MCEMP1 expression and its relationship with immune infiltration in gastric cancer: based bioinformatics analysis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LE Qi ¹ , LÜ Kun ¹ , JIANG Lei ² , WANG Jun ² ,  YAO Nan ²

1. The First Clinical Medical College of Lanzhou University, Lanzhou 730000, P, R. China;
2. The Sixth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, P, R. China;

Corresponding author：

YAO Nan, Email: yaonanPro@163.com

Keywords：

gastric cancer; mast cell expressing membrane protein 1; tumor microenvironment; immune infiltration; prognosis; bioinformatic

DOI：

10.7507/1007-9424.202107063

Video：

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Objective To investigate the relationship between the expression of mast cell expressed membrane protein 1 (MCEMP1) in gastric cancer and its relationship with prognosis and tumor immune infiltration. Methods Transcriptome expression profile data and clinical data information of gastric cancer and normal samples were downloaded from TCGA database, and differentially expressed genes in gastric cancer tumor microenvironment were extracted using R 4.0.5 software. Protein-protein interaction network of differentially expressed genes was constructed by using STRING online website, protein-protein interaction network and univariate Cox proportional hazards regression analysis were used for cross-tabulation analysis to obtain key genes. Kruskal-Wallis rank sum test was used to investigate the correlation between key genes and clinicopathological features. The possible signaling pathways involved in key genes were predicted by gene set enrichment analysis. We further analyzed the relationship between expression of key gene and the level of immune infiltration and immune molecules in gastric cancer by TISIDB online database and CIBERSORT algorithm. Results A total of 760 differentially expressed genes in gastric cancer were found and a key gene of MCEMP1 was derived from cross-tabulation analysis based on the results of protein-protein interaction network and univariate Cox proportional hazards regression analysis. Expression of MCEMP1 was significantly upregulated in gastric cancer tissues (P<0.001), and survival analysis showed that the overall survival rate of the group with high expression level of MCEMP1 was lower than that of low expression [HR=1.176, 95%CI (1.066, 1.297）, P=0.046]. Expression of MCEMP1 also correlated with age, T-stage, and clinical stage of gastric cancer (P<0.05) , and expression of MCEMP1 was significantly associated with a variety kinds of immune cells and expression of immune molecules (P<0.05). Conclusion MCEMP1 is a potential prognostic marker for gastric cancer and is associated with immune infiltration in gastric cancer.

Citation： LE Qi, LÜ Kun, JIANG Lei, WANG Jun, YAO Nan. MCEMP1 expression and its relationship with immune infiltration in gastric cancer: based bioinformatics analysis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(5): 599-606. doi: 10.7507/1007-9424.202107063 Copy

