Dhouha BACHA, Donia OUNISSI, Marwa WESLATI, Rahma BOUGHRIBA, Meriam HAZGUI, Saadia BOURAOUI

MUC1 and MUC5AC implication in Tunisian colorectal cancer patients

Background/aim: Mucins, such as MUC1 and MUC5AC, are known for their protective and moisturizing role in intestinal epithelium. Their expression is tightly controlled given their essential role in normal tissue homeostasis, whereas their deregulation leads to chronic inflammation, and even cancer. This study aimed to assess the expression profiles of MUC1 and MUC5AC and their implications in colorectal carcinogenesis. Materials and methods: A retrospective study of 202 patients who underwent colorectal cancer (CRC) surgery was conducted. The expression of MUC1 and MUC5AC was investigated by immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR). Statistical analysis of mucin expression pattern, as well as the clinicopathological criteria of the patients, was performed using the chi-square test, survival curves were plotted using the Kaplan—Meier product-limit method, and differences between the survival curves were tested using the log-rank test. Results: The expression of both mucins was abnormally high in the tumor tissues for both mRNA and protein. MUC1 expression was correlated with advanced cancer stages and lymph node metastases for both the mRNA (P < 0.016 and P < 0.002, respectively) and protein level (P < 0.006 and P < 0.001, respectively). However, MUC5AC expression did not pinpoint any significant association between the clinicopathological criteria, but patients who expressed MUC5AC showed an increase in overall survival (P < 0.009). Conclusion: The expression of MUC1 might be a poor prognostic biomarker in CRC and could play a role in tumor transformation and metastasis. However, MUC5AC expression might be a good prognostic in the Tunisian cohort.Keywords: Colorectal cancer, MUC1, MUC5AC, immunohistochemistry, RT-PCR

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1. Bu X-D, Li N, Tian X-Q, Li L, Wang J-S et al. Altered expression of MUC2 and MUC5AC in progression of colorectal carcinoma. World Journal of Gastroenterology 2010; 16 (32): 4089-4094. doi: 10.3748/wjg.v16.i32.4089
2. Çelik SK, Erdem B, Sağlar E, Polat Z, Mergen H. Evaluation of MUC1, CK20, and hTERT expression in peripheral blood of gastrointestinal cancer patients in search of diagnostic criteria. Turkish Journal of Biology 2014; 38 (6): 848-857. doi: 10.3906/ biy-1403-73
3. Patel DS, Khandeparkar SGS, Joshi AR, Kulkarni MM, Dhande B et al. Immunohistochemical study of MUC1, MUC2 and MUC5AC expression in primary breast carcinoma. Journal of Clinical and Diagnostic Research 2017; 11 (4): EC30-EC34. doi: 10.7860/JCDR/2017/26533.9707
4. Javanbakht M, Akhavanmoghadam J, Talaei AJ, Aghyani M, Mozafari M et al. Differential expression of two genes Oct-4 and MUC5AC associates with poor outcome in patients with gastric cancer. Clinical and Experimental Pharmacology & Physiology 2017; 44 (11): 1099-1105. doi: 10.1111/1440- 1681.12840
5. Dotan E, Alpaugh RK, Ruth K, Negin BP, Denlinger CS et al. Prognostic significance of MUC-1 in circulating tumor cells in patients with etastatic pancreatic adenocarcinoma. Pancreas 2016; 45 (8): 1131-1135. doi: 10.1097/MPA.0000000000000619
6. Díaz Del Arco C, Garré P, Molina Roldán E, Lorca V, Cerón Nieto MÁ et al. MUC1 expression in colorectal carcinoma: clinicopathological correlation and prognostic significance. Revista Española de Patología 2018; 51 (4): 204-209 (in Spanish). doi: 10.1016/j.patol.2018.03.002
