J, et al. LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1-Rac1 pathway. J Biol Chem, 2017, 292(36): 14989-15001.
15. de Sousa e Melo F, Kurtova AV, Harnoss JM, et al. A distinct role for Lgr5⁺ stem cells in primary and metastatic colon cancer. Nature, 2017, 543(7647): 676-680.
16. Shimokawa M, Ohta Y, Nishikori S, et al. Visualization and targeting of LGR5⁺ human colon cancer stem cells. Nature, 2017, 545(7653): 187-192.
17. Kurata A, Yamada M, Ohno SI, et al. Expression level of microRNA-200c is associated with cell morphology in vitro and histological differentiation through regulation of ZEB1/2 and E-cadherin in gastric carcinoma. Oncol Rep, 2018, 39(1): 91-100.
18. Schizas D, Moris D, Michalinos A, et al. E-cadherin in gastric carcinomas: Relations with histological parameters and its prognostic value. J BUON, 2017, 22(2): 383-389.
19. Kojima K, Minatani N, Ushiku H, et al. Prediction of onset of remnant gastric cancer by promoter DNA methylation of CDO1/HOPX/Reprimo/E-cadherin. Oncotarget, 2019, 10(25): 2423-2434.
20. Tang Y, Yang G, Zhang J, et al. E-cadherin is required for the homeostasis of Lgr5⁺ gastric antral stem cells. Int J Biol Sci, 2019, 15(1): 34-43.
21. Lin Y, Zhang CS, Li SJ, et al. LncRNA LOC554202 promotes proliferation and migration of gastric cancer cells through regulating p21 and E-cadherin. Eur Rev Med Pharmacol Sci, 2018, 22(24): 8690-8697.
22. Bahnassy AA, Helal TE, El-Ghazawy IM, et al. The role of E-cadherin and Runx3 in Helicobacter Pylori-associated gastric carcinoma is achieved through regulating P21waf and P27 expression. Cancer Genet, 2018, 228-229: 64-72.
23. Zhao K, He J, Wang YF, et al. EZH2-mediated epigenetic suppression of EphB3 inhibits gastric cancer proliferation and metastasis by affecting E-cadherin and vimentin expression. Gene, 2019, 686: 118-124.
24. Jang M, Koh I, Lee JE, et al. Increased extracellular matrix density disrupts E-cadherin/β-catenin complex in gastric cancer cells. Biomater Sci, 2018, 6(10): 2704-2713.
25. Chen Z, Wu J, Huang W, et al. Long non-coding RNA RP11-789C1.1 suppresses epithelial to mesenchymal transition in gastric cancer through the RP11-789C1.1/MiR-5003/E-cadherin axis. Cell Physiol Biochem, 2018, 47(6): 2432-2444.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research of expressions of E-cadherin and Lgr5 proteins in gastric cancer tissues

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