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2.	Thrift AP, El-Serag HB. Burden of gastric cancer. Clin Gastroenterol Hepatol, 2020, 18(3): 534-542.
3.	Digklia A, Wagner AD. Advanced gastric cancer: Current treatment landscape and future perspectives. World J Gastroenterol, 2016, 22(8): 2403-2414.
4.	吕海冰, 戴志成, 邹小明. 胃癌早期诊断相关标志物的研究进展. 中国普外基础与临床杂志, 2021, 28(8): 1108-1113.
5.	Ilson DH. Advances in the treatment of gastric cancer: 2019. Curr Opin Gastroenterol, 2019, 35(6): 551-554.
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7.	Locy H, de Mey S, de Mey W, et al. Immunomodulation of the tumor microenvironment: Turn Foe Into Friend. Front Immunol, 2018, 9: 2909. doi: 10.3389/fimmu.2018.02909.
8.	Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res, 2019, 79(18): 4557-4566.
9.	Lei X, Lei Y, Li JK, et al. Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy. Cancer Lett, 2020, 470: 126-133.
10.	Jiang Y, Wang C, Zhou S. Targeting tumor microenvironment in ovarian cancer: Premise and promise. Biochim Biophys Acta Rev Cancer, 2020, 1873(2): 188361. doi: 10.1016/j.bbcan.2020.188361.
11.	Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med, 2013, 19(11): 1423-1437.
12.	Zeng D, Zhou R, Yu Y, et al. Gene expression profiles for a prognostic immunoscore in gastric cancer. Br J Surg, 2018, 105(10): 1338-1348.
13.	Rojas A, Araya P, Gonzalez I, et al. Gastric tumor microenvironment. Adv Exp Med Biol, 2020, 1226: 23-35.
14.	Zeng D, Li M, Zhou R, et al. Tumor microenvironment characterization in gastric cancer identifies prognostic and immunotherapeutically relevant gene signatures. Cancer Immunol Res, 2019, 7(5): 737-750.
15.	Zheng P, Li W. Crosstalk between mesenchymal stromal cells and tumor-associated macrophages in gastric cancer. Front Oncol, 2020, 10: 571516. doi: 10.3389/fonc.2020.571516.
16.	Li K, Wang SW, Li Y, et al. Identification and expression of a new type Ⅱ transmembrane protein in human mast cells. Genomics, 2005, 86(1): 68-75.
17.	Jian R, Yang M, Xu F. Lentiviral-mediated silencing of mast cell-expressed membrane protein 1 promotes angiogenesis of rats with cerebral ischemic stroke. J Cell Biochem, 2019, 120(10): 16786-16797.
18.	Aller MA, Arias A, Arias JI, et al. Carcinogenesis: the cancer cell-mast cell connection. Inflamm Res, 2019, 68(2): 103-116.
19.	Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell, 2010, 140(6): 883-899.
20.	Moore MM, Chua W, Charles KA, et al. Inflammation and cancer: causes and consequences. Clin Pharmacol Ther, 2010, 87(4): 504-508.
21.	Khazaie K, Blatner NR, Khan MW, et al. The significant role of mast cells in cancer. Cancer Metastasis Rev, 2011, 30(1): 45-60.
22.	Komi DEA, Redegeld FA. Role of mast cells in shaping the tumor microenvironment. Clin Rev Allergy Immunol, 2020, 58(3): 313-325.
23.	Ribatti D, Ranieri G. Tryptase, a novel angiogenic factor stored in mast cell granules. Exp Cell Res, 2015, 332(2): 157-162.
24.	Piazuelo MB, Riechelmann RP, Wilson KT, et al. Resolution of gastric cancer-promoting inflammation: A novel strategy for anti-cancer therapy. Curr Top Microbiol Immunol, 2019, 421: 319-359.
25.	Zhang H, Liu H, Shen Z, et al. Tumor-infiltrating neutrophils is prognostic and predictive for postoperative adjuvant chemotherapy benefit in patients with gastric cancer. Ann Surg, 2018, 267(2): 311-318.
26.	Ishigami S, Natsugoe S, Tokuda K, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer, 2000, 88(3): 577-583.
27.	Eissmann MF, Dijkstra C, Jarnicki A, et al. IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nat Commun, 2019, 10(1): 2735. doi: 10.1038/s41467-019-10676-1.
28.	Yano H, Kinuta M, Tateishi H, et al. Mast cell infiltration around gastric cancer cells correlates with tumor angiogenesis and metastasis. Gastric Cancer, 1999, 2(1): 26-32.
29.	Chen Y, Zhang S, Wang Q, et al. Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein. J Hematol Oncol, 2017, 10(1): 36. doi: 10.1186/s13045-017-0408-0.
30.	Malmberg KJ, Carlsten M, Björklund A, et al. Natural killer cell-mediated immunosurveillance of human cancer. Semin Immunol, 2017, 31: 20-29.
31.	Rezalotfi A, Ahmadian E, Aazami H, et al. Gastric cancer stem cells effect on Th17/Treg balance; A bench to beside perspective. Front Oncol, 2019, 9: 226. doi: 10.3389/fonc.2019.00226.
32.	Allen BM, Hiam KJ, Burnett CE, et al. Systemic dysfunction and plasticity of the immune macroenvironment in cancer models. Nat Med, 2020, 26(7): 1125-1134.
33.	Zou W, Restifo NP. T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol, 2010, 10(4): 248-256.
34.	Guéry L, Hugues S. Th17 cell plasticity and functions in cancer immunity. Biomed Res Int, 2015, 2015: 314620. doi: 10.1155/2015/314620.
35.	Song EJ, Kang MJ, Kim YS, et al. Flagellin promotes the proliferation of gastric cancer cells via the Toll-like receptor 5. Int J Mol Med, 2011, 28(1): 115-119.
36.	Cai Z, Sanchez A, Shi Z, et al. Activation of Toll-like receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth. Cancer Res, 2011, 71(7): 2466-2475.
37.	Pradere JP, Dapito DH, Schwabe RF. The Yin and Yang of Toll-like receptors in cancer. Oncogene, 2014, 33(27): 3485-3495.
38.	Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer, 2009, 9(5): 361-371.
39.	Tu S, Bhagat G, Cui G, et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell, 2008, 14(5): 408-419.
40.	Dutta J, Fan Y, Gupta N, et al. Current insights into the regulation of programmed cell death by NF-kappaB. Oncogene, 2006, 25(51): 6800-6816.
41.	Tye H, Kennedy CL, Najdovska M, et al. STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell, 2012, 22(4): 466-478.

