Abstract
Purpose
The effect of E-cadherin on colorectal cancer is still controversial. In order to clarify the effect of E-cadherin on the prognosis and clinicopathological features of colorectal cancer, a meta-analysis was conducted.
Methods
PubMed, Embase and Cochrane Library were used to collect all relevant literature published before November 2021, and the corresponding data was extracted to analyze the correlation between the expression of E-cadherin and the prognosis and clinicopathological features of colorectal cancer. In addition, the Gene Expression Profiling Interactive Analysis (GEPIA) was used to validate our results.
Results
Fifty-two studies, including 9591 patients, were included in this meta-analysis. According to the meta-analysis, low expression of E-cadherin was significantly associated with shorter overall survival (OS) (hazard ratio [HR] 2.09, 95% confidence interval [CI]1.67–2.62; Z = 6.42, p = 0.000) and disease-free survival (DFS) (HR 2.03, 95% CI 1.71–2.42; Z = 7.95, p = 0.000). In addition, low expression of E-cadherin resulted in higher risk of low differentiation (odds ratio [OR] 0.35, 95% CI 0.25–0.50; p = 0.000), high risk of distant metastasis (OR 0.45, 95% CI 0.35–0.58; p = 0.000), high risk of vascular invasion (OR 0.61, 95% CI 0.45–0.83; p = 0.002), higher risk of lymph node metastasis (OR 0.54, 95% CI 0.42–0.69; p = 0.000), high risk of lymphatic invasion (OR 0.56, 95% CI 0.40–0.80; p = 0.001), high risk of deep infiltration (OR 0.63, 95% CI 0.50–0.80; p = 0.000), later TNM stage (OR 0.60, 95% CI 0.46–0.78; p = 0.000) and late Dukes' stage (OR 0.35,95% CI 0.25–0.49; p = 0.000), but wasn't associated with tumor size (OR 0.90, 95% CI 0.71–1.15; p = 0.406).The results of GEPIA showed that E-cadherin mRNA expression in colorectal cancer tumor tissues and normal tissues had no difference, and had no effect on OS and DFS.
Conclusion
Although not supported by GEPIA, our meta-analysis provided abundant data to suggest that low expression of E-cadherin is associated with poor prognosis in colorectal cancer patients and is an important factor influencing adverse clinicopathological features. Therefore, E-cadherin may be used to predict the prognosis of colorectal cancer and provide guidance for clinical treatment.
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References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, 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):209–49.
Mahar AL, Compton C, Halabi S, Hess KR, Weiser MR, Groome PA. Personalizing prognosis in colorectal cancer: A systematic review of the quality and nature of clinical prognostic tools for survival outcomes. J Surg Oncol. 2017;116(8):969–82.
Chapman MA, Buckley D, Henson DB, Armitage NC. Preoperative carcinoembryonic antigen is related to tumour stage and long-term survival in colorectal cancer. Br J Cancer. 1998;78(10):1346–9.
Morales-Gutiérrez C, Vegh I, Colina F, Gómez-Cámara A, Ignacio Landa J, Ballesteros D, et al. Survival of patients with colorectal carcinoma: possible prognostic value of tissular carbohydrate antigen 19.9 determination. Cancer. 1999;86(9):1675–81.
Lu M, Marsters S, Ye X, Luis E, Gonzalez L, Ashkenazi A. E-cadherin couples death receptors to the cytoskeleton to regulate apoptosis. Mol Cell. 2014;54(6):987–98.
Greenburg G, Hay ED. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol. 1982;95(1):333–9.
Purnak T, Ozaslan E, Efe C. Molecular basis of colorectal cancer. New Engl J Med. 2010;362(13):1246–7.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.
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):W98–102.
Dai YC, Fang CY, Yang HY, Jian YJ, Wang SC, Liu YW. The correlation of epithelial-mesenchymal transition-related gene expression and the clinicopathologic features of colorectal cancer patients in Taiwan. PLoS ONE. 2021;16(7): e0254000.
Vermani L, Kumar R, Kannan RR, Deka MK, Talukdar A, Kumar NS. Expression pattern of ALDH1, E-cadherin, Vimentin and Twist in early and late onset sporadic colorectal cancer. Biomark Med. 2020;14(14):1371–82.
Triki M, Kallel R, Feki J, Mellouli M, Charfi S, Ayadi L, et al. Prognostic significance of E-cadherin and Cox 2 expression in Tunisian patients with colorectal mucinous adenocarcinoma. Ann Diagn Pathol. 2020;49:151624.
Qu J, Jiang Y, Liu H, Deng H, Yu J, Qi X, et al. Prognostic Value of E-cadherin-, CD44-, and MSH2-associated Nomograms in Patients With Stage II and III Colorectal Cancer. Transl Oncol. 2017;10(2):121–31.
