Interplay Between Heme Oxygenase-1 and miR-378 Affects Non-Small Cell Lung Carcinoma Growth, Vascularization, and Metastasis

Abstract

Aims: 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. Results: 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. Innovation and Conclusion: 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:

Identification of angiogenesis-related miRNAs in a population of patients with renal clear cell carcinoma

“…One study reported increased levels of miR-378 in the serum of patients with ccRCC (20) and another study reported overexpression of miR-378 in human non-small cell lung carcinoma and an association of expression with enhanced tumor proliferation and migration (26). However, in the present study, miR-378 levels were lower in tumor samples than in normal tissues.…”

“…Our results are also consistent with the report of Redova et al (25) who found that more miRNAs were downregulated in ccRCC tissues than in normal tissues (73 of 78 miRNAs). Notably, several studies of non-small cell lung cancer (NSCLC) have also indicated an important role for miR-378 in tumor progression and angiogenesis (26,27). This miRNA appears to target the tumor suppressors Sufu and Fus-1 (28).…”

Over-Expressions of Serum miR-182-5p, miR-363-3p, and miR-378a-3p serve as Biomarkers in Hepatocellular Carcinoma

“…The binding interaction causes translational inhibition and/or mRNA degradation [7]. Moreover, dysregulation of miRNAs expression may contribute to tumorigenesis by inhibiting the expression of tumor suppressor genes or promoting the expression of proto-oncogenes [8]. Several studies have demonstrated that miRNAs have high stability in human serum or plasma due to protection from RNases [9][10][11], suggesting their potential use as diagnostic biomarkers.…”

MicroRNA miR-24-3p Promotes Porcine Reproductive and Respiratory Syndrome Virus Replication through Suppression of Heme Oxygenase-1 Expression

“…For example, miR-377 and miR-217 can decrease HO-1 expression in endothelial cells by a direct interaction with the 3= untranslated region (UTR) of HO-1 mRNA (29), whereas miR-378 decreases HO-1 expression in lung cancer cells (30). We hypothesized that there may also be miRNAs targeting HO-1 in PRRSV-permissive cells, which may subsequently affect the regulation of PRRSV replication.…”