Effects of IGF-1 on Proliferation, Angiogenesis, Tumor Stem Cell Populations and Activation of AKT and Hedgehog Pathways in Oral Squamous Cell Carcinoma.
Effects of IGF-1 on Proliferation, Angiogenesis, Tumor Stem Cell Populations and Activation of AKT and Hedgehog Pathways in Oral Squamous Cell Carcinoma.
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DOI：
10.3390/ijms21186487
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发表时间：
2020-09-05
影响因子：
5.6
通讯作者：
Rocha CAG
中科院分区：
文献类型：
--
作者：
Ferreira Mendes JM;de Faro Valverde L;Torres Andion Vidal M;Paredes BD;Coelho P;Allahdadi KJ;Coletta RD;Souza BSF;Rocha CAG
(1)背景：PI3K-AKT通路的激活控制着肿瘤的大部分特征，Hedgehog(HH)通路与口腔鳞状细胞癌的发生发展密切相关。我们假设成纤维细胞衍生的胰岛素样生长因子-1(IGF-1)作用于口腔鳞状细胞癌(OSCC)细胞，导致HH途径的非规范激活，维持AKT活性，促进肿瘤侵袭性。(2)方法：将IGF-1高表达的原代成纤维细胞(MF1-IGF1)转化为CRISPR/Cas9介导的IGF1R沉默SCC-4细胞。SCC-4细胞与成纤维细胞共培养，或与成纤维细胞条件培养液(CM)或重组IGF-1孵育，用于功能检测和AKT和HH信号转导通路的评估。(3)基因表达分析证实，MF1-IGF1中高表达IGF-1，而SCC-4中不表达IGF-1，而IGF1R表达上调。IGF1R沉默与SCC-4细胞存活率下降有关。IHH在MF1和MF1-IGF1中均有表达，经CM-MF1刺激后，SCC-4细胞中GLI1mRNA表达水平升高。在加入MF1-IGF1-CM的SCC-4细胞中，PI3K-AKT和HH通路(GLI1、IHH和SMO)均被激活。RIGF-1促进肿瘤细胞的增殖、迁移、侵袭和肿瘤球体的形成，而CM-MF1则显著促进血管生成。(4)结论：IGF-1通过刺激SCC-4细胞的增殖、迁移、侵袭和干细胞分化而发挥促肿瘤作用。在SCC-4中，IGF-1激活了AKT和HH通路，加强了IGF-1对这些信号通路调控的影响。
(1) Background: Activation of the PI3K-AKT pathway controls most hallmarks of cancer, and the hedgehog (HH) pathway has been associated with oral squamous cell carcinoma (OSCC) development and progression. We hypothesized that fibroblast-derived insulin-like growth factor-1 (IGF-1) acts in oral squamous cell carcinoma (OSCC) cells, leading to the non-canonical activation of the HH pathway, maintaining AKT activity and promoting tumor aggressiveness. (2) Methods: Primary fibroblasts (MF1) were genetically engineered for IGF-1 overexpression (MF1-IGF1) and CRISPR/Cas9-mediated IGF1R silencing was performed in SCC-4 cells. SCC-4 cells were co-cultured with fibroblasts or incubated with fibroblast conditioned medium (CM) or rIGF-1 for functional assays and the evaluation of AKT and HH pathways. (3) Results: Gene expression analysis confirmed IGF-1 overexpression in MF1-IGF1 and the absence of IGF-1 expression in SCC-4, while elevated IGF1R expression was detected. IGF1R silencing was associated with decreased survival of SCC-4 cells. Ihh was expressed in both MF1 and MF1-IGF1, and increased levels of GLI1 mRNA were observed in SCC-4 after stimulation with CM-MF1. Activation of both PI3K-AKT and the HH pathway (GLI1, Ihh and SMO) were identified in SCC-4 cells cultured in the presence of MF1-IGF1-CM. rIGF-1 promoted tumor cell proliferation, migration, invasion and tumorsphere formation, whereas CM-MF1 significantly stimulated angiogenesis. (4) Conclusions: IGF-1 exerts pro-tumorigenic effects by stimulating SCC-4 cell proliferation, migration, invasion and stemness. AKT and HH pathways were activated by IGF-1 in SCC-4, reinforcing its influence on the regulation of these signaling pathways.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
2.2
作者：
Goncalves, Gabrielle V. M.;Silva, Daniela N.;Soares, Milena B. P.
通讯作者：
Soares, Milena B. P.
CRISPR-CAS9介导的基因失活的高度活性SGRNA的合理设计。
影响因子：
46.9
作者：
Doench, John G.;Hartenian, Ella;Graham, Daniel B.;Tothova, Zuzana;Hegde, Mudra;Smith, Ian;Sullender, Meagan;Ebert, Benjamin L.;Xavier, Ramnik J.;Root, David E.
通讯作者：
Root, David E.
影响因子：
6.5
作者：
Hilmi, Caroline;Larribere, Lionel;Bertolotto, Corine
通讯作者：
Bertolotto, Corine
IGF1-R的抑制克服了T-ALL中IGFBP7诱导的化学疗法抗性。
影响因子：
3.8
作者：
Bartram I;Erben U;Ortiz-Tanchez J;Blunert K;Schlee C;Neumann M;Heesch S;Baldus CD
通讯作者：
Baldus CD