Iseki Y, Shibutani M, Maeda K, Nagahara H, Ikeya T, Hirakawa K. Significance of E-cadherin and CD44 expression in patients with unresectable metastatic colorectal cancer. Oncol Lett. 2017;14(1):1025–34.
Wang Y, Wu Z, Hu L. Epithelial-mesenchymal transition phenotype, metformin, and survival for colorectal cancer patients with diabetes mellitus II. Gastroenterol Res Pract. 2017;2017:2520581.
Cai X, Qi WX, Wang L, Zhang Z. Correlation of multiple proteins with clinic-pathological features and its prognostic significance in colorectal cancer with signet-ring cell component. Eur Rev Med Pharmacol Sci. 2016;20(16):3358–67.
Yan X, Liu L, Li H, Qin H, Sun Z. Clinical significance of Fusobacterium nucleatum, epithelial-mesenchymal transition, and cancer stem cell markers in stage III/IV colorectal cancer patients. Onco Targets Ther. 2017;10:5031–46.
Sun W, Dou J, Zhang L, Qiao L, Shen N, Gao W. Expression of CD133, E-cadherin and WWOX in colorectal cancer and related analysis. Pak J Med Sci. 2017;33(2):425–9.
Palaghia M, Mihai C, Lozneanu L, Ciobanu D, Trofin AM, Rotariu A, et al. E-cadherin expression in primary colorectal cancer and metastatic lymph nodes. Rom J Morphol Embryol. 2016;57(1):205–9.
Chung YC, Wei WC, Hung CN, Kuo JF, Hsu CP, Chang KJ, et al. Rab11 collaborates E-cadherin to promote collective cell migration and indicates a poor prognosis in colorectal carcinoma. Eur J Clin Invest. 2016;46(12):1002–11.
Sugiyama M, Oki E, Nakaji Y, Tsutsumi S, Ono N, Nakanishi R, Sugiyama M, et al. High expression of the Notch ligand Jagged-1 is associated with poor prognosis after surgery for colorectal cancer. Cancer Sci. 2016;107(11):1705–16.
Kim SA, Inamura K, Yamauchi M, Nishihara R, Mima K, Sukawa Y, et al. Loss of CDH1 (E-cadherin) expression is associated with infiltrative tumour growth and lymph node metastasis. Br J Cancer. 2016;114(2):199–206.
Xiao S, Liu L, Lu X, Long J, Zhou X, Fang M. The prognostic significance of bromodomain PHD-finger transcription factor in colorectal carcinoma and association with vimentin and E-cadherin. J Cancer Res Clin Oncol. 2015;141(8):1465–74.
Yan X, Yan L, Liu S, Shan Z, Tian Y, Jin Z. N-cadherin, a novel prognostic biomarker, drives malignant progression of colorectal cancer. Mol Med Rep. 2015;12(2):2999–3006.
Seo KJ, Kim M, Kim J. Prognostic implications of adhesion molecule expression in colorectal cancer. Int J Clin Exp Pathol. 2015;8(4):4148–57.
Yun JA, Kim SH, Hong HK, Yun SH, Kim HC, Chun HK, et al. Loss of E-Cadherin expression is associated with a poor prognosis in stage III colorectal cancer. Oncology. 2014;86(5–6):318–28.
Bruun J, Kolberg M, Nesland JM, Svindland A, Nesbakken A, Lothe RA. Prognostic significance of β-catenin, E-cadherin, and SOX9 in colorectal cancer: results from a large population-representative series. Front Oncol. 2014;4:118.
Ionescu C, Braicu C, Chiorean R, Cojocneanu Petric R, Neagoe E, Pop L, et al. TIMP-1 expression in human colorectal cancer is associated with SMAD3 gene expression levels: a pilot study. J Gastrointestin Liver Dis. 2014;23(4):413–8.
Kim YH, Kim G, Kwon CI, Kim JW, Park PW, Hahm KB. TWIST1 and SNAI1 as markers of poor prognosis in human colorectal cancer are associated with the expression of ALDH1 and TGF-β1. Oncol Rep. 2014;31(3):1380–8.
Lee SJ, Choi SY, Kim WJ, Ji M, Lee TG, Son BR, et al. Combined aberrant expression of E-cadherin and S100A4, but not β-catenin is associated with disease-free survival and overall survival in colorectal cancer patients. Diagn Pathol. 2013;8:99.
Elzagheid A, Buhmeida A, Laato M, El-Faitori O, Syrjänen K, Collan Y, et al. Loss of E-cadherin expression predicts disease recurrence and shorter survival in colorectal carcinoma. APMIS. 2012;120(7):539–48.