1. Bray F, Ferlay J, Soerjomataram I, et al. 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.
2. Thrift AP, El-Serag HB. Burden of gastric cancer. Clin Gastroenterol Hepatol, 2020, 18(3): 534-542.
3. Digklia A, Wagner AD. Advanced gastric cancer: Current treatment landscape and future perspectives. World J Gastroenterol, 2016, 22(8): 2403-2414.
4. 吕海冰, 戴志成, 邹小明. 胃癌早期诊断相关标志物的研究进展. 中国普外基础与临床杂志, 2021, 28(8): 1108-1113.
5. Ilson DH. Advances in the treatment of gastric cancer: 2019. Curr Opin Gastroenterol, 2019, 35(6): 551-554.
6. Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov, 2015, 14(8): 561-584.
7. Locy H, de Mey S, de Mey W, et al. Immunomodulation of the tumor microenvironment: Turn Foe Into Friend. Front Immunol, 2018, 9: 2909. doi: 10.3389/fimmu.2018.02909.
8. Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res, 2019, 79(18): 4557-4566.
9. Lei X, Lei Y, Li JK, et al. Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy. Cancer Lett, 2020, 470: 126-133.
10. Jiang Y, Wang C, Zhou S. Targeting tumor microenvironment in ovarian cancer: Premise and promise. Biochim Biophys Acta Rev Cancer, 2020, 1873(2): 188361. doi: 10.1016/j.bbcan.2020.188361.
11. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med, 2013, 19(11): 1423-1437.
12. Zeng D, Zhou R, Yu Y, et al. Gene expression profiles for a prognostic immunoscore in gastric cancer. Br J Surg, 2018, 105(10): 1338-1348.
13. Rojas A, Araya P, Gonzalez I, et al. Gastric tumor microenvironment. Adv Exp Med Biol, 2020, 1226: 23-35.
14. Zeng D, Li M, Zhou R, et al. Tumor microenvironment characterization in gastric cancer identifies prognostic and immunotherapeutically relevant gene signatures. Cancer Immunol Res, 2019, 7(5): 737-750.
15. Zheng P, Li W. Crosstalk between mesenchymal stromal cells and tumor-associated macrophages in gastric cancer. Front Oncol, 2020, 10: 571516. doi: 10.3389/fonc.2020.571516.
16. Li K, Wang SW, Li Y, et al. Identification and expression of a new type Ⅱ transmembrane protein in human mast cells. Genomics, 2005, 86(1): 68-75.
17. Jian R, Yang M, Xu F. Lentiviral-mediated silencing of mast cell-expressed membrane protein 1 promotes angiogenesis of rats with cerebral ischemic stroke. J Cell Biochem, 2019, 120(10): 16786-16797.
18. Aller MA, Arias A, Arias JI, et al. Carcinogenesis: the cancer cell-mast cell connection. Inflamm Res, 2019, 68(2): 103-116.
19. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell, 2010, 140(6): 883-899.
20. Moore MM, Chua W, Charles KA, et al. Inflammation and cancer: causes and consequences. Clin Pharmacol Ther, 2010, 87(4): 504-508.
21. Khazaie K, Blatner NR, Khan MW, et al. The significant role of mast cells in cancer. Cancer Metastasis Rev, 2011, 30(1): 45-60.
22. Komi DEA, Redegeld FA. Role of mast cells in shaping the tumor microenvironment. Clin Rev Allergy Immunol, 2020, 58(3): 313-325.
23. Ribatti D, Ranieri G. Tryptase, a novel angiogenic factor stored in mast cell granules. Exp Cell Res, 2015, 332(2): 157-162.
