The Molecular Mechanism of miR-205-5p Targeting ERBB3 to Regulate PI3K/AKT/mTOR Pathway and Inhibit Angiogenesis in Hemorrhoids

Zhixiao LI; Xia ZHENG; Chunling LI; Qingsheng LIU; Heng ZHANG

doi:10.12259/j.issn.2095-610X.S20240604

Volume 45 Issue 6

Jul. 2024

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Article Navigation > Journal of Kunming Medical University > 2024 > 45(6): 22-35

Zhixiao LI, Xia ZHENG, Chunling LI, Qingsheng LIU, Heng ZHANG. The Molecular Mechanism of miR-205-5p Targeting ERBB3 to Regulate PI3K/AKT/mTOR Pathway and Inhibit Angiogenesis in Hemorrhoids[J]. Journal of Kunming Medical University, 2024, 45(6): 22-35. doi: 10.12259/j.issn.2095-610X.S20240604

Citation:

Zhixiao LI, Xia ZHENG, Chunling LI, Qingsheng LIU, Heng ZHANG. The Molecular Mechanism of miR-205-5p Targeting ERBB3 to Regulate PI3K/AKT/mTOR Pathway and Inhibit Angiogenesis in Hemorrhoids[J]. Journal of Kunming Medical University, 2024, 45(6): 22-35. doi: 10.12259/j.issn.2095-610X.S20240604

Citation:

Zhixiao LI, Xia ZHENG, Chunling LI, Qingsheng LIU, Heng ZHANG. The Molecular Mechanism of miR-205-5p Targeting ERBB3 to Regulate PI3K/AKT/mTOR Pathway and Inhibit Angiogenesis in Hemorrhoids[J]. Journal of Kunming Medical University, 2024, 45(6): 22-35. doi: 10.12259/j.issn.2095-610X.S20240604

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The Molecular Mechanism of miR-205-5p Targeting ERBB3 to Regulate PI3K/AKT/mTOR Pathway and Inhibit Angiogenesis in Hemorrhoids

doi: 10.12259/j.issn.2095-610X.S20240604

1.
The 3rd Affiliated Hospital of Yunnan University of Traditional Chinese Medicine，Kunming Yunnan 650500
2.
Dept. of Anorectal，Kunming Municipal Hospital of Traditional Chinese Medicine，Kunming Yunnan 650500，China

Received Date: 2024-01-27
Available Online: 2024-05-23
Publish Date: 2024-06-25

Abstract

Abstract

Objective To explore the molecular mechanism of miR-205-5p targeting ERBB3 to regulate PI3K/AKT/mTOR pathway and inhibit angiogenesis in hemorrhoids. Methods The hemorrhoidal nucleus and normal perianal tissues of 12 patients from July 2021 to June 2022 were collected, the expression of miR-205-5p and ERBB3 in the samples was detected by qRT-PCR, and the targeting relationship was verified by dual-luciferase. miR-205-5p mimic, pcDNA-ERBB3, miR-205-5p inhibitor, sh-ERBB3, oe-ERBB3 and negative control plasmids were respectively or co-transfected into hemorrhoidal model rats and HUVEC cells. The pathological changes and apoptosis of perianal tissue in each group were observed by HE and TUNEL staining, and the localization of expression of ERBB3 and VEGFR2 proteins were detected by immunohistochemistry, and the expression levels of ERBB3, VEGFR2, Cyclin D1, cleaved-caspase 3, Bax, Bcl-2 and PI3K/AKT/mTOR pathway related proteins were detected by Western blot. The proliferation, migration, invasion, apoptosis and angiogenesis of HUVEC were detected by MTT, wound healing, transwell, flow cytometry and angiogenesis assay. Results MiR-205-5p was lowly expressed and ERBB3 was highly expressed in clinical samples of hemorrhoids （P < 0.001）, and miR-205-5p targeted the 3'UTR of ERBB3 （WT）（P < 0.001）. The expression of ERBB3 in hemorrhoidal rats and HUVEC cells in miR-205-5p mimic group was significantly decreased （P < 0.01, P < 0.001）, and the levels of VEGFR2 （P < 0.001）, Cyclin D1 （P < 0.01）,Bcl-2 （P < 0.001）, p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR （P < 0.001） were significantly down-regulated, the levels of Cleaved-caspase 3 and Bax were significantly up-regulated （P < 0.01）, the perianal histopathology of rats was improved, the proliferation, migration and invasion activities of HUVEC cells were reduced （P < 0.001）, the apoptosis rate was increased （P < 0.001）, and the number and branches of angiogenesis were reduced （P < 0.001）, and these effects were eventually reversed by pcDNA-ERBB3 （P < 0.001）. Conclusion MiR-205-5p can reduce angiogenesis and relieve hemorrhoids by targeting the inhibition of ERBB3 expression, down-regulating the activity of PI3K/AKT/mTOR pathway, inhibiting cell proliferation, migration and invasion, and promoting apoptosis.
- Hemorrhoids,
- miR-205-5p,
- ERBB3,
- PI3K/AKT/mTOR pathway,
- Angiogenesis