7. Wang H, Jin S, Lu H, Mi S, Shao W et al. Expression of survivin, MUC2 and MUC5 in colorectal cancer and their association with clinicopathological characteristics. Oncology Letters 2017; 14 (1): 1011-1016. doi: 10.3892/ol.2017.6218
8. Khanh DT, Mekata E, Mukaisho K, Sugihara H, Shimizu T et al. Transmembrane mucin MUC1 overexpression and its association with CD10+ myeloid cells, transforming growth factor-β1 expression, and tumor budding grade in colorectal cancer. Cancer Science 2013; 104 (7): 958-964. doi: 10.1111/ cas.12170
9. Jia Y, Persson C, Hou L, Zheng Z, Yeager M et al. A comprehensive analysis of common genetic variation in MUC1, MUC5AC, MUC6 genes and risk of stomach cancer. Cancer Causes & Control 2010; 21 (2): 313-321. doi: 10.1007/ s10552-009-9463-3
10. Kesari MV, Gaopande VL, Joshi AR, Babanagare SV, Gogate BP et al. Immunohistochemical study of MUC1, MUC2 and MUC5AC in colorectal carcinoma and review of literature. Indian Journal of Gastroenterololy 2015; 34 (1): 63-67. doi: 10.1007/s12664-015-0534-y
11. Betge J, Schneider NI, Harbaum L, Pollheimer MJ, Lindtner RA et al. MUC1, MUC2, MUC5AC, and MUC6 in colorectal cancer: expression profiles and clinical significance. Virchows Archiv 2016; 469 (3): 255-265. doi: 10.1007/s00428-016-1970-5
12. Terada T. An immunohistochemical study of primary signetring cell carcinoma of the stomach and colorectum: II. expression of MUC1, MUC2, MUC5AC, and MUC6 in normal mucosa and in 42 cases. International Journal of Clinical and Experimental Pathology 2013; 6 (4): 613-621.
13. Walsh MD, Clendenning M, Williamson E, Pearson S-A, Walters RJ et al. Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype. Modern Pathology 2013; 26 (12): 1642-1656. doi: 10.1038/modpathol.2013.101
14. Raghoebir L, Biermann K, Kempen MB, Dubbink HJ, Dinjens WNM et al. Aberrant SOX2 expression in colorectal cancers does not correlate with mucinous differentiation and gastric mucin MUC5AC expression. Virchows Archiv 2014; 465 (4): 395-400. doi: 10.1007/s00428-014-1638-y
15. Krishn SR, Kaur S, Smith LM, Johansson SL, Jain M et al. Mucins and associated glycan signatures in colon adenomacarcinoma sequence: prospective pathological implication(s) for early diagnosis of colon cancer. Cancer Letters 2016; 374 (2): 304-314. doi: 10.1016/j.canlet.2016.02.016
16. Briggs CD, Neal CP, Mann CD, Steward WP, Manson MM et al. Prognostic molecular markers in cholangiocarcinoma: a systematic review. European Journal of Cancer 2009; 45 (1): 33-47. doi: 10.1016/j.ejca.2008.08.024
17. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK et al. (editors). AJCC Cancer Staging Manual (American Joint Committee on Cancer). 8th ed. Berlin, Germany: Springer International Publishing; 2017. doi: 10.1007/978-3-319- 40618-3
18. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2018; 68 (6): 394-424. doi: 10.3322/caac.21492
19. Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS et al. Colorectal cancer statistics, 2017. CA: A Cancer Journal for Clinicians 2017; 67 (3): 177-193. doi: 10.3322/caac.21395
20. Val-Bernal JF, Salcedo W, Val D, Parra A, Garijo MF. Mucin-secreting clear cell renal cell carcinoma. A rare variant of conventional renal cell carcinoma. Annals of Diagnostic Pathology 2013; 17 (2): 226-229. doi: 10.1016/j. anndiagpath.2011.11.001
