Abstract
Cancer-associated fibroblasts (CAFs), a major component of cancer stroma, play an important role in cancer progression but little is known about how CAFs affect tumorigenesis and development. MicroRNAs (miRNAs) are small non-coding RNAs that can negatively regulate target mRNA expression at post-transcriptional levels. In head and neck cancer (HNC), our analysis of miRNA arrays showed that miR-7, miR-196 and miR-335 were significantly up-regulated in CAFs when compared with their paired normal fibroblasts (NFs). FAP, α-SMA and FSP, specific markers of CAFs, were significantly expressed in CAFs. Functionally, exogenous expression of miR-7 in NFs induced a functional conversion of NFs into CAFs. In contrast, inhibition of miR-7 expression in CAFs could induce a functional conversion of CAFs into NFs. Our study demonstrated that overexpression of miR-7 in NFs significantly increased the migration activity and growth rates of cancer cells in co-culture experiments. Mechanistically, we confirmed that the RASSF2-PAR-4 axis was mainly responsible for miR-7 functions in CAFs using bioinformatics methods. Overexpression of miR-7 in CAFs led to down-regulation of RASSF2, which dramatically decreased the secretion of PAR-4 from CAFs and then enhanced the proliferation and migration of the co-cultured cancer cells. Thus, these results reveal that the inactivation of the RASSF2-PAR-4 axis controlled by miR-7 may be a novel strategy for gene therapy in HNCs.
Highlights
Head and neck cancer (HNC), mainly consisting of squamous cell carcinoma, occurs in middle-aged to elderly adults and has a poor prognosis
The results showed that the α-smooth muscle actin (α-SMA) was seldom expressed in the paired adjacent normal tissues but was highly expressed in the Cancer-associated fibroblasts (CAFs), which surrounded the squamous cell carcinoma cell nests
normal fibroblasts (NFs) were tested by western blotting (Figure 1B), and the results revealed that CAFs expressed significantly high levels of α-SMA
Summary
Head and neck cancer (HNC), mainly consisting of squamous cell carcinoma, occurs in middle-aged to elderly adults and has a poor prognosis. The cancer microenvironment is composed of many cells, such as stromal cells, fibroblasts and endotheliocytes These cells promote the proliferation, invasion, migration and metastasis of cancer cells. In this microenvironment, cancer cells can establish cross-talk with stromal cells in autocrine or paracrine manners via chemokines, cytokines and inflammatory factors to change the signaling pathways and biological functions of cancer [5]. A published study has reported that cancer cell-secreted SDF-1 could be transported to CAFs, which in turn increased the invasion, migration and proliferation of cancer cells. NFs inhibited these activities www.impactjournals.com/oncotarget of cancer cells It is still unknown how NFs transform into CAFs and whether the transformation could induce the malignant activity of cancer [6, 7]
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