Progress in pathogenesis of hemorrhoids: research of molecular biology_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YANG Yiting ¹ , LU Bingnan ¹ , LIU Sailiang ² , GAO Wei ³ ,  YU Minhao ⁴

1. Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P. R. China;
2. Department of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, P. R. China;
3. Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P. R. China;
4. Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, P. R. China;

Corresponding author：

YU Minhao, Email: fishmeangood@163.com

Keywords：

hemorrhoids; pathogenesis; molecular biology

DOI：

10.7507/1007-9424.202204063

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To understand the progress of molecular biology research on the pathogenesis of hemorrhoids. Method The literatures relevant to reseaches on the molecular biology of hemorrhoid pathogenesis in recent years had been reviewed. Results The generally accepted theories of hemorrhoids included anal cushion downward movement theory, varicose vein theory, and vascular proliferation theory. The molecular biological studies related to the theory of anal cushion downward movement found that the increased expression of matrix metalloproteinase-9 and the abnormal expression of smooth muscle actin could damage the supporting tissue of anal cushion, causing the downward movement and prolapse of anal cushion, and then formed hemorrhoids; The molecular biology researches related to varicose vein theory found that the increase of nitric oxide synthase and transient receptor potential vanilloid 1 could promote the production of nitric oxide, causing varicose veins, and then leaded to the pathogenesis of hemorrhoids; The molecular biology researches related to vascular proliferation theory found that the low expressions of miR-412-5p and miR-4729, and the overexpressions of vascular endothelial growth factor and fibroblast growth factor were related to the vascular proliferation of hemorrhoids. In addition, the secondary inflammatory reaction after the onset of hemorrhoids also played an important role in the occurrence and development of hemorrhoids. Conclusions The occurrence and development of hemorrhoids is the result of the intersection and interaction of various mechanisms such as anal cushion downward movement, varicose veins, vascular proliferation, and secondary inflammatory reaction. The molecular biology research on the pathogenesis of hemorrhoids is helpful to better explain the occurrence of hemorrhoids from a microcosmic perspective, and lay a foundation for further exploring the etiology of hemorrhoids.

Citation： YANG Yiting, LU Bingnan, LIU Sailiang, GAO Wei, YU Minhao. Progress in pathogenesis of hemorrhoids: research of molecular biology. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(10): 1390-1394. doi: 10.7507/1007-9424.202204063 Copy

