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  3. Rescuing Dicer expression in inflamed colon tissues alleviates colitis and prevents colitis-associated tumorigenesis

Rescuing Dicer expression in inflamed colon tissues alleviates colitis and prevents colitis-associated tumorigenesis

  • Theranostics. 2020 Apr 27;10(13):5749-5762. doi: 10.7150/thno.41894.
Xiaoli Wu 1,  Xiao Chen 2 3,  Hui Liu 2 3,  Zhong-Wei He 2 3,  Zheng Wang 2 3,  Lin-Jie Wei 2 3,  Wei-Yun Wang 2 3,  Shouhui Zhong 2 3,  Qin He 4,  Zhechao Zhang 5,  Rongying Ou 5,  Jian Gao 6,  Youchun Lei 7,  Wenjun Yang 8,  Guanbin Song 9,  Yi Jin 10,  Lingli Zhou 11,  Yunsheng Xu 4,  Kai-Fu Tang 2 3
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, P.R. China.
  • 2 Digestive Cancer Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, P.R. China.
  • 3 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, P.R. China.
  • 4 Department of Dermato-Venereology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, P.R. China.
  • 5 Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, P.R. China.
  • 6 Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China.
  • 7 Department of Gastroenterology, The Sixth People's Hospital of Chongqing, Chongqing 404100, P.R. China.
  • 8 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, P.R. China.
  • 9 Department of Bioengineering, College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing 400030, P.R. China.
  • 10 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, P.R. China.
  • 11 Department of Pathology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, P.R. China.
PMID: 32483416 DOI: 10.7150/thno.41894
Abstract

Chronic inflammation is known to promote carcinogenesis; Dicer heterozygous mice are more likely to develop colitis-associated tumors. This study investigates whether Dicer is downregulated in inflamed colon tissues before malignancy occurs and whether increasing Dicer expression in inflamed colon tissues can alleviate colitis and prevent colitis-associated tumorigenesis. Methods: Gene expression in colon tissues was analyzed by immunohistochemistry, immunoblots, and real-time RT-PCR. Hydrogen peroxide or N-acetyl-L-cysteine was used to induce or alleviate oxidative stress, respectively. Mice were given azoxymethane followed by dextran sulfate sodium to induce colitis and colon tumors. Berberine, anastrozole, or pranoprofen was used to rescue Dicer expression in inflammatory colon tissues. Results: Oxidative stress repressed Dicer expression in inflamed colon tissues by inducing miR-215 expression. Decreased Dicer expression increased DNA damage and cytosolic DNA and promoted interleukin-6 expression upon hydrogen peroxide treatment. Dicer overexpression in inflamed colon tissues alleviated inflammation and repressed colitis-associated carcinogenesis. Furthermore, we found that anastrozole, berberine, and pranoprofen could promote Dicer expression and protect cells from hydrogen peroxide-induced DNA damage, thereby reducing cytosolic DNA and partially repressing interleukin-6 expression upon hydrogen peroxide treatment. Rescuing Dicer expression using anastrozole, berberine, or pranoprofen in inflamed colon tissues alleviated colitis and prevented colitis-associated tumorigenesis. Conclusions: Dicer was downregulated in inflamed colon tissues before malignancy occurred. Decreased Dicer expression further exaggerated inflammation, which may promote carcinogenesis. Anastrozole, berberine, and pranoprofen alleviated colitis and colitis-associated tumorigenesis by promoting Dicer expression. Our study provides insight into potential colitis treatment and colitis-associated colon Cancer prevention strategies.

Keywords

Dicer; anastrozole; berberine; colitis-associated carcinogenesis; pranoprofen.

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