24. Piazuelo MB, Riechelmann RP, Wilson KT, et al. Resolution of gastric cancer-promoting inflammation: A novel strategy for anti-cancer therapy. Curr Top Microbiol Immunol, 2019, 421: 319-359.
25. Zhang H, Liu H, Shen Z, et al. Tumor-infiltrating neutrophils is prognostic and predictive for postoperative adjuvant chemotherapy benefit in patients with gastric cancer. Ann Surg, 2018, 267(2): 311-318.
26. Ishigami S, Natsugoe S, Tokuda K, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer, 2000, 88(3): 577-583.
27. Eissmann MF, Dijkstra C, Jarnicki A, et al. IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nat Commun, 2019, 10(1): 2735. doi: 10.1038/s41467-019-10676-1.
28. Yano H, Kinuta M, Tateishi H, et al. Mast cell infiltration around gastric cancer cells correlates with tumor angiogenesis and metastasis. Gastric Cancer, 1999, 2(1): 26-32.
29. Chen Y, Zhang S, Wang Q, et al. Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein. J Hematol Oncol, 2017, 10(1): 36. doi: 10.1186/s13045-017-0408-0.
30. Malmberg KJ, Carlsten M, Björklund A, et al. Natural killer cell-mediated immunosurveillance of human cancer. Semin Immunol, 2017, 31: 20-29.
31. Rezalotfi A, Ahmadian E, Aazami H, et al. Gastric cancer stem cells effect on Th17/Treg balance; A bench to beside perspective. Front Oncol, 2019, 9: 226. doi: 10.3389/fonc.2019.00226.
32. Allen BM, Hiam KJ, Burnett CE, et al. Systemic dysfunction and plasticity of the immune macroenvironment in cancer models. Nat Med, 2020, 26(7): 1125-1134.
33. Zou W, Restifo NP. T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol, 2010, 10(4): 248-256.
34. Guéry L, Hugues S. Th17 cell plasticity and functions in cancer immunity. Biomed Res Int, 2015, 2015: 314620. doi: 10.1155/2015/314620.
35. Song EJ, Kang MJ, Kim YS, et al. Flagellin promotes the proliferation of gastric cancer cells via the Toll-like receptor 5. Int J Mol Med, 2011, 28(1): 115-119.
36. Cai Z, Sanchez A, Shi Z, et al. Activation of Toll-like receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth. Cancer Res, 2011, 71(7): 2466-2475.
37. Pradere JP, Dapito DH, Schwabe RF. The Yin and Yang of Toll-like receptors in cancer. Oncogene, 2014, 33(27): 3485-3495.
38. Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer, 2009, 9(5): 361-371.
39. Tu S, Bhagat G, Cui G, et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell, 2008, 14(5): 408-419.
40. Dutta J, Fan Y, Gupta N, et al. Current insights into the regulation of programmed cell death by NF-kappaB. Oncogene, 2006, 25(51): 6800-6816.
41. Tye H, Kennedy CL, Najdovska M, et al. STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell, 2012, 22(4): 466-478.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

MCEMP1 expression and its relationship with immune infiltration in gastric cancer: based bioinformatics analysis

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