1.	俞婷, 谢珉宁, 陈兴华, 等. 上海金山区痔病发作的流行病学特点研究. 湖南中医杂志, 2021, 37(4): 123-126.
2.	Ng KS, Holzgang M, Young C. Still a case of “No Pain, No Gain”? An updated and critical review of the pathogenesis, diagnosis, and management options for hemorrhoids in 2020. Ann Coloproctol, 2020, 36(3): 133-147.
3.	Rubbini M, Ascanelli S. Classification and guidelines of hemorrhoidal disease: present and future. World J Gastrointest Surg, 2019, 11(3): 117-121.
4.	Thomson WH. The nature of haemorrhoids. Br J Surg, 1975, 62(7): 542-552.
5.	Gass OC, Adams J. Hemorrhoids: etiology and pathology. Am J Surg, 1950, 79(1): 40-43.
6.	张翔, 白景舒. 痔发病机制诊断和治疗概述. 中国肛肠病杂志, 2019, 39(9): 72-74.
7.	Mondal S, Adhikari N, Banerjee S, et al. Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: a minireview. Eur J Med Chem, 2020, 194: 112260. doi: 10.1016/j.ejmech.2020.112260.
8.	秦蕾, 秦鑫. MMP-9、VEGFR2因子在内痔患者组织中的表达及意义. 中国细胞生物学学报, 2020, 42(10): 1800-1805.
9.	戴浩. 十全育真汤加减对脱垂性内痔组织中MMP-7、MMP-9的影响. 呼和浩特: 内蒙古医科大学, 2020.
10.	Serra R, Gallelli L, Grande R, et al. Hemorrhoids and matrix metalloproteinases: a multicenter study on the predictive role of biomarkers. Surgery, 2016, 159(2): 487-494.
11.	Yang H, Chen H, Liu F, et al. Up-regulation of matrix metalloproteinases-9 in the kidneys of diabetic rats and the association with neutrophil gelatinase-associated lipocalin. BMC Nephrol, 2021, 22(1): 211. doi: 10.1186/s12882-021-02396-w.
12.	Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res, 2006, 69(3): 562-573.
13.	Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci, 2020, 21(24): 9739. doi: 10.3390/ijms21249739.
14.	Li SL, Jing FY, Ma LL, et al. Myofibrotic malformation vessels: unique angiodysplasia toward the progression of hemorrhoidal disease. Drug Des Devel Ther, 2015, 9: 4649-4656.
15.	冯大勇, 王春晖, 冯月宁, 等. 从细胞因子生物学角度探讨痔的发病机制. 中国医刊, 2016, 51(3): 28-30.
16.	Wang H, Wang L, Xie Z, et al. Nitric oxide (NO) and NO synthases (NOS)-based targeted therapy for colon cancer. Cancers (Basel), 2020, 12(7): 1881. doi: 10.3390/cancers12071881.
17.	Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev, 1991, 43(2): 109-142.
18.	韩炜, 王振军, 赵博, 等. 痔组织弹性纤维退变和血管生成的机制及其意义. 中华胃肠外科杂志, 2005, 8(1): 56-59.
19.	Lohsiriwat V, Wilson VG, Scholefield JH, et al. Regional distribution of nitric oxide synthase in human anorectal tissue: a pilot study on the potential role for nitric oxide in haemorrhoids. Curr Vasc Pharmacol, 2020, 18(1): 43-49.
20.	Gokce AH, Gokce FS, Durmus S, et al. The effect of nitric oxide, endothelial nitric oxide synthetase, and asymmetric dimethylarginine in hemorrhoidal disease. Rev Assoc Med Bras (1992), 2020, 66(8): 1128-1133.
21.	di Mola FF, Friess H, Köninger J, et al. Haemorrhoids and transient receptor potential vanilloid 1. Gut, 2006, 55(11): 1665-1666.
22.	Varela-López E, Del Valle-Mondragón L, Castrejón-Téllez V, et al. Role of the transient receptor potential vanilloid type 1 (TRPV1) in the regulation of nitric oxide release in Wistar rat aorta. Oxid Med Cell Longev, 2021, 2021: 8531975. doi: 10.1155/2021/8531975.
23.	Correia de Sousa M, Gjorgjieva M, Dolicka D, et al. Deciphering miRNAs’ action through miRNA editing. Int J Mol Sci, 2019, 20(24): 6249. doi: 10.3390/ijms20246249.
24.	Song C, Zhou H, Lu H, et al. Aberrant expression for microRNA is potential crucial factors of haemorrhoid. Hereditas, 2020, 157(1): 25. doi: 10.1186/s41065-020-00139-9.
25.	Wang C, Lu H, Luo C, et al. miR-412-5p targets Xpo1 to regulate angiogenesis in hemorrhoid tissue. Gene, 2019, 705: 167-176.
26.	Liu T, Zhou H, Lu H, et al. MiR-4729 regulates TIE1 mRNA m6A modification and angiogenesis in hemorrhoids by targeting METTL14. Ann Transl Med, 2021, 9(3): 232. doi: 10.21037/atm-20-3399.
27.	Karaman S, Leppänen VM, Alitalo K. Vascular endothelial growth factor signaling in development and disease. Development, 2018, 145(14): dev151019. doi: 10.1242/dev.151019.
28.	Okada-Ban M, Thiery JP, Jouanneau J. Fibroblast growth factor-2. Int J Biochem Cell Biol, 2000, 32(3): 263-267.
29.	朱华锋, 汪春兰, 赵宇. VEGF和FGF-2在血管生成中的协同作用研究进展. 中华整形外科杂志, 2006, 22(1): 72-75.
30.	梁文龙, 曹杰, 杨平, 等. 血管内皮生长因子受体2在痔黏膜中的分布特征及临床意义. 实用医学杂志, 2015, 31(17): 2830-2832.
31.	王琪, 经芳艳, 邓永键. 内痔粘膜及血管上皮细胞VEGF/FGF2的表达与内痔分期的相关性分析. 中国临床解剖学杂志, 2019, 37(4): 409-413.
32.	Porwal A, Kundu GC, Bhagwat G, et al. Polyherbal formulation Anoac-H suppresses the expression of RANTES and VEGF for the management of bleeding hemorrhoids and fistula. Mol Med Rep, 2021, 24(4): 736. doi: 10.3892/mmr.2021.12376.
33.	刘史佳, 申龙树, 戴国梁, 等. IL-17、IL-6、TNF-α细胞因子在痔疮患者中的表达. 药学与临床研究, 2016, 24(3): 201-204.
34.	朱志红, 曹莫寒, 王志民, 等. 痔脱垂组织中TNF-α、IL-1β、IFN-γ表达和Treitz肌形态及密度变化的研究. 中国现代普通外科进展, 2021, 24(10): 791-795.
35.	孙松朋, 龙俊红, 张书信. 痔病患者显微镜下痔组织出血情况及其影响因素研究. 中国全科医学, 2020, 23(33): 4190-4195.
36.	石健宇, 王相龙. 内痔患者血凝情况改变的相关性研究. 中国肛肠病杂志, 2020, 40(12): 78.
37.	Hashempur MH, Khademi F, Rahmanifard M, et al. An evidence-based study on medicinal plants for hemorrhoids in medieval Persia. J Evid Based Complementary Altern Med, 2017, 22(4): 969-981.