21. Niv Y, Rokkas T. Mucin expression in colorectal cancer (CRC): systematic review and meta-analysis. Journal of Clinical Gastroenterology 2019; 53 (6): 434-440. doi: 10.1097/ MCG.0000000000001050
22. Reynolds IS, Fichtner M, McNamara DA, Kay EW, Prehn JHM et al. Mucin glycoproteins block apoptosis; promote invasion, proliferation, and migration; and cause chemoresistance through diverse pathways in epithelial cancers. Cancer Metastasis Reviews 2019; 38 (1-2): 237-257. doi: 10.1007/ s10555-019-09781-w
23. Zhu X, Long X, Luo X, Song Z, Li S et al. Abrogation of MUC5AC expression aontributes to the apoptosis and cell cycle arrest of colon cancer cells. Cancer Biotherapy & Radiopharmaceuticals 2016; 31 (7): 261-267. doi: 10.1089/cbr.2016.2054
24. Furr AE, Ranganathan S, Finn OJ. Aberrant expression of MUC1 mucin in pediatric inflammatory bowel disease. Pediatric and Developmental Pathology 2010; 13 (1): 24-31. doi: 10.2350/08-06-0479.1
25. Khemiri M, Doghri R, Mrad K, Friedrich K, Oueslati R. Mucin-1 expression and localization in epithelial cells shows characteristic and distinct patterns in inflammatory bowel diseases and colorectal cancer. International Journal of Clinical & Experimental Pathology 2019; 12 (5): 1731-1737.
26. Xu F, Liu F, Zhao H, An G, Feng G. Prognostic significance of mucin antigen MUC1 in various human apithelial cancers: a meta-analysis. Medicine (Baltimore) 2015; 94 (50): e2286. doi: 10.1097/MD.0000000000002286
27. Zeng Y, Zhang Q, Zhang Y, Lu M, Liu Y et al. MUC1 Predicts colorectal cancer metastasis: a systematic review and metaanalysis of case controlled studies. PLOS ONE 2015; 10 (9): e0138049. doi: 10.1371/journal.pone.0138049
28. Cascio S, Finn OJ. Complex of MUC1, CIN85 and Cbl in colon cancer progression and metastasis. Cancers 2015; 7 (1): 342- 352. doi: 10.3390/cancers7010342
29. Li C, Zuo D, Liu T, Yin L, Li C et al. Prognostic and clinicopathological cignificance of MUC family members in colorectal cancer: a systematic review and meta-analysis. Gastroenterology Research and Practice 2019; 2019 (4): 1-16. doi: 10.1155/2019/2391670
30. Pothuraju R, Rachagani S, Krishn SR, Chaudhary S, Nimmakayala RK et al. Molecular implications of MUC5AC-CD44 axis in colorectal cancer progression and chemoresistance. Molecular Cancer 2020; 19 (37). doi: 10.1186/s12943-020-01156-y
31. Krishn SR, Ganguly K, Kaur S, Batra SK. Ramifications of secreted mucin MUC5AC in malignant journey: a holistic view. Carcinogenesis 2018; 39 (5): 633-651. doi: 10.1093/ carcin/bgy019
32. Kaur S, Smith LM, Patel A, Menning M, Watley DC et al. A combination of MUC5AC and CA19-9 improves the diagnosis of pancreatic cancer: a multicenter study. The American Journal of Gastroenterology 2017; 112 (1): 172-183. doi: 10.1038/ajg.2016.482
33. Lakshmanan I, Rachagani S, Hauke R, Krishn SR, Paknikar S et al. MUC5AC interactions with integrin β4 enhances the migration of lung cancer cells through FAK signaling. Oncogene 2016; 35 (31): 4112-4121. doi: 10.1038/onc.2015.478
34. Bauernfeind AL, Babbitt CC. The predictive nature of transcript expression levels on protein expression in adult human brain. BMC Genomics 2017; 18 (1): 322. doi: 10.1186/s12864-017- 3674-x
35. Kasprzak A, Siodła E, Andrzejewska M, Szmeja J, SeraszekJaros A et al. Differential expression of mucin 1 and mucin 2 in colorectal cancer. World Journal of Gastroenterology 2018; 24 (36): 4164-4177. doi: 10.3748/wjg.v24.i36.4164