Dichotomous role of miR193b-3p in diabetic foot ulcers maintains inhibition of healing and suppression of tumor formation.
Dichotomous role of miR193b-3p in diabetic foot ulcers maintains inhibition of healing and suppression of tumor formation.
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DOI：
10.1126/scitranslmed.abg8397
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发表时间：
2022-05-11
影响因子：
17.1
通讯作者：
Tomic-Canic, Marjana
中科院分区：
文献类型：
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作者：
Marjanovic, Jelena;Ramirez, Horacio A.;Jozic, Ivan;Stone, Rivka C.;Wikramanayake, Tongyu C.;Head, Cheyanne R.;Abujamra, Beatriz Abdo;Ojeh, Nkemcho;Kirsner, Robert S.;Lev-Tov, Hadar;Pastar, Irena;Tomic-Canic, Marjana
尽管存在以β-连环蛋白激活和c-myc过表达为标志的过度增殖环境，但慢性糖尿病足溃疡（DFU）周围的表皮在临床上是肥大的和非迁移性的，但不发生恶性转化。我们鉴定了miR 193 b-3 p作为促成这种独特细胞表型的主调节因子。我们确定肿瘤抑制因子miR 193 b-3 p的诱导是DFU的独特特征，在静脉性腿部溃疡、急性伤口或皮肤鳞状细胞癌（SCC）中未发现。DFU的基因组分析鉴定了协调细胞运动性的miR 193 b-3 p靶基因网络的抑制。通过miR 193 b-3 p在人器官型和鼠体内伤口模型中的过表达进一步证实了对迁移和伤口闭合的抑制，而miR 193 b-3 p敲低加速了人离体和糖尿病鼠体内伤口的伤口再上皮化。miR 193 b-3 p对角质形成细胞迁移的显性负效应在前迁移miR 31 - 5 p和miR 15 b-5 p的存在下得以维持，它们也在DFU中过表达。miR 193 b-3 p通过破坏应激纤维形成和降低GTdR RhoA的活性介导抗迁移活性。相反，发现通常参与恶性转化的miR 193 b-3 p靶点在DFU和SCC之间受到差异调节，包括原癌基因KRAS（Kirsten大鼠肉瘤病毒原癌基因）和KIT（KIT原癌基因）。尽管miR 193 b-3 p作为肿瘤抑制因子有助于DFU中的低肿瘤发生率，但它也作为DFU中细胞迁移和上皮形成的主要抑制剂。因此，miR 193 b-3 p可以代表伤口愈合诱导、癌症治疗和诊断的靶标。
Despite the hyperproliferative environment marked by activation of β-catenin and overexpression of c-myc, the epidermis surrounding chronic diabetic foot ulcers (DFUs) is clinically hypertrophic and nonmigratory yet does not undergo malignant transformation. We identified miR193b-3p as a master regulator that contributes to this unique cellular phenotype. We determined that induction of tumor suppressor miR193b-3p is a unique feature of DFUs that is not found in venous leg ulcers, acute wounds, or cutaneous squamous cell carcinoma (SCC). Genomic analyses of DFUs identified suppression of the miR193b-3p target gene network that orchestrates cell motility. Inhibition of migration and wound closure was further confirmed by overexpression of miR193b-3p in human organotypic and murine in vivo wound models, whereas miR193b-3p knockdown accelerated wound reepithelialization in human ex vivo and diabetic murine wounds in vivo. The dominant negative effect of miR193b-3p on keratinocyte migration was maintained in the presence of promigratory miR31–5p and miR15b-5p, which were also overexpressed in DFUs. miR193b-3p mediated antimigratory activity by disrupting stress fiber formation and by decreasing activity of GTPase RhoA. Conversely, miR193b-3p targets that typically participate in malignant transformation were found to be differentially regulated between DFUs and SCC, including the proto-oncogenes KRAS (Kirsten rat sarcoma viral proto-oncogene) and KIT (KIT proto-oncogene). Although miR193b-3p acts as a tumor suppressor contributing to low tumor incidence in DFUs, it also acts as a master inhibitor of cellular migration and epithelialization in DFUs. Thus, miR193b-3p may represent a target for wound healing induction, cancer therapeutics, and diagnostics.
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MicroRNA-193B的放松管制会通过髓样细胞白血病-1影响肝癌的增殖。
影响因子：
2.9
作者：
Yin W;Nie Y;Chen L;Wang Q;Liu S;He X;Wang W
通讯作者：
Wang W
影响因子：
4
作者：
Choi, Kyung Hee;Shin, Chang Hoon;Kim, Hyeon Ho
通讯作者：
Kim, Hyeon Ho
影响因子：
--
作者：
Carlson, Mark W;Alt-Holland, Addy;Egles, Christophe;Garlick, Jonathan A
通讯作者：
Garlick, Jonathan A
影响因子：
17.1
作者：
Eming SA;Martin P;Tomic-Canic M
通讯作者：
Tomic-Canic M
DOI：
10.1126/stke.2002.119.pe6
发表时间：
2002-02-12
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
--
作者：
Alenghat, Francis J;Ingber, Donald E
通讯作者：
Ingber, Donald E