1. 俞婷, 谢珉宁, 陈兴华, 等. 上海金山区痔病发作的流行病学特点研究. 湖南中医杂志, 2021, 37(4): 123-126.
2. Ng KS, Holzgang M, Young C. Still a case of “No Pain, No Gain”? An updated and critical review of the pathogenesis, diagnosis, and management options for hemorrhoids in 2020. Ann Coloproctol, 2020, 36(3): 133-147.
3. Rubbini M, Ascanelli S. Classification and guidelines of hemorrhoidal disease: present and future. World J Gastrointest Surg, 2019, 11(3): 117-121.
4. Thomson WH. The nature of haemorrhoids. Br J Surg, 1975, 62(7): 542-552.
5. Gass OC, Adams J. Hemorrhoids: etiology and pathology. Am J Surg, 1950, 79(1): 40-43.
6. 张翔, 白景舒. 痔发病机制诊断和治疗概述. 中国肛肠病杂志, 2019, 39(9): 72-74.
7. Mondal S, Adhikari N, Banerjee S, et al. Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: a minireview. Eur J Med Chem, 2020, 194: 112260. doi: 10.1016/j.ejmech.2020.112260.
8. 秦蕾, 秦鑫. MMP-9、VEGFR2因子在内痔患者组织中的表达及意义. 中国细胞生物学学报, 2020, 42(10): 1800-1805.
9. 戴浩. 十全育真汤加减对脱垂性内痔组织中MMP-7、MMP-9的影响. 呼和浩特: 内蒙古医科大学, 2020.
10. Serra R, Gallelli L, Grande R, et al. Hemorrhoids and matrix metalloproteinases: a multicenter study on the predictive role of biomarkers. Surgery, 2016, 159(2): 487-494.
11. Yang H, Chen H, Liu F, et al. Up-regulation of matrix metalloproteinases-9 in the kidneys of diabetic rats and the association with neutrophil gelatinase-associated lipocalin. BMC Nephrol, 2021, 22(1): 211. doi: 10.1186/s12882-021-02396-w.
12. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res, 2006, 69(3): 562-573.
13. Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci, 2020, 21(24): 9739. doi: 10.3390/ijms21249739.
14. Li SL, Jing FY, Ma LL, et al. Myofibrotic malformation vessels: unique angiodysplasia toward the progression of hemorrhoidal disease. Drug Des Devel Ther, 2015, 9: 4649-4656.
15. 冯大勇, 王春晖, 冯月宁, 等. 从细胞因子生物学角度探讨痔的发病机制. 中国医刊, 2016, 51(3): 28-30.
16. Wang H, Wang L, Xie Z, et al. Nitric oxide (NO) and NO synthases (NOS)-based targeted therapy for colon cancer. Cancers (Basel), 2020, 12(7): 1881. doi: 10.3390/cancers12071881.
17. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev, 1991, 43(2): 109-142.
18. 韩炜, 王振军, 赵博, 等. 痔组织弹性纤维退变和血管生成的机制及其意义. 中华胃肠外科杂志, 2005, 8(1): 56-59.
19. Lohsiriwat V, Wilson VG, Scholefield JH, et al. Regional distribution of nitric oxide synthase in human anorectal tissue: a pilot study on the potential role for nitric oxide in haemorrhoids. Curr Vasc Pharmacol, 2020, 18(1): 43-49.
20. Gokce AH, Gokce FS, Durmus S, et al. The effect of nitric oxide, endothelial nitric oxide synthetase, and asymmetric dimethylarginine in hemorrhoidal disease. Rev Assoc Med Bras (1992), 2020, 66(8): 1128-1133.
