Research of Lgr5 and Ki-67 protein expressions in gastric cancer tissue_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

FENG Ning ¹ , ZHU Ruiping ² , CHENG Yao ² , LIN Feng ¹ , XUE Fan ¹ , CUI Yougang ¹ , ZHANG Xu ¹ , MA Yang ¹ ,  LIU Wenzhi ¹

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

Corresponding author：

LIU Wenzhi, Email: Email：doc070735@yahoo.com

Keywords：

gastric cancer; Lgr5 protein; ki-67 protein; tumor stem cell; Helicobacter pylori

DOI：

10.7507/1007-9424.201905077

Video：

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Objective To determine the expressions of Lgr5 protein and Ki-67 protein in gastric cancer tissues, and to analyze the possible function in the carcinogenesis and development of gastric cancer.Methods The SABC immunohistochemical method was adopted to examine the expressions of Lgr5 protein and Ki-67 protein in the 69 paraffin slices of gastric cancer from the patients, with the adjacent normal gastric tissue as the control group. The statistical relationship between the expressions of these two kinds of proteins and clinicopathologic features of gastric cancer was examined respectively.Results In the gastric cancer tissue group, the expressions of Lgr5 protein and Ki-67 protein upregulated in comparison to the adjacent normal gastric tissue group [Lgr5 protein: 87.0% (60/69) versus 16.7% (5/30), χ²=45.81, P<0.001; Ki-67 protein: 79.7% (55/69) versus 36.7% (11/30), χ²=17.43, P<0.001]. The expressions of Lgr5 protein and Ki-67 protein all upregulated in the N1–N3 stage groups, lowly differentiated+undifferentiated groups and positive Helicobacter pylori (HP) groups. The expression of Lgr5 protein upregulated in the T3+T4 stage groups in comparison to T1+T2 stage groups, while, no significant relationship was found in the expression of Ki-67 protein and tumor T staging. No significant relationship was found between the gender or metastasis and the expression of these two proteins. There was a positive correlation between the Lgr5 protein expression and the Ki-67 protein expression in the gastric cancer (r_s=0.340, P=0.004).Conclusions In the development progress of gastric cancer, the Lgr5 protein might get involved in the mechanism of tumor invasion, lymph nodal metastasis, and low differentiation. Ki-67 protein might get involved in the mechanism of lymph nodal metastasis and low differentiation. The two proteins, together with the HP infection, might play a synergistic role in tumorigenesis and development.

Citation： FENG Ning, ZHU Ruiping, CHENG Yao, LIN Feng, XUE Fan, CUI Yougang, ZHANG Xu, MA Yang, LIU Wenzhi. Research of Lgr5 and Ki-67 protein expressions in gastric cancer tissue. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(11): 1293-1297. doi: 10.7507/1007-9424.201905077 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.	de Lau W, Barker N, Low TY, et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature, 2011, 476(7360): 293-297.
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 miR4310/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.	王嘉, 俞继卫, 姜波健. 胃肠道干细胞及其在胃肿瘤中的作用的研究进展. 中国普外基础与临床杂志, 2013, 20(2): 114-119.
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.	Gerdes J, Schwab U, Lemke H, et al. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer, 1983, 31(1): 13-20.
18.	Huang G, Chen S, Wang D, et al. High Ki67 expression has prognostic value in surgically-resected T3 gastric adenocarcinoma. Clin Lab, 2016, 62(1-2): 141-153.
19.	Badary DM, Abdel-Wanis ME, Hafez MZ, et al. Immunohistochemical analysis of PTEN, HER2/neu, and ki67 expression in patients with gastric cancer and their association with survival. Pathophysiology, 2017, 24(2): 99-106.
20.	Zhou Y, Li Y, Zheng J, et al. Detecting of gastric cancer by Bcl-2 and Ki67. Int J Clin Exp Pathol, 2015, 8(6): 7287-7290.
21.	Zheng Y, Wang L, Zhang JP, et al. Expression of p53, c-erbB-2 and Ki67 in intestinal metaplasia and gastric carcinoma. World J Gastroenterol, 2010, 16(3): 339-344.
22.	Tzanakis NE, Peros G, Karakitsos P, et al. Prognostic significance of p53 and Ki67 proteins expression in Greek gastric cancer patients. Acta Chir Belg, 2009, 109(5): 606-611.
23.	Geramizadeh B, Salehzadeh A, Taghavi A, et al. Comparison of proliferative (Ki67) and cell adhesion (E-cadherin) markers between gastric intestinal metaplasia and Barrett’s esophagus. Indian J Gastroenterol, 2009, 28(3): 115-116.
24.	孙立婷, 郭丽英. Ki-67 抗原与乳腺癌的相关性研究. 中国普外基础与临床杂志, 2014, 21(5): 650-653.
25.	Min KW, Kim DH, Son BK, et al. A high Ki67/BCL2 index could predict lower disease-free and overall survival in intestinal-type gastric cancer. Eur Surg Res, 2017, 58(3-4): 158-168.

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. de Lau W, Barker N, Low TY, et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature, 2011, 476(7360): 293-297.
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 miR4310/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. 王嘉, 俞继卫, 姜波健. 胃肠道干细胞及其在胃肿瘤中的作用的研究进展. 中国普外基础与临床杂志, 2013, 20(2): 114-119.
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. Gerdes J, Schwab U, Lemke H, et al. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer, 1983, 31(1): 13-20.
18. Huang G, Chen S, Wang D, et al. High Ki67 expression has prognostic value in surgically-resected T3 gastric adenocarcinoma. Clin Lab, 2016, 62(1-2): 141-153.
19. Badary DM, Abdel-Wanis ME, Hafez MZ, et al. Immunohistochemical analysis of PTEN, HER2/neu, and ki67 expression in patients with gastric cancer and their association with survival. Pathophysiology, 2017, 24(2): 99-106.
20. Zhou Y, Li Y, Zheng J, et al. Detecting of gastric cancer by Bcl-2 and Ki67. Int J Clin Exp Pathol, 2015, 8(6): 7287-7290.
21. Zheng Y, Wang L, Zhang JP, et al. Expression of p53, c-erbB-2 and Ki67 in intestinal metaplasia and gastric carcinoma. World J Gastroenterol, 2010, 16(3): 339-344.
22. Tzanakis NE, Peros G, Karakitsos P, et al. Prognostic significance of p53 and Ki67 proteins expression in Greek gastric cancer patients. Acta Chir Belg, 2009, 109(5): 606-611.
23. Geramizadeh B, Salehzadeh A, Taghavi A, et al. Comparison of proliferative (Ki67) and cell adhesion (E-cadherin) markers between gastric intestinal metaplasia and Barrett’s esophagus. Indian J Gastroenterol, 2009, 28(3): 115-116.
24. 孙立婷, 郭丽英. Ki-67 抗原与乳腺癌的相关性研究. 中国普外基础与临床杂志, 2014, 21(5): 650-653.
25. Min KW, Kim DH, Son BK, et al. A high Ki67/BCL2 index could predict lower disease-free and overall survival in intestinal-type gastric cancer. Eur Surg Res, 2017, 58(3-4): 158-168.

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Research of Lgr5 and Ki-67 protein expressions in gastric cancer tissue

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