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References(30)

References

[1]	Wang C,Lu H,Luo C,et al. miR-412-5p targets Xpo1 to regulate angiogenesis in hemorrhoid tissue[J]. Gene,2019,705(26):167-176. doi: 10.1016/j.gene.2019.04.058
[2]	Qureshi W A. Office management of hemorrhoids[J]. Am J Gastroenterol,2018,113(6):795-798. doi: 10.1038/s41395-018-0020-0
[3]	Wang K,Zhang Y,Ma X,et al. Identification of the microRNA alterations in extracellular vesicles derived from human haemorrhoids[J]. Exp Physiol,2023,108(5):752-761. doi: 10.1113/EP090549
[4]	Song C,Zhou H,Lu H,et al. Aberrant expression for microRNA is potential crucial factors of haemorrhoid[J]. Hereditas,2020,157(1):25. doi: 10.1186/s41065-020-00139-9
[5]	王辰. miR-412-5p靶向xpo1调控痔核组织血管增生以及痔血宁合剂干预的机制研究 [D]. 上海: 上海中医药大学, 2019.
[6]	Liu T,Zhou H,Lu H,et al. MiR-4729 regulates TIE1 mRNA m6A modification and angiogenesis in hemorrhoids by targeting METTL14[J]. Ann Transl Med,2021,9(3):232. doi: 10.21037/atm-20-3399
[7]	Wang S,Aurora A B,Johnson B A,et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis[J]. Dev Cell,2008,15(2):261-271. doi: 10.1016/j.devcel.2008.07.002
[8]	Fish J E,Santoro M M,Morton S U,et al. miR-126 regulates angiogenic signaling and vascular integrity[J]. Dev Cell,2008,15(2):272-284. doi: 10.1016/j.devcel.2008.07.008
[9]	Huang J,Wang X,Wen G,et al. miRNA-205-5p functions as a tumor suppressor by negatively regulating VEGFA and PI3K/Akt/mTOR signaling in renal carcinoma cells[J]. Oncol Rep,2019,42(5):1677-1688.
[10]	An G,Liang S,Sheng C,et al. Upregulation of microRNA-205 suppresses vascular endothelial growth factor expression-mediated PI3K/Akt signaling transduction in human keloid fibroblasts[J]. Exp Biol Med (Maywood),2017,242(3):275-285. doi: 10.1177/1535370216669839
[11]	Yang X,Chen Y,Li M,et al. ERBB3 methylation and immune infiltration in tumor microenvironment of cervical cancer[J]. Sci Rep,2022,12(1):8112. doi: 10.1038/s41598-022-11415-1
[12]	Duan B,Zhu Z,You B,et al. Overexpression of ERBB3 promotes proliferation,migration,and angiogenesis in nasopharyngeal carcinoma[J]. Int J Clin Exp Pathol,2019,12(8):2931-2940.
[13]	Russell K S,Stern D F,Polverini P J,et al. Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis[J]. Am J Physiol,1999,277(6):H2205-2211.
[14]	Shi J,Lv H,Tang C,et al. Mangiferin inhibits cell migration and angiogenesis via PI3K/AKT/mTOR signaling in high glucose-and hypoxia-induced RRCECs [J]. Mol Med Rep,2021,23(6),473.
[15]	Aigner F, Bodner G, Gruber H, et al. The vascular nature of hemorrhoids[J]. J Gastrointest Surg,2006,10(7):1044-1050.
[16]	谢逸轩,王赛,朱飞鹏,等. 基于中西医临床病症特点的痔疮动物模型分析[J]. 中药新药与临床药理,2022,33(7):939-943.