Lampropoulos P, Zizi-Sermpetzoglou A, Rizos S, Kostakis A, Nikiteas N, Papavassiliou AG. Prognostic significance of transforming growth factor beta (TGF-β) signaling axis molecules and E-cadherin in colorectal cancer. Tumour Biol. 2012;33(4):1005–14.
Chen X, Wang Y, Xia H, Wang Q, Jiang X, Lin Z, et al. Loss of E-cadherin promotes the growth, invasion and drug resistance of colorectal cancer cells and is associated with liver metastasis. Mol Biol Rep. 2012;39(6):6707–14.
Lu MH, Huang CC, Pan MR, Chen HH, Hung WC. Prospero homeobox 1 promotes epithelial-mesenchymal transition in colon cancer cells by inhibiting E-cadherin via miR-9. Clin Cancer Res. 2012;18(23):6416–25.
Ozgüven BY, Karaçetin D, Kabukçuoğlu F, Taşkin T, Yener Ş. Immunohistochemical study of E-cadherin and β-catenin expression in colorectal carcinomas. Pol J Pathol. 2011;62(1):19–24.
Matsuoka T, Mitomi H, Fukui N, Kanazawa H, Saito T, Hayashi T, et al. Cluster analysis of claudin-1 and -4, E-cadherin, and β-catenin expression in colorectal cancers. J Surg Oncol. 2011;103(7):674–86.
Tóth L, András C, Molnár C, Tanyi M, Csiki Z, Molnár P, et al. Investigation of β-catenin and E-cadherin expression in Dukes B2 stage colorectal cancer with tissue microarray method. Is it a marker of metastatic potential in rectal cancer? Pathol Oncol Res. 2012;18(2):429–37.
Kang H, Min BS, Lee KY, Kim NK, Kim SN, Choi J, et al. Loss of E-cadherin and MUC2 expressions correlated with poor survival in patients with stages II and III colorectal carcinoma. Ann Surg Oncol. 2011;18(3):711–9.
Karamitopoulou E, Zlobec I, Koumarianou A, Patsouris ES, Peros G, Lugli A. Expression of p16 in lymph node metastases of adjuvantly treated stage III colorectal cancer patients identifies poor prognostic subgroups: a retrospective analysis of biomarkers in matched primary tumor and lymph node metastases. Cancer. 2010;116(19):4474–86.
Fang QX, Lü LZ, Yang B, Zhao ZS, Wu Y, Zheng XC. L1, β-catenin, and E-cadherin expression in patients with colorectal cancer: correlation with clinicopathologic features and its prognostic significance. J Surg Oncol. 2010;102(5):433–42.
Pap Z, Pávai Z, Dénes L, Kovalszky I, Jung J. An immunohistochemical study of colon adenomas and carcinomas: E-cadherin, Syndecan-1, Ets-1. Pathol Oncol Res. 2009;15(4):579–87.
Filiz AI, Senol Z, Sucullu I, Kurt Y, Demirbas S, Akin ML. The survival effect of E-cadherin and catenins in colorectal carcinomas. Colorectal Dis. 2010;12(12):1223–30.
Chen S, Liu J, Li G, Mo F, Xu X, Zhang T, et al. Altered distribution of beta-catenin and prognostic roles in colorectal carcinogenesis. Scand J Gastroenterol. 2008;43(4):456–64.
Ngan CY, Yamamoto H, Seshimo I, Ezumi K, Terayama M, Hemmi H, et al. A multivariate analysis of adhesion molecules expression in assessment of colorectal cancer. J Surg Oncol. 2007;95(8):652–62.
Zlobec I, Lugli A, Baker K, Roth S, Minoo P, Hayashi S, et al. Role of APAF-1, E-cadherin and peritumoral lymphocytic infiltration in tumour budding in colorectal cancer. J Pathol. 2007;212(3):260–8.
Kwak JM, Min BW, Lee JH, Choi JS, Lee SI, Park SS, et al. The prognostic significance of E-cadherin and liver intestine-cadherin expression in colorectal cancer. Dis Colon Rectum. 2007;50(11):1873–80.
Roca F, Mauro LV, Morandi A, Bonadeo F, Vaccaro C, Quintana GO, et al. Prognostic value of E-cadherin, beta-catenin, MMPs (7 and 9), and TIMPs (1 and 2) in patients with colorectal carcinoma. J Surg Oncol. 2006;93(2):151–60.
Shiono S, Ishii G, Nagai K, Murata Y, Tsuta K, Nitadori J, et al. Immunohistochemical prognostic factors in resected colorectal lung metastases using tissue microarray analysis. Eur J Surg Oncol. 2006;32(3):308–9.
Shioiri M, Shida T, Koda K, Oda K, Seike K, Nishimura M, et al. Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients. Br J Cancer. 2006;94(12):1816–22.