21. di Mola FF, Friess H, Köninger J, et al. Haemorrhoids and transient receptor potential vanilloid 1. Gut, 2006, 55(11): 1665-1666.
22. Varela-López E, Del Valle-Mondragón L, Castrejón-Téllez V, et al. Role of the transient receptor potential vanilloid type 1 (TRPV1) in the regulation of nitric oxide release in Wistar rat aorta. Oxid Med Cell Longev, 2021, 2021: 8531975. doi: 10.1155/2021/8531975.
23. Correia de Sousa M, Gjorgjieva M, Dolicka D, et al. Deciphering miRNAs’ action through miRNA editing. Int J Mol Sci, 2019, 20(24): 6249. doi: 10.3390/ijms20246249.
24. Song C, Zhou H, Lu H, et al. Aberrant expression for microRNA is potential crucial factors of haemorrhoid. Hereditas, 2020, 157(1): 25. doi: 10.1186/s41065-020-00139-9.
25. Wang C, Lu H, Luo C, et al. miR-412-5p targets Xpo1 to regulate angiogenesis in hemorrhoid tissue. Gene, 2019, 705: 167-176.
26. Liu T, Zhou H, Lu H, et al. MiR-4729 regulates TIE1 mRNA m6A modification and angiogenesis in hemorrhoids by targeting METTL14. Ann Transl Med, 2021, 9(3): 232. doi: 10.21037/atm-20-3399.
27. Karaman S, Leppänen VM, Alitalo K. Vascular endothelial growth factor signaling in development and disease. Development, 2018, 145(14): dev151019. doi: 10.1242/dev.151019.
28. Okada-Ban M, Thiery JP, Jouanneau J. Fibroblast growth factor-2. Int J Biochem Cell Biol, 2000, 32(3): 263-267.
29. 朱华锋, 汪春兰, 赵宇. VEGF和FGF-2在血管生成中的协同作用研究进展. 中华整形外科杂志, 2006, 22(1): 72-75.
30. 梁文龙, 曹杰, 杨平, 等. 血管内皮生长因子受体2在痔黏膜中的分布特征及临床意义. 实用医学杂志, 2015, 31(17): 2830-2832.
31. 王琪, 经芳艳, 邓永键. 内痔粘膜及血管上皮细胞VEGF/FGF2的表达与内痔分期的相关性分析. 中国临床解剖学杂志, 2019, 37(4): 409-413.
32. Porwal A, Kundu GC, Bhagwat G, et al. Polyherbal formulation Anoac-H suppresses the expression of RANTES and VEGF for the management of bleeding hemorrhoids and fistula. Mol Med Rep, 2021, 24(4): 736. doi: 10.3892/mmr.2021.12376.
33. 刘史佳, 申龙树, 戴国梁, 等. IL-17、IL-6、TNF-α细胞因子在痔疮患者中的表达. 药学与临床研究, 2016, 24(3): 201-204.
34. 朱志红, 曹莫寒, 王志民, 等. 痔脱垂组织中TNF-α、IL-1β、IFN-γ表达和Treitz肌形态及密度变化的研究. 中国现代普通外科进展, 2021, 24(10): 791-795.
35. 孙松朋, 龙俊红, 张书信. 痔病患者显微镜下痔组织出血情况及其影响因素研究. 中国全科医学, 2020, 23(33): 4190-4195.
36. 石健宇, 王相龙. 内痔患者血凝情况改变的相关性研究. 中国肛肠病杂志, 2020, 40(12): 78.
37. Hashempur MH, Khademi F, Rahmanifard M, et al. An evidence-based study on medicinal plants for hemorrhoids in medieval Persia. J Evid Based Complementary Altern Med, 2017, 22(4): 969-981.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Progress in pathogenesis of hemorrhoids: research of molecular biology

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