[17]	Han S,Lin F,Ruan Y,et al. miR-132-3p promotes the cisplatin-induced apoptosis and inflammatory response of renal tubular epithelial cells by targeting SIRT1 via the NF-κB pathway[J]. Int Immunopharmacol,2021,99(10):108022. doi: 10.1016/j.intimp.2021.108022
[18]	Kir D,Schnettler E,Modi S,et al. Regulation of angiogenesis by microRNAs in cardiovascular diseases[J]. Angiogenesis,2018,21(4):699-710. doi: 10.1007/s10456-018-9632-7
[19]	Zhang J,Zhang J,Pang X,et al. MiR-205-5p suppresses angiogenesis in gastric cancer by downregulating the expression of VEGFA and FGF1[J]. Exp Cell Res,2021,404(2):112579. doi: 10.1016/j.yexcr.2021.112579
[20]	Chen S,Wang Y,Su Y,et al. miR-205-5p/PTK7 axis is involved in the proliferation,migration and invasion of colorectal cancer cells[J]. Mol Med Rep,2018,17(5):6253-6260.
[21]	Huang P,Zhang Y,Wang F,et al. MiRNA-205-5p regulates the ERBB4/AKT signaling pathway to inhibit the proliferation and migration of HAVSMCs induced by ox-LDL[J]. Pathol Res Pract,2022,233(5):153858. doi: 10.1016/j.prp.2022.153858
[22]	Oltra M,Vidal-Gil L,Maisto R,et al. Oxidative stress-induced angiogenesis is mediated by miR-205-5p[J]. J Cell Mol Med,2020,24(2):1428-1436. doi: 10.1111/jcmm.14822
[23]	Sun J,Wu K,Chen S,et al. UHRF2 promotes Hepatocellular Carcinoma Progression by Upregulating ErbB3/Ras/Raf Signaling Pathway[J]. Int J Med Sci,2021,18(14):3097-3105. doi: 10.7150/ijms.60030
[24]	Wu J,Liu C,Yu G. Downregulation of circ_PLXND1 inhibits tumorigenesis of non-small cell lung carcinoma via miR-1287-5p/ERBB3 axis[J]. Thorac Cancer,2023,14(17):1543-1555. doi: 10.1111/1759-7714.14897
[25]	Yen L,Benlimame N,Nie Z R,et al. Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers[J]. Mol Biol Cell,2002,13(11):4029-4044. doi: 10.1091/mbc.e02-02-0084
[26]	Tu Y,Liu L,Zhao D,et al. Corrigendum: Overexpression of miRNA-497 inhibits tumor angiogenesis by targeting VEGFR2[J]. Sci Rep,2016,6(1):21221. doi: 10.1038/srep21221
[27]	Li J,Cao X,Chu T,et al. The circHMGCS1-miR-205-5p-ErBB3 axis mediated the Sanggenon C-induced anti-proliferation effects on human prostate cancer[J]. Pharmacol Res,2023,187(1):106584. doi: 10.1016/j.phrs.2022.106584
[28]	De Bacco F,Orzan F,Erriquez J,et al. ERBB3 overexpression due to miR-205 inactivation confers sensitivity to FGF,metabolic activation,and liability to ERBB3 targeting in glioblastoma[J]. Cell Rep,2021,36(4):109455. doi: 10.1016/j.celrep.2021.109455
[29]	Wang X,Liang Z,Xu X,et al. miR-148a-3p represses proliferation and EMT by establishing regulatory circuits between ERBB3/AKT2/c-myc and DNMT1 in bladder cancer[J]. Cell Death Dis,2016,7(12):e2503. doi: 10.1038/cddis.2016.373
[30]	李娟,师若迪,陈雨婷,等. 枸杞多糖通过miRNA-21-5p靶向PTEN调控PI3K/Akt/mTOR通路抗人视网膜色素上皮细胞光损伤机制[J]. 中华中医药杂志,2023,38(8):3588-3593.

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