IL-6/STAT3通路介导lncRNA H19上调在小鼠溃疡性结肠炎相关结直肠癌发病中的作用

doi:10.13481/j.1671-587x.20200104

吉林大学学报(医学版) ›› 2020, Vol. 46 ›› Issue (01): 20-25.doi: 10.13481/j.1671-587x.20200104

IL-6/STAT3通路介导lncRNA H19上调在小鼠溃疡性结肠炎相关结直肠癌发病中的作用

邓颖^1,2, 朱宇珍¹, 吴科锋¹, 郑学宝³, 叶华¹

1. 广东医科大学广东省天然药物研究与开发重点实验室, 广东湛江 524023;
2. 茂名市人民医院消化内科, 广东茂名 525000;
3. 广州中医药大学中医药数理工程研究院, 广东广州 510006

收稿日期:2019-04-24 出版日期:2020-01-28 发布日期:2020-02-03
通讯作者: 叶华,副研究员(Tel:0759-2388405,E-mail:yehua2008@foxmail.com) E-mail:yehua2008@foxmail.com
作者简介:邓颖(1989-),男,广东省茂名市人,医师,医学硕士,主要从事消化系统疾病及其治疗药物方面的研究。
基金资助:
国家自然科学基金资助课题（81573932）；广东省科技厅自然科学基金资助课题（2018A0303130252）；广东省教育厅特色创新类项目资助课题（2017KTSCX081）；广东省中医药局建设中医药强省科研项目资助课题（20182069）

Effect of lncRNA H19 up-regulation mediated by IL-6/ STAT3 pathway in pathogenesis of ulcerative colitis-associated colorectal cancer in mice

DENG Ying^1,2, ZHU Yuzhen¹, WU Kefeng¹, ZHENG Xuebao³, YE Hua¹

1. Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, China;
2. Department of Gastroenterology, Maoming People's Hospital, Maoming 525000, China;
3. Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

Received:2019-04-24 Online:2020-01-28 Published:2020-02-03

摘要/Abstract

摘要： 目的：检测长链非编码RNA H19（lncRNA H19，H19）和白细胞介素6/信号传导及转录激活蛋白3（IL-6/STAT3）通路在小鼠溃疡性结肠炎相关结直肠癌（CAC）组织中的表达，并探讨其可能的作用机制。方法：22只C57BL/6小鼠随机分为对照组（n=10）和模型组（n=12），模型组小鼠采用氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）联合诱导建立CAC小鼠模型。第120天处死小鼠，评估小鼠疾病活动度（DAI），计算成瘤率，测量结肠长度，HE染色观察小鼠结肠组织病理形态表现，ELISA法检测小鼠血清IL-6水平，qPCR法检测小鼠结肠组织中H19、let-7a、IL-6、STAT3和c-Myc mRNA表达水平，Western blotting法检测小鼠结肠组织中磷酸化STAT3（p-STAT3）和c-Myc蛋白表达水平。结果：与对照组比较，模型组小鼠成瘤率为100%，结肠长度明显缩短（P<0.01），DAI评分增加，HE染色显示结肠组织呈上皮内瘤变，结肠组织中H19、IL-6、STAT3和c-Myc mRNA表达水平均明显升高（P<0.01），let-7a mRNA表达水平明显降低（P<0.01），血清IL-6水平升高（P<0.01），结肠组织中p-STAT3和c-Myc蛋白表达水平明显升高（P<0.01）。结论：小鼠CAC的发病可能与IL-6/STAT3通路介导的c-Myc和H19表达上调及let-7a表达下调有关。

关键词: 长链非编码RNA H19, 白细胞介素6, 信号传导及转录激活蛋白3, let-7a, c-Myc, 溃疡性结肠炎, 结直肠癌

Abstract: Objective: To detect the expressions of lncRNA H19(H19) and IL-6/STAT3 pathway in the ulcerative colitis-associated colorectal cancer(CAC) tissue of the mice, and to explore its possible mechanism. Methods: A total of 22 C57BL/6 mice were randomly divided into control group(n=10) and model group(n=12). The CAC models were induced by azomethane(AOM) combined with dextran sodium sulfate(DSS) in the mice in model group. The mice were sacrificed on the 120th day, the disease activity index(DAI) of the mice was evaluated, the tumor formation rate was evaluated,the colon length was measured, and the pathomorphology of colon tissue of the mice was observed by HE staining. The serum IL-6 level of the mice was detected by ELISA.The expression levels of H19, let-7a, IL-6, STAT3 and c-Myc mRNA in colon tissue of the mice were detected by qPCR method.The expression levels of p-STAT3 and c-Myc proteins in colon tissue of the mice were detected by Western blotting method. Results: Compared with control group, the tumor formation rate of the mice in model group was 100%, the colon length was significantly shortened (P<0.01), the DAI score was increased (P<0.01), the colon tissue showed the intraepithelial neoplasia by HE staining,the expression levels of H19, IL-6, STAT3 and c-myc mRNA in colon tissue were significantly increased (P<0.01), the expression level of let-7a mRNA in colon tissue was significantly decreased (P<0.01), the serum IL-6 level was increased (P<0.01), and the expression levels of p-STAT3 and c-Myc proteins in colon tissue were increased (P<0.01). Conclusion: The pathogenesis of CAC in the mice may be related to the up-regulation of c-Myc and H19 and down-regulation of let-7a, which are mediated by IL-6/STAT3 pathway.

