Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Antioxid Redox Signal. 2013 Sep 1;19(7):644-60. doi: 10.1089/ars.2013.5184. Epub 2013 Jun 27.
Heme oxygenase-1 (HO-1, HMOX1) can prevent tumor initiation; while in various tumors, it has been demonstrated to promote growth, angiogenesis, and metastasis. Here, we investigated whether HMOX1 can modulate microRNAs (miRNAs) and regulate human non-small cell lung carcinoma (NSCLC) development.
Stable HMOX1 overexpression in NSCLC NCI-H292 cells up-regulated tumor-suppressive miRNAs, whereas it significantly diminished the expression of oncomirs and angiomirs. The most potently down-regulated was miR-378. HMOX1 also up-regulated p53, down-regulated angiopoietin-1 (Ang-1) and mucin-5AC (MUC5AC), reduced proliferation, migration, and diminished angiogenic potential. Carbon monoxide was a mediator of HMOX1 effects on proliferation, migration, and miR-378 expression. In contrast, stable miR-378 overexpression decreased HMOX1 and p53; while enhanced expression of MUC5AC, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and Ang-1, and consequently increased proliferation, migration, and stimulation of endothelial cells. Adenoviral delivery of HMOX1 reversed miR-378 effect on the proliferation and migration of cancer cells. In vivo, HMOX1 overexpressing tumors were smaller, less vascularized and oxygenated, and less metastatic. Overexpression of miR-378 exerted opposite effects. Accordingly, in patients with NSCLC, HMOX1 expression was lower in metastases to lymph nodes than in primary tumors.
In vitro and in vivo data indicate that the interplay between HMOX1 and miR-378 significantly modulates NSCLC progression and angiogenesis, suggesting miR-378 as a new therapeutic target. REBOUND TRACK: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16, 293-296, 2012) with the following serving as open reviewers: James F. George, Mahin D. Maines, Justin C. Mason, and Yasufumi Sato.
血红素加氧酶-1（HO-1，HMOX1）可以预防肿瘤的发生；而在各种肿瘤中，它已被证明可以促进生长、血管生成和转移。在这里，我们研究了 HMOX1 是否可以调节 microRNAs（miRNAs）并调节人类非小细胞肺癌（NSCLC）的发展。
在 NSCLC NCI-H292 细胞中稳定过表达 HMOX1 可上调肿瘤抑制性 miRNAs，而显著降低癌基因和血管生成 miRNA 的表达。下调最显著的是 miR-378。HMOX1 还上调了 p53，下调了血管生成素-1（Ang-1）和粘蛋白-5AC（MUC5AC），降低了增殖、迁移，并降低了血管生成潜能。一氧化碳是 HMOX1 对增殖、迁移和 miR-378 表达影响的介导物。相反，稳定的 miR-378 过表达降低了 HMOX1 和 p53；同时增强了 MUC5AC、血管内皮生长因子（VEGF）、白细胞介素-8（IL-8）和 Ang-1 的表达，从而增加了增殖、迁移和内皮细胞的刺激。腺病毒递送 HMOX1 逆转了 miR-378 对癌细胞增殖和迁移的影响。在体内，过表达 HMOX1 的肿瘤更小、血管化和氧合程度更低、转移程度更低。过表达 miR-378 则产生相反的效果。因此，在 NSCLC 患者中，淋巴结转移的 HMOX1 表达低于原发性肿瘤。
体外和体内数据表明，HMOX1 和 miR-378 之间的相互作用显著调节 NSCLC 的进展和血管生成，提示 miR-378 作为一种新的治疗靶点。
这项工作在标准同行评审中被拒绝，然后由反弹同行评审（抗氧化还原信号 16，293-296，2012）挽救，以下是开放评审员：James F. George、Mahin D. Maines、Justin C. Mason 和 Yasufumi Sato。
