Abstract
Cancer-associated fibroblasts (CAFs) interact closely with cancer cells, supporting their growth and invasion. To investigate the role of microRNA-21 (miR-21) in lung adenocarcinoma, and especially in its CAF component, in situ hybridisation was applied to samples from 89 invasive lung adenocarcinoma cases. MiR-21 expression was observed in both cancer cells and CAFs. When the patients were stratified by expression, miR-21 levels in CAFs (n = 9), but not in cancer cells (n = 21), were inversely correlated with patient survival; patients with miR-21high CAFs exhibited lower survival than those with miR-21low CAFs. The underlying mechanism was investigated in vitro. Conditioned medium (CM) from A549 lung cancer cells increased miR-21 expression in MRC-5 and IMR-90 lung fibroblasts through the transforming growth factor-β pathway, and induced CAF-like morphology and migratory capacity. MiR-21 up-regulation in lung fibroblasts induced a novel CAF-secreted protein, calumenin, as well as known CAF markers (periostin, α-smooth muscle actin, and podoplanin). Moreover, CM from the lung fibroblasts increased A549 cell proliferation in a calumenin-dependent manner. Thus, miR-21 expression in lung fibroblasts may trigger fibroblast trans-differentiation into CAFs, supporting cancer progression. Therefore, CAF miR-21 represents a pivotal prognostic marker for this scar-forming cancer of the lungs.
Highlights
Cancer-stromal interactions play critical roles in cancer cell growth, invasion, metastasis, angiogenesis, and chemoresistance[1,2,3]
Stromal fibroblasts that displayed high miR-21 expression overlapped with myofibroblasts positive for α-smooth muscle actin (α-SMA; Fig. 1g,h)
The induction of fibroblast miR-21 expression by Conditioned medium (CM) from A549 cells was abrogated by treatment with the TGF-β1 receptor inhibitor A83-01. These results suggested that the induction of lung fibroblast miR-21 expression by A549 lung cancer cell CM is modulated through the TGF-β1 pathway
Summary
Cancer-stromal interactions play critical roles in cancer cell growth, invasion, metastasis, angiogenesis, and chemoresistance[1,2,3]. CAFs represent an attractive target for the development of novel drugs, studies have mainly focused on cancer cell-derived miRNAs, while the roles of stromal-derived miRNAs remain to be elucidated. In a colorectal cancer study, miR-21 expression was increased in stromal cells as compared to normal tissues, and the ectopic expression of miR-21 drove the trans-differentiation of fibroblasts into myofibroblasts and increased invasion in vitro[13]. Our data suggest that miR-21 expression in lung fibroblasts induces CAF phenotypes and plays an important role in the progression of lung adenocarcinoma. It is a potential novel molecular marker for lung adenocarcinoma prognosis
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