Key words: long noncoding RNAs H19, interleukin-6, signal transducer and activator of transcription-3, let-7a, c-Myc, ulcerative colitis, colorectal cancer

中图分类号:

R735.3

邓颖, 朱宇珍, 吴科锋, 郑学宝, 叶华. IL-6/STAT3通路介导lncRNA H19上调在小鼠溃疡性结肠炎相关结直肠癌发病中的作用[J]. 吉林大学学报(医学版), 2020, 46(01): 20-25.

DENG Ying, ZHU Yuzhen, WU Kefeng, ZHENG Xuebao, YE Hua. Effect of lncRNA H19 up-regulation mediated by IL-6/ STAT3 pathway in pathogenesis of ulcerative colitis-associated colorectal cancer in mice[J]. Journal of Jilin University(Medicine Edition), 2020, 46(01): 20-25.

参考文献

[1] HATA K, ANZAI H, IKEUCHI H, et al. Surveillance colonoscopy for ulcerative colitis-associated colorectal cancer offers better overall survival in real-world surgically resected cases[J]. Am J Gastroenterol, 2019, 114(3):483-489.
[2] LUO C X, ZHANG H. The role of proinflammatory pathways in the pathogenesis of colitis-associated colorectal cancer[J]. Mediators Inflamm, 2017, 2017:5126048.
[3] SUN W, SHI Y, WANG Z F, et al. Interaction of long-chain non-coding RNAs and important signaling pathways on human cancers (Review)[J]. Int J Oncol, 2018, 53(6):2343-2355.
[4] DHANOA J K, SETHI R S, VERMA R, et al. Long non-coding RNA:its evolutionary relics and biological implications in mammals:a review[J]. J Anim Sci Technol, 2018, 60:25.
[5] ROBERTS T C, MORRIS K V, WEINBERG M S. Perspectives on the mechanism of transcriptional regulation by long non-coding RNAs[J]. Epigenetics, 2014, 9(1):13-20.
[6] GABORY A, JAMMES H, DANDOLO L. The H19 locus:role of an imprinted non-coding RNA in growth and development[J]. Bioessays, 2010, 32(6):473-480.
[7] CHEN S W, ZHU J, MA J, et al. Overexpression of long non-coding RNA H19 is associated with unfavorable prognosis in patients with colorectal cancer and increased proliferation and migration in colon cancer cells[J]. Oncol Lett, 2017,14(2):2446-2452.
[8] LV J, YU Y Q, LI S Q, et al. Aflatoxin B1 promotes cell growth and invasion in hepatocellular carcinoma HepG2 cells through H19 and E2F1[J]. Asian Pac J Cancer Prev, 2014, 15(6):2565-2570.
[9] ZHANG E B, HAN L, YIN D D, et al. c-Myc-induced, long, noncoding H19 affects cell proliferation and predicts a poor prognosis in patients with gastric cancer[J]. Med Oncol, 2014,31(5):914.
[10] MA C, NONG K, ZHU H, et al. H19 promotes pancreatic cancer metastasis by derepressing let-7's suppression on its target HMGA2-mediated EMT[J]. Tumour Biol, 2014, 35(9):9163-9169.
[11] LI C F, LI Y C, WANG Y, et al. The effect of LncRNA H19/miR-194-5p axis on the epithelial-mesenchymal transition of colorectal adenocarcinoma[J]. Cell Physiol Biochem, 2018, 50(1):196-213.
[12] SNIDER A J, BIALKOWSKA A B, GHALEB A M, et al. Murine model for colitis-associated cancer of the colon[J]. Methods Mol Biol, 2016, 1438:245-253.
[13] MONKKONEN T, DEBNATH J. Inflammatory signaling cascades and autophagy in cancer[J]. Autophagy, 2018, 14(2):190-198.
[14] HUYNH J, CHAND A, GOUGH D, et al. Therapeutically exploiting STAT3 activity in cancer-using tissue repair as a road map[J]. Nat Rev Cancer, 2019, 19(2):82-96
[15] WALDNER M J, FOERSCH S, NEURATH M F. Interleukin-6:A key regulator of colorectal cancer development[J]. Int J Biol Sci, 2012, 8(9):1248-1253.
[16] CUI J D, MO J M, LUO M, et al. C-Myc-activated long non-coding RNA H19 downregulates miR-107 and promotes cell cycle progression of non-small cell lung cancer[J]. Int J Clin Exp Pathol, 2015, 8(10):12400-12409.
[17] TSANG W P, NG E K, NG S S, et al. Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer[J]. Carcinogenesis, 2010, 31(3):350-358.
[18] AKAO Y, NAKAGAWA Y, NAOE T. Let-7 microRNA functions as a potential growth suppressor in human colon cancer cells[J]. Biol Pharm Bull, 2006, 29(5):903-906.
[19] KALLEN A N, ZHOU X B, XU J, et al. The imprinted H19 lncRNA antagonizes let-7 microRNAs[J]. Mol Cell, 2013, 52(1):101-112
[20] SAMPSON V B, RONG N H,HAN J,et al. MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells[J]. Cancer Res, 2007, 67(20):9762-9770.

IL-6/STAT3通路介导lncRNA H19上调在小鼠溃疡性结肠炎相关结直肠癌发病中的作用

Effect of lncRNA H19 up-regulation mediated by IL-6/ STAT3 pathway in pathogenesis of ulcerative colitis-associated colorectal cancer in mice

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