An Essential Mesenchymal Function for miR-143/145 in Intestinal Epithelial Regeneration

被引：196

作者：

Chivukula, Raghu R. ^{[1
]}

Shi, Guanglu ^{[2
]}

Acharya, Asha ^{[2
]}

Mills, Eric W. ^{[1
]}

Zeitels, Lauren R. ^{[1
]}

Anandam, Joselin L. ^{[3
]}

Abdelnaby, Abier A. ^{[3
]}

Balch, Glen C. ^{[3
]}

Mansour, John C. ^{[3
]}

Yopp, Adam C. ^{[3
]}

Maitra, Anirban ^{[4
]}

Mendell, Joshua T. ^{[2
,5
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Med Scientist Training Program, Baltimore, MD 21205 USA

[2] UT Southwestern Med Ctr, Dept Mol Biol, Dallas, TX 75390 USA

[3] UT Southwestern Med Ctr, Dept Surg, Dallas, TX 75390 USA

[4] UT MD Anderson Canc Ctr, Sheikh Ahmed Bin Zayed Al Nahyan Ctr Pancreat Can, Houston, TX 77030 USA

[5] UT Southwestern Med Ctr, Harold C Simmons Canc Ctr, Dallas, TX 75390 USA

来源：

CELL | 2014年 / 157卷 / 05期

关键词：

SMOOTH-MUSCLE-CELLS; GENE-EXPRESSION; STEM-CELLS; IN-VIVO; MICRORNAS; CANCER; MYOFIBROBLASTS; GROWTH; COLON; CRYPT;

D O I：

10.1016/j.cell.2014.03.055

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Downregulation of the miR-143/145 microRNA (miRNA) cluster has been repeatedly reported in colon cancer and other epithelial tumors. In addition, overexpression of these miRNAs inhibits tumorigenesis, leading to broad consensus that they function as cell-autonomous epithelial tumor suppressors. We generated mice with deletion of miR-143/145 to investigate the functions of these miRNAs in intestinal physiology and disease in vivo. Although intestinal development proceeded normally in the absence of these miRNAs, epithelial regeneration after injury was dramatically impaired. Surprisingly, we found that miR-143/145 are expressed and function exclusively within the mesenchymal compartment of intestine. Defective epithelial regeneration in miR-143/145-deficient mice resulted from the dysfunction of smooth muscle and myofibroblasts and was associated with derepression of the miR-143 target Igfbp5, which impaired IGF signaling after epithelial injury. These results provide important insights into the regulation of epithelial wound healing and argue against a cell-autonomous tumor suppressor role for miR-143/145 in colon cancer.

引用

页码：1104 / 1116

页数：13

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