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, 謝珉寧, 陳興華, 等. 上海金山區痔病發作的流行病學特點研究. 湖南中醫雜志, 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.	張翔, 白景舒. 痔發病機制診斷和治療概述. 中國肛腸病雜志, 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因子在內痔患者組織中的表達及意義. 中國細胞生物學學報, 2020, 42(10): 1800-1805.
9.	戴浩. 十全育真湯加減對脫垂性內痔組織中MMP-7、MMP-9的影響. 呼和浩特: 內蒙古醫科大學, 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.	馮大勇, 王春暉, 馮月寧, 等. 從細胞因子生物學角度探討痔的發病機制. 中國醫刊, 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.	韓煒, 王振軍, 趙博, 等. 痔組織彈性纖維退變和血管生成的機制及其意義. 中華胃腸外科雜志, 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, K?ninger 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, Lepp?nen 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.	朱華鋒, 汪春蘭, 趙宇. VEGF和FGF-2在血管生成中的協同作用研究進展. 中華整形外科雜志, 2006, 22(1): 72-75.
30.	梁文龍, 曹杰, 楊平, 等. 血管內皮生長因子受體2在痔黏膜中的分布特征及臨床意義. 實用醫學雜志, 2015, 31(17): 2830-2832.
31.	王琪, 經芳艷, 鄧永鍵. 內痔粘膜及血管上皮細胞VEGF/FGF2的表達與內痔分期的相關性分析. 中國臨床解剖學雜志, 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.	劉史佳, 申龍樹, 戴國梁, 等. IL-17、IL-6、TNF-α細胞因子在痔瘡患者中的表達. 藥學與臨床研究, 2016, 24(3): 201-204.
34.	朱志紅, 曹莫寒, 王志民, 等. 痔脫垂組織中TNF-α、IL-1β、IFN-γ表達和Treitz肌形態及密度變化的研究. 中國現代普通外科進展, 2021, 24(10): 791-795.
35.	孫松朋, 龍俊紅, 張書信. 痔病患者顯微鏡下痔組織出血情況及其影響因素研究. 中國全科醫學, 2020, 23(33): 4190-4195.
36.	石健宇, 王相龍. 內痔患者血凝情況改變的相關性研究. 中國肛腸病雜志, 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, 謝珉寧, 陳興華, 等. 上海金山區痔病發作的流行病學特點研究. 湖南中醫雜志, 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. 張翔, 白景舒. 痔發病機制診斷和治療概述. 中國肛腸病雜志, 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因子在內痔患者組織中的表達及意義. 中國細胞生物學學報, 2020, 42(10): 1800-1805.
9. 戴浩. 十全育真湯加減對脫垂性內痔組織中MMP-7、MMP-9的影響. 呼和浩特: 內蒙古醫科大學, 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. 馮大勇, 王春暉, 馮月寧, 等. 從細胞因子生物學角度探討痔的發病機制. 中國醫刊, 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. 韓煒, 王振軍, 趙博, 等. 痔組織彈性纖維退變和血管生成的機制及其意義. 中華胃腸外科雜志, 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, K?ninger 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, Lepp?nen 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. 朱華鋒, 汪春蘭, 趙宇. VEGF和FGF-2在血管生成中的協同作用研究進展. 中華整形外科雜志, 2006, 22(1): 72-75.
30. 梁文龍, 曹杰, 楊平, 等. 血管內皮生長因子受體2在痔黏膜中的分布特征及臨床意義. 實用醫學雜志, 2015, 31(17): 2830-2832.
31. 王琪, 經芳艷, 鄧永鍵. 內痔粘膜及血管上皮細胞VEGF/FGF2的表達與內痔分期的相關性分析. 中國臨床解剖學雜志, 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. 劉史佳, 申龍樹, 戴國梁, 等. IL-17、IL-6、TNF-α細胞因子在痔瘡患者中的表達. 藥學與臨床研究, 2016, 24(3): 201-204.
34. 朱志紅, 曹莫寒, 王志民, 等. 痔脫垂組織中TNF-α、IL-1β、IFN-γ表達和Treitz肌形態及密度變化的研究. 中國現代普通外科進展, 2021, 24(10): 791-795.
35. 孫松朋, 龍俊紅, 張書信. 痔病患者顯微鏡下痔組織出血情況及其影響因素研究. 中國全科醫學, 2020, 23(33): 4190-4195.
36. 石健宇, 王相龍. 內痔患者血凝情況改變的相關性研究. 中國肛腸病雜志, 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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