Elzagheid A, Algars A, Bendardaf R, Lamlum H, Ristamaki R, Collan Y, et al. E-cadherin expression pattern in primary colorectal carcinomas and their metastases reflects disease outcome. World J Gastroenterol. 2006;12(27):4304–9.
Delektorskaya VV, Perevoshchikov AG, Golovkov DA, Kushlinskii NE. Expression of E-cadherin, beta-catenin, and CD-44v6 cell adhesion molecules in primary tumors and metastases of colorectal adenocarcinoma. Bull Exp Biol Med. 2005;139(6):706–10.
Bravou V, Klironomos G, Papadaki E, Taraviras S, Varakis J. ILK over-expression in human colon cancer progression correlates with activation of beta-catenin, down-regulation of E-cadherin and activation of the Akt-FKHR pathway. J Pathol. 2006;208(1):91–9.
Fernebro E, Bendahl PO, Dictor M, Persson A, Fernö M, Nilbert M. Immunohistochemical patterns in rectal cancer: application of tissue microarray with prognostic correlations. Int J Cancer. 2004;111(6):921–8.
Aoki S, Shimamura T, Shibata T, Nakanishi Y, Moriya Y, Sato Y, et al. Prognostic significance of dysadherin expression in advanced colorectal carcinoma. Br J Cancer. 2003;88(5):726–32.
Garinis GA, Spanakis NE, Menounos PG, Manolis EN, Peros G. Transcriptional impairment of beta-catenin/E-cadherin complex is not associated with beta-catenin mutations in colorectal carcinomas. Br J Cancer. 2003;88(2):206–9.
Ikeguchi M, Taniguchi T, Makino M, Kaibara N. Reduced E-cadherin expression and enlargement of cancer nuclei strongly correlate with hematogenic metastasis in colorectal adenocarcinoma. Scand J Gastroenterol. 2000;35(8):839–46.
Nanashima A, Yamaguchi H, Sawai T, Yasutake T, Tsuji T, Jibiki M, et al. Expression of adhesion molecules in hepatic metastases of colorectal carcinoma: relationship to primary tumours and prognosis after hepatic resection. J Gastroenterol Hepatol. 1999;14(10):1004–9.
Ghadimi BM, Behrens J, Hoffmann I, Haensch W, Birchmeier W, Schlag PM. Immunohistological analysis of E-cadherin, alpha-, beta- and gamma-catenin expression in colorectal cancer: implications for cell adhesion and signaling. Eur J Cancer. 1999;35(1):60–5.
Ilyas M, Tomlinson IP, Hanby A, Talbot IC, Bodmer WF. Allele loss, replication errors and loss of expression of E-cadherin in colorectal cancers. Gut. 1997;40(5):654–9.
Mohri Y. Prognostic significance of E-cadherin expression in human colorectal cancer tissue. Surg Today. 1997;27(7):606–12.
Gagliardi G, Kandemir O, Liu D, Guida M, Benvestito S, Ruers TG, et al. Changes in E-cadherin immunoreactivity in the adenoma-carcinoma sequence of the large bowel. Virchows Arch. 1995;426(2):149–54.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.
Hammond WA, Swaika A, Mody K. Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol. 2016;8(1):57–84.
Guarino M, Rubino B, Ballabio G. The role of epithelial-mesenchymal transition in cancer pathology. Pathology. 2007;39(3):305–18.
Bates RC, Pursell BM, Mercurio AM. Epithelial-mesenchymal transition and colorectal cancer: gaining insights into tumor progression using LIM 1863 cells. Cells Tissues Organs. 2007;185(1–3):29–39.
Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008;68(10):3645–54.
He X, Chen Z, Jia M, Zhao X. Downregulated E-cadherin expression indicates worse prognosis in Asian patients with colorectal cancer: evidence from meta-analysis. PLoS ONE. 2013;8(7): e70858.
Xing X, Tang YB, Yuan G, Wang Y, Wang J, Yang Y, et al. The prognostic value of E-cadherin in gastric cancer: a meta-analysis. Int J Cancer. 2013;132(11):2589–96.
Vogel C, Marcotte EM. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet. 2012;13(4):227–32.
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Kaibin Chang: Conceived and designed the study, methodology, literature search, data curation, writing original draft. Lei Jiang: Literature search, data curation, statistical analysis. Yifeng Sun: Statistical analysis, software. He Li: Expert opinion, manuscript editing and review. All authors have read and approved the final manuscript.
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Chang, K., Jiang, L., Sun, Y. et al. Effect of E-cadherin on Prognosis of Colorectal Cancer: A Meta-Analysis Update. Mol Diagn Ther 26, 397–409 (2022). https://doi.org/10.1007/s40291-022-00593-3
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DOI: https://doi.org/10.1007/s40291-022-00593-3